Development of neurologic diseases in a patient with primate T lymphotropic virus type 1 (PTLV-1).

PubMed

Enose-Akahata, Yoshimi; Caruso, Breanna; Haner, Benjamin; Charlip, Emily; Nair, Govind; Massoud, Raya; Billioux, Bridgette J; Ohayon, Joan; Switzer, William M; Jacobson, Steven

2016-08-12

Virus transmission from various wild and domestic animals contributes to an increased risk of emerging infectious diseases in human populations. HTLV-1 is a human retrovirus associated with acute T-cell leukemia and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HTLV-1 originated from ancient zoonotic transmission from nonhuman primates, although cases of zoonotic infections continue to occur. Similar to HTLV-1, the simian counterpart, STLV-1, causes chronic infection and leukemia and lymphoma in naturally infected monkeys, and combined are called primate T-lymphotropic viruses (PTLV-1). However, other clinical syndromes typically seen in humans such as a chronic progressive myelopathy have not been observed in nonhuman primates. Little is known about the development of neurologic and inflammatory diseases in human populations infected with STLV-1-like viruses following nonhuman primate exposure. We performed detailed laboratory analyses on an HTLV-1 seropositive patient with typical HAM/TSP who was born in Liberia and now resides in the United States. Using a novel droplet digital PCR for the detection of the HTLV-1 tax gene, the proviral load in PBMC and cerebrospinal fluid cells was 12.98 and 51.68 %, respectively; however, we observed a distinct difference in fluorescence amplitude of the positive droplet population suggesting possible mutations in proviral DNA. A complete PTLV-1 proviral genome was amplified from the patient's PBMC DNA using an overlapping PCR strategy. Phylogenetic analysis of the envelope and LTR sequences showed the virus was highly related to PTLV-1 from sooty mangabey monkeys (smm) and humans exposed via nonhuman primates in West Africa. These results demonstrate the patient is infected with a simian variant of PTLV-1, suggesting for the first time that PTLV-1smm infection in humans may be associated with a chronic progressive neurologic disease.

Fecal parasite risk in the endangered proboscis monkey is higher in an anthropogenically managed forest environment compared to a riparian rain forest in Sabah, Borneo

PubMed Central

Klaus, Annette; Strube, Christina; Röper, Kathrin Monika; Radespiel, Ute; Schaarschmidt, Frank; Nathan, Senthilvel; Goossens, Benoit

2018-01-01

Understanding determinants shaping infection risk of endangered wildlife is a major topic in conservation medicine. The proboscis monkey, Nasalis larvatus, an endemic primate flagship species for conservation in Borneo, is endangered through habitat loss, but can still be found in riparian lowland and mangrove forests, and in some protected areas. To assess socioecological and anthropogenic influence on intestinal helminth infections in N. larvatus, 724 fecal samples of harem and bachelor groups, varying in size and the number of juveniles, were collected between June and October 2012 from two study sites in Malaysian Borneo: 634 samples were obtained from groups inhabiting the Lower Kinabatangan Wildlife Sanctuary (LKWS), 90 samples were collected from groups of the Labuk Bay Proboscis Monkey Sanctuary (LBPMS), where monkeys are fed on stationary feeding platforms. Parasite risk was quantified by intestinal helminth prevalence, host parasite species richness (PSR), and eggs per gram feces (epg). Generalized linear mixed effect models were applied to explore whether study site, group type, group size, the number of juveniles per group, and sampling month predict parasite risk. At the LBPMS, prevalence and epg of Trichuris spp., strongylids, and Strongyloides spp. but not Ascaris spp., as well as host PSR were significantly elevated. Only for Strongyloides spp., prevalence showed significant changes between months; at both sites, the beginning rainy season with increased precipitation was linked to higher prevalence, suggesting the external life cycle of Strongyloides spp. to benefit from humidity. Higher prevalence, epgs, and PSR within the LBPMS suggest that anthropogenic factors shape host infection risk more than socioecological factors, most likely via higher re-infection rates and chronic stress. Noninvasive measurement of fecal parasite stages is an important tool for assessing transmission dynamics and infection risks for endangered tropical wildlife. Findings will contribute to healthcare management in nature and in anthropogenically managed environments. PMID:29630671

Fecal parasite risk in the endangered proboscis monkey is higher in an anthropogenically managed forest environment compared to a riparian rain forest in Sabah, Borneo.

PubMed

Klaus, Annette; Strube, Christina; Röper, Kathrin Monika; Radespiel, Ute; Schaarschmidt, Frank; Nathan, Senthilvel; Goossens, Benoit; Zimmermann, Elke

2018-01-01

Understanding determinants shaping infection risk of endangered wildlife is a major topic in conservation medicine. The proboscis monkey, Nasalis larvatus, an endemic primate flagship species for conservation in Borneo, is endangered through habitat loss, but can still be found in riparian lowland and mangrove forests, and in some protected areas. To assess socioecological and anthropogenic influence on intestinal helminth infections in N. larvatus, 724 fecal samples of harem and bachelor groups, varying in size and the number of juveniles, were collected between June and October 2012 from two study sites in Malaysian Borneo: 634 samples were obtained from groups inhabiting the Lower Kinabatangan Wildlife Sanctuary (LKWS), 90 samples were collected from groups of the Labuk Bay Proboscis Monkey Sanctuary (LBPMS), where monkeys are fed on stationary feeding platforms. Parasite risk was quantified by intestinal helminth prevalence, host parasite species richness (PSR), and eggs per gram feces (epg). Generalized linear mixed effect models were applied to explore whether study site, group type, group size, the number of juveniles per group, and sampling month predict parasite risk. At the LBPMS, prevalence and epg of Trichuris spp., strongylids, and Strongyloides spp. but not Ascaris spp., as well as host PSR were significantly elevated. Only for Strongyloides spp., prevalence showed significant changes between months; at both sites, the beginning rainy season with increased precipitation was linked to higher prevalence, suggesting the external life cycle of Strongyloides spp. to benefit from humidity. Higher prevalence, epgs, and PSR within the LBPMS suggest that anthropogenic factors shape host infection risk more than socioecological factors, most likely via higher re-infection rates and chronic stress. Noninvasive measurement of fecal parasite stages is an important tool for assessing transmission dynamics and infection risks for endangered tropical wildlife. Findings will contribute to healthcare management in nature and in anthropogenically managed environments.

Blood schizontocidal activity of WR 238605 (Tafenoquine) against Plasmodium cynomolgi and Plasmodium fragile infections in rhesus monkeys.

PubMed

Puri, S K; Dutta, G P

2003-04-01

A new 8-aminoquinoline antimalarial WR 238605 (Tafenoquine), developed initially as a primaquine alternative for prevention of Plasmodium vivax relapses was evaluated for blood schizontocidal activity against two simian malaria infections namely Plasmodium cynomolgi B and Plasmodium fragile in rhesus monkeys. Treatment with WR 238605 at a dose of 3.16 mg(base)/kg/day x 7 days cured established trophozoite induced infections in monkeys with both these parasites. The lower dose of 1.00 mg/kg/day cured 9 out of 12 monkeys infected with P. cynomolgi B and 10 out of 11 monkeys infected with P. fragile. Primaquine was only partially curative at 10.0 mg(base)/kg/day x 7 dose regimen against both these infections. The potent blood schizontocidal activity of tafenoquine adds to the armoury of antimalarial drugs.

Population density-dependent hair cortisol concentrations in rhesus monkeys (Macaca mulatta)

PubMed Central

Dettmer, A.M.; Novak, M.A.; Meyer, J.S.; Suomi, S.J.

2014-01-01

Summary Population density is known to influence acute measures of hypothalamic-pituitary-adrenal (HPA) axis activity in a variety of species, including fish, deer, birds, and humans. However, the effects of population density on levels of chronic stress are unknown. Given the fact that exposure to chronically elevated levels of circulating glucocorticoids results in a host of health disparities in animals and humans alike, it is important to understand how population density may impact chronic stress. We assessed hair cortisol concentrations (HCCs), which are reliable indicators of chronic HPA axis activity, in rhesus monkeys (Macaca mulatta) to determine the influence of population density on these values. In Experiment 1, we compared HCCs of monkeys living in high-density (HD; 1 monkey/0.87m2) and low-density (LD; 1 monkey/63.37m2) environments (N=236 hair samples) and found that HD monkeys exhibited higher hair cortisol across all age categories (infant, juvenile, young adult, adult, and aged) except infancy and aged (F(5)=4.240, p=0.001), for which differences were nearly significant. HD monkeys also received more severe fight wounds than LD monkeys (χ2=26.053, p<0.001), though no effects of dominance status emerged. In Experiment 2, we examined how HCCs change with fluctuating population levels across five years in the adult LD monkeys (N=155 hair samples) and found that increased population density was significantly positively correlated with HCCs in this semi-naturalistic population (r(s)=0.975, p=0.005). These are the first findings to demonstrate that increased population density is associated with increased chronic, endogenous glucocorticoid exposure in a nonhuman primate species. We discuss the implications of these findings with respect to laboratory research, population ecology, and human epidemiology. PMID:24636502

Population density-dependent hair cortisol concentrations in rhesus monkeys (Macaca mulatta).

PubMed

Dettmer, A M; Novak, M A; Meyer, J S; Suomi, S J

2014-04-01

Population density is known to influence acute measures of hypothalamic-pituitary-adrenal (HPA) axis activity in a variety of species, including fish, deer, birds, and humans. However, the effects of population density on levels of chronic stress are unknown. Given the fact that exposure to chronically elevated levels of circulating glucocorticoids results in a host of health disparities in animals and humans alike, it is important to understand how population density may impact chronic stress. We assessed hair cortisol concentrations (HCCs), which are reliable indicators of chronic HPA axis activity, in rhesus monkeys (Macaca mulatta) to determine the influence of population density on these values. In Experiment 1, we compared HCCs of monkeys living in high-density (HD; 1 monkey/0.87m(2)) and low-density (LD; 1 monkey/63.37m(2)) environments (N=236 hair samples) and found that HD monkeys exhibited higher hair cortisol across all age categories (infant, juvenile, young adult, adult, and aged) except infancy and aged (F(5)=4.240, p=0.001), for which differences were nearly significant. HD monkeys also received more severe fight wounds than LD monkeys (χ(2)=26.053, p<0.001), though no effects of dominance status emerged. In Experiment 2, we examined how HCCs change with fluctuating population levels across 5 years in the adult LD monkeys (N=155 hair samples) and found that increased population density was significantly positively correlated with HCCs in this semi-naturalistic population (r(s)=0.975, p=0.005). These are the first findings to demonstrate that increased population density is associated with increased chronic, endogenous glucocorticoid exposure in a nonhuman primate species. We discuss the implications of these findings with respect to laboratory research, population ecology, and human epidemiology. Published by Elsevier Ltd.

Immune and Genetic Correlates of Vaccine Protection Against Mucosal Infection by SIV in Monkeys

PubMed Central

Letvin, Norman L.; Rao, Srinivas S.; Montefiori, David C.; Seaman, Michael S.; Sun, Yue; Lim, So-Yon; Yeh, Wendy W.; Asmal, Mohammed; Gelman, Rebecca S.; Shen, Ling; Whitney, James B.; Seoighe, Cathal; Lacerda, Miguel; Keating, Sheila; Norris, Philip J.; Hudgens, Michael G.; Gilbert, Peter B.; Buzby, Adam P.; Mach, Linh V.; Zhang, Jinrong; Balachandran, Harikrishnan; Shaw, George M.; Schmidt, Stephen D.; Todd, John-Paul; Dodson, Alan; Mascola, John R.; Nabel, Gary J.

2013-01-01

The RV144 vaccine trial in Thailand demonstrated that an HIV vaccine could prevent infection in humans and highlights the importance of understanding protective immunity against HIV. We used a nonhuman primate model to define immune and genetic mechanisms of protection against mucosal infection by the simian immunodeficiency virus (SIV). A plasmid DNA prime/recombinant adenovirus serotype 5 (rAd5) boost vaccine regimen was evaluated for its ability to protect monkeys from infection by SIVmac251 or SIVsmE660 isolates after repeat intrarectal challenges. Although this prime-boost vaccine regimen failed to protect against SIVmac251 infection, 50% of vaccinated monkeys were protected from infection with SIVsmE660. Among SIVsmE660-infected animals, there was an about one-log reduction in peak plasma virus RNA in monkeys expressing the major histocompatibility complex class I allele Mamu-A*01, implicating cytotoxic T lymphocytes in the control of SIV replication once infection is established. Among Mamu-A*01–negative monkeys challenged with SIVsmE660, no CD8+ T cell response or innate immune response was associated with protection against virus acquisition. However, low levels of neutralizing antibodies and an envelope-specific CD4+ T cell response were associated with vaccine protection in these monkeys. Moreover, monkeys that expressed two TRIM5 alleles that restrict SIV replication were more likely to be protected from infection than monkeys that expressed at least one permissive TRIM5 allele. This study begins to elucidate the mechanism of vaccine protection against immunodeficiency viruses and highlights the need to analyze these immune and genetic correlates of protection in future trials of HIV vaccine strategies. PMID:21543722

Immune and Genetic Correlates of Vaccine Protection Against Mucosal Infection by SIV in Monkeys.

PubMed

Letvin, Norman L; Rao, Srinivas S; Montefiori, David C; Seaman, Michael S; Sun, Yue; Lim, So-Yon; Yeh, Wendy W; Asmal, Mohammed; Gelman, Rebecca S; Shen, Ling; Whitney, James B; Seoighe, Cathal; Lacerda, Miguel; Keating, Sheila; Norris, Philip J; Hudgens, Michael G; Gilbert, Peter B; Buzby, Adam P; Mach, Linh V; Zhang, Jinrong; Balachandran, Harikrishnan; Shaw, George M; Schmidt, Stephen D; Todd, John-Paul; Dodson, Alan; Mascola, John R; Nabel, Gary J

2011-05-04

The RV144 vaccine trial in Thailand demonstrated that an HIV vaccine could prevent infection in humans and highlights the importance of understanding protective immunity against HIV. We used a nonhuman primate model to define immune and genetic mechanisms of protection against mucosal infection by the simian immunodeficiency virus (SIV). A plasmid DNA prime/recombinant adenovirus serotype 5 (rAd5) boost vaccine regimen was evaluated for its ability to protect monkeys from infection by SIVmac251 or SIVsmE660 isolates after repeat intrarectal challenges. Although this prime-boost vaccine regimen failed to protect against SIVmac251 infection, 50% of vaccinated monkeys were protected from infection with SIVsmE660. Among SIVsmE660-infected animals, there was about a one-log reduction in peak plasma virus RNA in monkeys expressing the major histocompatibility complex class I allele Mamu-A*01, implicating cytotoxic T lymphocytes in the control of SIV replication once infection is established. Among Mamu-A*01-negative monkeys challenged with SIVsmE660, no CD8(+) T cell response or innate immune response was associated with protection against virus acquisition. However, low levels of neutralizing antibodies and an envelope-specific CD4(+) T cell response were associated with vaccine protection in these monkeys. Moreover, monkeys that expressed two TRIM5 alleles that restrict SIV replication were more likely to be protected from infection than monkeys that expressed at least one permissive TRIM5 allele. This study begins to elucidate the mechanisms of vaccine protection against immunodeficiency viruses and highlights the need to analyze these immune and genetic correlates of protection in future trials of HIV vaccine strategies.

Simian varicella virus reactivation in cynomolgus monkeys

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mahalingam, Ravi; Traina-Dorge, Vicki; Wellish, Mary

2007-11-10

SVV infection of primates closely resembles VZV infection of humans. Like VZV, SVV becomes latent in ganglionic neurons. We used this model to study the effect of immunosuppression on varicella reactivation. Cynomolgus monkeys latently infected with SVV were irradiated and treated with tacrolimus and prednisone. Of four latently infected monkeys that were immunosuppressed and subjected to the stress of transportation and isolation, one developed zoster, and three others developed features of subclinical reactivation. Another non-immunosuppressed latently infected monkey that was subjected to the same stress of travel and isolation showed features of subclinical reactivation. Virus reactivation was confirmed not onlymore » by the occurrence of zoster in one monkey, but also by the presence of late SVV RNA in ganglia, and the detection of SVV DNA in non-ganglionic tissue, and SVV antigens in skin, ganglia and lung.« less

Immunovirological analyses of chronically simian immunodeficiency virus SIVmnd-1- and SIVmnd-2-infected mandrills (Mandrillus sphinx).

PubMed

Apetrei, Cristian; Sumpter, Beth; Souquiere, Sandrine; Chahroudi, Ann; Makuwa, Maria; Reed, Patricia; Ribeiro, Ruy M; Pandrea, Ivona; Roques, Pierre; Silvestri, Guido

2011-12-01

Simian immunodeficiency virus (SIV) infection in African nonhuman primate (NHP) natural hosts is usually nonpathogenic, despite high levels of virus replication. We have previously shown that chronic SIV infection in sooty mangabeys (SMs) and African green monkeys (AGMs) is associated with low levels of immune activation and bystander T cell apoptosis. To compare these features with those observed in another natural host, the mandrill (MND), we conducted a cross-sectional survey of the 23 SIV-infected and 25 uninfected MNDs from the only semifree colony of mandrills available worldwide. Viral loads (VLs) were determined and phenotypic and functional analysis of peripheral blood- and lymph node-derived lymphocytes was performed. We found that mandrills chronically infected with SIVmnd-1 or SIVmnd-2 have similar levels of viral replication, and we observed a trend toward lower CD4+ T cell counts in chronically SIVmnd-2-infected MNDs than SIVmnd-1-infected MNDs. No correlation between CD4+ T cell counts and VLs in SIV-infected MNDs could be established. Of note, the levels of T cell activation, proliferation, and apoptosis were comparable between SIVmnd-1- and SIVmnd-2-infected MNDs and to those observed in uninfected animals, with the only exception being an increase in tumor necrosis factor alpha-producing CD8+ T cells in SIVmnd-2-infected MNDs. Overall, these findings recapitulate previous observations in SIV-infected SMs and AGMs and lend further evidence to the hypothesis that low levels of immune activation protect natural SIV hosts from disease progression.

TNF neutralization results in disseminated disease during acute and latent M. tuberculosis infection with normal granuloma structure

PubMed Central

Lin, Philana Ling; Myers, Amy; Smith, Le’Kneitah; Bigbee, Carolyn; Bigbee, Matthew; Fuhrman, Carl; Grieser, Heather; Chiosea, Ion; Voitenek, Nikolai N.; Capuano, Saverio V.; Klein, Edwin; Flynn, JoAnne L.

2010-01-01

An increased risk of tuberculosis has been documented in humans treated with tumor necrosis factor alpha (TNF) neutralizing agents. In murine models, impaired signaling by TNF caused exacerbation of both acute and chronic infection associated with aberrant granuloma formation and maintenance. The non-human primate model of tuberculosis provides an opportunity to study immune modulation in the setting of TNF neutralization during primary and latent tuberculosis. Administration of TNF neutralizing agents prior to M. tuberculosis infection resulted in fulminant and disseminated disease by 8 weeks post-infection. Neutralization of TNF in latently infected cynomolgus macaques caused reactivation in a majority of animals as determined by gross pathology and bacterial burden. A spectrum of dissemination was noted including extrapulmonary disease. Surprisingly, monkeys who developed primary and reactivation tuberculosis after TNF neutralization had similar granuloma structure and composition compared to active control monkeys. TNF neutralization was associated with increased IL-12, decreased CCL4, increased chemokine receptor expression and reduced mycobacteria-specific IFN-γ production in blood but not to the affected mediastinal lymph nodes. Finally, the first signs of reactivation often occurred in thoracic lymph nodes. These findings have important clinical implications for determining the mechanism of TNF-neutralization-related tuberculosis. PMID:20112395

Simian immunodeficiency virus infections in vervet monkeys (Clorocebus aethiops) at an Australian zoo.

PubMed

Joy, A; Vogelnest, L; Middleton, D J; Dale, C J; Campagna, D; Purcell, D F; Kent, S J

2001-06-01

A number of monkey species, including African green monkeys and African vervet monkeys (Chlorocebus aethiops), are frequently infected in the wild and in captivity with a Simian immunodeficiency virus strain, SIVagm, a primate lentivirus. Up to 50% of African green monkeys are estimated to be infected with SIVagm. SIV strains are very closely related to HIV-2 strains, which are a cause of AIDS in humans, predominantly in western Africa, although cases in Australia have also been reported. It is generally thought that SIV is non-pathogenic in several natural hosts, including African green monkeys. Nevertheless many SIV strains induce a profound immunodeficiency virtually identical to HIV-1 induced AIDS in humans when administered to Asian macaque species such as rhesus (Macaca mulatta) or pigtailed macaques (M nemestrina). SIV infection of Asian macaque species is frequently employed as an animal model for AIDS vaccine studies. In November 1996 a group of 10 African vervet monkeys were imported from the USA for display at Victoria's Open Range Zoo in Werribee. Two animals in this group of monkeys later developed a fatal gastroenteric illness. These diagnoses led us to initiate SIV testing of the colony.

Occurrence of hemotropic mycoplasmas in non-human primates (Alouatta caraya, Sapajus nigritus and Callithrix jacchus) of southern Brazil.

PubMed

Cubilla, Michelle P; Santos, Leonilda C; de Moraes, Wanderlei; Cubas, Zalmir S; Leutenegger, Christian M; Estrada, Marko; Vieira, Rafael F C; Soares, Maurilio J; Lindsay, LeAnn L; Sykes, Jane E; Biondo, Alexander W

2017-06-01

Hemoplasmas, the erythrocyte-associated mycoplasmas, have been detected in several primates, causing mostly subclinical infection. This study aimed to determine the prevalence of hemoplasma infection in captive and free-ranging monkeys from southern Brazil, as well as factors and hematological abnormalities associated with infection. Blood samples from 40 non-human primates (NHP) were tested for hemoplasmas and coinfections. An overall of 10/40 (25.0%) NHP tested positive for hemoplasmas using PCR-based assays, including 9/14 (64.3%) black howler monkeys (Alouatta caraya) and 1/24 (4.2%) black-horned capuchin (Sapajus nigritus). Infection was not statistically associated with anemia, but wild-born monkeys and male black howler monkeys were more likely to be positive when compared with captive-born animals and female black howler monkeys, respectively. The sequences from the black howler monkey hemoplasma were similar (94% identity) to the squirrel monkey hemoplasma ("Candidatus Mycoplasma kahanei") and were phylogenetically located in a different cluster when compared to the human hemoplasma ("Candidatus Mycoplasma haemohominis"). Copyright © 2017 Elsevier Ltd. All rights reserved.

Nonprogressive and Progressive Primate Immunodeficiency Lentivirus Infections

PubMed Central

Brenchley, Jason M.; Silvestri, Guido; Douek, Daniel C.

2010-01-01

Natural hosts for simian immunodeficiency virus (SIV)can be, and are often naturally, infected with species-specific SIVs, but do not develop acquired immunodeficiency syndrome (AIDS). These natural hosts maintain high SIV viral loads, but avoid immunodeficiency. Elucidating the mechanisms that allow natural hosts to co-exist with SIV without overt disease may provide crucial information for understanding AIDS pathogenesis. Over the past few years, several key features of natural SIV infections have been described in studies conducted predominantly in sooty mangabeys (SMs), African green monkeys (AGMs), and mandrills. Natural SIV hosts are able to avoid the chronic, generalized immune system activation that is associated with disease progression in HIV-infected individuals and are known to down-modulate the expression of the receptors for SIV. In this perspective we propose that a critical factor that differentiates nonprogressive from progressive HIV or SIV infection is the maintenance of T cell immune competence in the face of a virus that infects and kills CD4+ T cells Elucidation of the mechanisms underlying the preservation of immune function during and after the acute phase of natural SIV infection may lead to the design of novel preventive and therapeutic interventions for treatment of chronic HIV infection. PMID:20620940

Molecular characterization and epidemiological investigation of Cryptosporidium hominis IkA18G1 and C. hominis monkey genotype IiA17, two unusual subtypes diagnosed in Swedish patients.

PubMed

Lebbad, Marianne; Winiecka-Krusnell, Jadwiga; Insulander, Mona; Beser, Jessica

2018-05-01

Cryptosporidium hominis is considered a strictly human-adapted species, and it is only occasionally diagnosed in animals. However, two variants, C. hominis monkey genotype and C. hominis Ik, were originally described in non-human hosts, monkeys and horses, respectively. During a Swedish national Cryptosporidium study, where all samples were analyzed at the small subunit rRNA and the 60 kDa (gp60) glycoprotein loci, we identified two patients infected with C. hominis monkey genotype (subtype IiA17) and two infected with C. hominis subtype IkA18G1. The isolates were further analyzed at the actin and the 70 kDa heat shock protein loci, and these analyses showed that these two subtype families are closely related to each other and to human-adapted C. hominis as well as to Cryptosporidium cuniculus. The two patients with C. hominis monkey genotype infection (a father and son) had visited a monkey farm in Thailand prior to infection, while the two cases with C. hominis Ik were unrelated, both probably infected in Sweden. This is the first time that a monkey genotype infection in humans has been related to contact with monkeys and where the gp60 subtype was identified. It is also the first time that human infection caused by C. hominis subtype Ik is described. Even though we were not able to detect any parasites in the animal samples, zoonotic transmission cannot be ruled out in any of these cases because both subtype families are regarded as animal adapted. Copyright © 2018 Elsevier Inc. All rights reserved.

Vestibular functions and sleep in space experiments. [using rhesus and owl monkeys

NASA Technical Reports Server (NTRS)

Perachio, A. A.

1977-01-01

Physical indices of sleep were continuously monitored in an owl monkey living in a chamber continuously rotating at a constant angular velocity. The electrophysiological data obtained from chronically implanted electrodes was analyzed to determine the chronic effects of vestibular stimulation on sleep and wakefulness cycles. The interaction of linear and angular acceleration on the vestibulo-ocular reflex was investigated in three rhesus monkeys at various angular accelerations.

[Vaccination of rhesus monkeys with recombinant antigen fragments and protection from hepatitis E virus infection].

PubMed

Ma, Yan-bing; Xie, Tian-hong; Zhang, Guang-ming; Li, Chun-hong; Dai, Xie-Jie; Dai, Chang-bai; Sun, Mao-sheng; Lu, Jian; Bi, Sheng-li

2002-12-01

To observe anti-HEV IgG response to vaccination of recombinant antigen fragments and evaluate its protection from Hepatitis E Virus infection in rhesus monkeys (Macaca mulatta). Twelve monkeys were divided into three groups and immunized respectively with three different recombinant antigens: namely Ag1 (carboxyl terminal 431 amino acids of ORF2), Ag2 (128aa fragment at the carboxyl terminal of ORF2), and Ag3 (full length ORF3 ligated with two ORF2 fragments encoded by 6743-7126nt and 6287-6404nt). The monkeys were challenged intravenously with fecal suspension from experimentally infected rhesus monkeys, and the other three monkeys served as the placebo group for challenge with HEV. The dynamic changes of the levels of ALT and anti-HEV IgG were examined. Pathological changes of liver tissue were observed by light microscope. Excretion of virus was detected by RT-nPCR. Hepatic histopathology of two monkeys in the placebo group was consistent with acute viral hepatitis, and ALT was elevated 3-4 weeks after inoculated with virus, up to 10-20 times higher than normal level. The liver tissue of monkeys immunized with antigen kept normal, ALT in several monkeys elevated mildly, and anti-HEV IgG conversation occurred at 1-2 weeks after vaccination, with the titer reaching 1:12,800. The virus RNA could be detected by RT-nPCR from days 7 to 50 in monkeys of control group, and from days 7 to 21 in vaccinated monkeys after challenged with virus. The recombinant antigens could induce the production of anti-HEV IgG, which protected rhesus monkeys from acute Hepatitis symptoms related to HEV infection.

STUDIES ON YELLOW FEVER IN SOUTH AMERICA

PubMed Central

Davis, Nelson C.; Shannon, Raymond C.

1929-01-01

1. Yellow fever virus has been transmitted from monkey to monkey both by the bites of Aëdes (Ochlerotatus) scapularis which had fed upon monkeys infected with yellow fever and by the injection of the ground up bodies of such mosquitoes. 2. A fatal infection has been obtained by the injection of the ground up bodies of Aëdes (Ochlerotatus) serratus, which had previously fed on an infected monkey, and a mild infection has been secured by the similar injection of Aëdes (Taeniorhynchus) taeniorhynchus. 3. No definite infection has been secured either by the bites or by the injection of Culex quinquefasciatus (C. fatigans). However, some of the experimental animals bitten by this species have been relatively immune following inoculations of blood or tissues containing virus. PMID:19869666

Studies on malaria and Anopheles balabacensis in Cambodia

PubMed Central

Eyles, Don E.; Wharton, R. H.; Cheong, W. H.; Warren, McWilson

1964-01-01

During the past few years Anopheles balabacensis has come to be recognized as a very important human malaria vector in Thailand and the Indochinese area, but little has been published on its bionomics except from North Borneo. Studies of the feeding habits of A. balabacensis in Cambodia showed it to be predominantly a forest mosquito. It was readily attracted to monkeys in the forest canopy but also readily attacked man on the ground. Very few of this species were attracted to domestic animals. Malaria infections were found more frequently in mosquitos captured in villages, but a significant number were infected from the forest beyond flight range of human habitation. The human population showed a high percentage of persons infected with malaria, Plasmodium falciparum predominating. Cambodian monkeys were found also to be infected with P. cynomolgi. Although none of thirteen monkeys injected with sporozoites from wild-caught mosquitos came down with malaria, it was concluded that A. balabacensis probably was the vector of both human and monkey malaria and that the risk of cross-infection was considerable if monkey malarias infective to man exist in the area. PMID:14122444

La Crosse virus infectivity, pathogenesis, and immunogenicity in mice and monkeys

PubMed Central

Bennett, Richard S; Cress, Christina M; Ward, Jerrold M; Firestone, Cai-Yen; Murphy, Brian R; Whitehead, Stephen S

2008-01-01

Background La Crosse virus (LACV), family Bunyaviridae, was first identified as a human pathogen in 1960 after its isolation from a 4 year-old girl with fatal encephalitis in La Crosse, Wisconsin. LACV is a major cause of pediatric encephalitis in North America and infects up to 300,000 persons each year of which 70–130 result in severe disease of the central nervous system (CNS). As an initial step in the establishment of useful animal models to support vaccine development, we examined LACV infectivity, pathogenesis, and immunogenicity in both weanling mice and rhesus monkeys. Results Following intraperitoneal inoculation of mice, LACV replicated in various organs before reaching the CNS where it replicates to high titer causing death from neurological disease. The peripheral site where LACV replicates to highest titer is the nasal turbinates, and, presumably, LACV can enter the CNS via the olfactory neurons from nasal olfactory epithelium. The mouse infectious dose50 and lethal dose50 was similar for LACV administered either intranasally or intraperitoneally. LACV was highly infectious for rhesus monkeys and infected 100% of the animals at 10 PFU. However, the infection was asymptomatic, and the monkeys developed a strong neutralizing antibody response. Conclusion In mice, LACV likely gains access to the CNS via the blood stream or via olfactory neurons. The ability to efficiently infect mice intranasally raises the possibility that LACV might use this route to infect its natural hosts. Rhesus monkeys are susceptible to LACV infection and develop strong neutralizing antibody responses after inoculation with as little as 10 PFU. Mice and rhesus monkeys are useful animal models for LACV vaccine immunologic testing although the rhesus monkey model is not optimal. PMID:18267012

EXPERIMENTS ON THE TRANSMISSION OF SCARLET FEVER TO THE LOWER MONKEYS

PubMed Central

Draper, George; Hanford, John M.

1913-01-01

1. The reported successful transfer of scarlet fever to both higher and lower monkeys is not definitely established. 2. In the course of the experiments here reported, the infectious agent can be assumed to have been carried over to the monkeys. The failure to cause infection probably proceeds from the insusceptibility of the monkeys employed, or to the manner of introducing the agent. 3. The temperature curve and leucocyte count of monkeys are unsatisfactory criteria for the diagnosis of disease in those animals. 4. Monkeys frequently have transient blotchy, erythematous eruptions on the face and neck, and almost always a bran-like desquamation. 5. Monkeys are highly resistant to infection with microorganisms from human beings. PMID:19867663

Recent refinements to cranial implants for rhesus macaques (Macaca mulatta)

PubMed Central

Johnston, Jessica M.; Cohen, Yale E.; Shirley, Harry; Tsunada, Joji; Bennur, Sharath; Christison-Lagay, Kate; Veeder, Christin L.

2017-01-01

The advent of cranial implants revolutionized primate neurophysiological research because they allow researchers to stably record neural activity from monkeys during active behavior. Cranial implants have improved over the years since their introduction, but chronic implants still increase the risk for medical complications including bacterial contamination and resultant infection, chronic inflammation, bone and tissue loss and complications related to the use of dental acrylic. These complications can lead to implant failure and early termination of study protocols. In an effort to reduce complications, we describe several refinements that have helped us improve cranial implants and the wellbeing of implanted primates. PMID:27096188

Plasmacytoid Dendritic Cell Infection and Sensing Capacity during Pathogenic and Nonpathogenic Simian Immunodeficiency Virus Infection

PubMed Central

Jochems, Simon P.; Jacquelin, Beatrice; Chauveau, Lise; Huot, Nicolas; Petitjean, Gaël; Lepelley, Alice; Liovat, Anne-Sophie; Ploquin, Mickaël J.; Cartwright, Emily K.; Bosinger, Steven E.; Silvestri, Guido; Barré-Sinoussi, Françoise; Lebon, Pierre; Schwartz, Olivier

2015-01-01

ABSTRACT Human immunodeficiency virus (HIV) in humans and simian immunodeficiency virus (SIV) in macaques (MAC) lead to chronic inflammation and AIDS. Natural hosts, such as African green monkeys (AGM) and sooty mangabeys (SM), are protected against SIV-induced chronic inflammation and AIDS. Here, we report that AGM plasmacytoid dendritic cells (pDC) express extremely low levels of CD4, unlike MAC and human pDC. Despite this, AGM pDC efficiently sensed SIVagm, but not heterologous HIV/SIV isolates, indicating a virus-host adaptation. Moreover, both AGM and SM pDC were found to be, in contrast to MAC pDC, predominantly negative for CCR5. Despite such limited CD4 and CCR5 expression, lymphoid tissue pDC were infected to a degree similar to that seen with CD4+ T cells in both MAC and AGM. Altogether, our finding of efficient pDC infection by SIV in vivo identifies pDC as a potential viral reservoir in lymphoid tissues. We discovered low expression of CD4 on AGM pDC, which did not preclude efficient sensing of host-adapted viruses. Therefore, pDC infection and efficient sensing are not prerequisites for chronic inflammation. The high level of pDC infection by SIVagm suggests that if CCR5 paucity on immune cells is important for nonpathogenesis of natural hosts, it is possibly not due to its role as a coreceptor. IMPORTANCE The ability of certain key immune cell subsets to resist infection might contribute to the asymptomatic nature of simian immunodeficiency virus (SIV) infection in its natural hosts, such as African green monkeys (AGM) and sooty mangabeys (SM). This relative resistance to infection has been correlated with reduced expression of CD4 and/or CCR5. We show that plasmacytoid dendritic cells (pDC) of natural hosts display reduced CD4 and/or CCR5 expression, unlike macaque pDC. Surprisingly, this did not protect AGM pDC, as infection levels were similar to those found in MAC pDC. Furthermore, we show that AGM pDC did not consistently produce type I interferon (IFN-I) upon heterologous SIVmac/HIV type 1 (HIV-1) encounter, while they sensed autologous SIVagm isolates. Pseudotyping SIVmac/HIV-1 overcame this deficiency, suggesting that reduced uptake of heterologous viral strains underlays this lack of sensing. The distinct IFN-I responses depending on host species and HIV/SIV isolates reveal the host/virus species specificity of pDC sensing. PMID:25903334

Trypanosoma cruzi infection of squirrel monkeys: comparison of blood smear examination, commercial enzyme-linked immunosorbent assay, and polymerase chain reaction analysis as screening tests for evaluation of monkey-related injuries.

PubMed

Ndao, M; Kelly, N; Normandin, D; Maclean, J D; Whiteman, A; Kokoskin, E; Arevalo, I; Ward, B J

2000-12-01

Wild-caught New World monkeys (NWM) from Central or South America are often infected with Trypanosoma species, including T. cruzi. In humans, T. cruzi causes Chagas' disease. Even in closed monkey colonies, T. cruzi can be propagated by blood-to-blood exposure, sexual activity, and transplacental transmission. Animal handlers and laboratory staff who deal with blood and tissues from infected NWM are at riskfor acquiring Chagas' disease via accidental exposure. We screened 162 blood samples from wild-caught Saimiri sp. monkeys for Trypanosoma species infections by use of blood smear examination, ELISA, and polymerase chain reaction (PCR) analysis. Blood samples from 19 employees with recent history of monkey-associated injuries also were tested. Six percent (10/162) of the monkey samples were T. cruzi positive on the basis of blood smear examination results, 10.4% (17/162) were positive by ELISA results, and 26.5% (43/162) were positive by PCR results. Other organisms identified by PCR analysis included T. rangeli in two animals, Plasmodium spp. in two animals (P. malariae confirmed by PCR results) and microfilariae in one animal (morphologically, Mansonella perstans). Evidence of trypanosome infection was not found in the 19 employee samples on the basis of results of any of the three aforementioned tests. Close attention must be paid to worker safety where wild-caught NWM are used. The PCR analysis has a clear advantage over conventional techniques (ELISA, blood smear) for screening NWM for trypanosome infections during quarantine and after employee injury.

Lethal canine distemper virus outbreak in cynomolgus monkeys in Japan in 2008.

PubMed

Sakai, Kouji; Nagata, Noriyo; Ami, Yasushi; Seki, Fumio; Suzaki, Yuriko; Iwata-Yoshikawa, Naoko; Suzuki, Tadaki; Fukushi, Shuetsu; Mizutani, Tetsuya; Yoshikawa, Tomoki; Otsuki, Noriyuki; Kurane, Ichiro; Komase, Katsuhiro; Yamaguchi, Ryoji; Hasegawa, Hideki; Saijo, Masayuki; Takeda, Makoto; Morikawa, Shigeru

2013-01-01

Canine distemper virus (CDV) has recently expanded its host range to nonhuman primates. A large CDV outbreak occurred in rhesus monkeys at a breeding farm in Guangxi Province, China, in 2006, followed by another outbreak in rhesus monkeys at an animal center in Beijing in 2008. In 2008 in Japan, a CDV outbreak also occurred in cynomolgus monkeys imported from China. In that outbreak, 46 monkeys died from severe pneumonia during a quarantine period. A CDV strain (CYN07-dV) was isolated in Vero cells expressing dog signaling lymphocyte activation molecule (SLAM). Phylogenic analysis showed that CYN07-dV was closely related to the recent CDV outbreaks in China, suggesting continuing chains of CDV infection in monkeys. In vitro, CYN07-dV uses macaca SLAM and macaca nectin4 as receptors as efficiently as dog SLAM and dog nectin4, respectively. CYN07-dV showed high virulence in experimentally infected cynomolgus monkeys and excreted progeny viruses in oral fluid and feces. These data revealed that some of the CDV strains, like CYN07-dV, have the potential to cause acute systemic infection in monkeys.

Persistent Pneumocystis colonization leads to the development of chronic obstructive pulmonary disease (COPD) in a non-human primate model of AIDS

PubMed Central

Shipley, Timothy W.; Kling, Heather M.; Morris, Alison; Patil, Sangita; Kristoff, Jan; Guyach, Siobhan E.; Murphy, Jessica M.; Shao, Xiuping; Sciurba, Frank C.; Rogers, Robert M.; Richards, Thomas; Thompson, Paul; Montelaro, Ronald C.; Coxson, Harvey O.; Hogg, James C.; Norris, Karen A.

2010-01-01

HIV-infected patients are at increased risk for development of pulmonary complications, including chronic obstructive pulmonary disease (COPD). Inflammation associated with sub-clinical infection has been postulated to promote COPD. Persistence of Pneumocystis (Pc) is associated with HIV and COPD, although a causal relationship has not been established. We used a simian/human immunodeficiency virus (SHIV) model of HIV infection to study pulmonary effects of Pc colonization. SHIV-infected/Pc-colonized monkeys developed progressive obstructive pulmonary disease characterized by increased emphysematous tissue and bronchial-associated lymphoid tissue. Elevated Th2 cytokines and pro-inflammatory mediators in bronchoalveolar lavage fluid coincided with Pc colonization and pulmonary function decline. These results support the concept that an infectious agent contributes to development of HIV-associated lung disease and suggests that Pc colonization may be a risk factor for the development of HIV-associated COPD. Furthermore, this model allows examination of early host responses important to disease progression thus identifying potential therapeutic targets for COPD. PMID:20533880

Reemergence of Reston ebolavirus in Cynomolgus Monkeys, the Philippines, 2015.

PubMed

Demetria, Catalino; Smith, Ina; Tan, Titus; Villarico, Daniel; Simon, Edson Michael; Centeno, Rex; Tachedjian, Mary; Taniguchi, Satoshi; Shimojima, Masayuki; Miranda, Noel Lee J; Miranda, Mary Elizabeth; Rondina, Melissa Marie R; Capistrano, Rowena; Tandoc, Amado; Marsh, Glenn; Eagles, Debbie; Cruz, Ramses; Fukushi, Shuetsu

2018-07-01

In August 2015, a nonhuman primate facility south of Manila, the Philippines, noted unusual deaths of 6 cynomolgus monkeys (Macaca fascicularis), characterized by generalized rashes, inappetence, or sudden death. We identified Reston ebolavirus (RESTV) infection in monkeys by using serologic and molecular assays. We isolated viruses in tissues from infected monkeys and determined viral genome sequences. RESTV found in the 2015 outbreak is genetically closer to 1 of the 4 RESTVs that caused the 2008 outbreak among swine. Eight macaques, including 2 also infected with RESTV, tested positive for measles. Concurrently, the measles virus was circulating throughout the Philippines, indicating that the infection of the macaques may be a reverse zoonosis. Improved biosecurity measures will minimize the public health risk, as well as limit the introduction of disease and vectors.

Vaccine protection against acquisition of neutralization-resistant SIV challenges in rhesus monkeys.

PubMed

Barouch, Dan H; Liu, Jinyan; Li, Hualin; Maxfield, Lori F; Abbink, Peter; Lynch, Diana M; Iampietro, M Justin; SanMiguel, Adam; Seaman, Michael S; Ferrari, Guido; Forthal, Donald N; Ourmanov, Ilnour; Hirsch, Vanessa M; Carville, Angela; Mansfield, Keith G; Stablein, Donald; Pau, Maria G; Schuitemaker, Hanneke; Sadoff, Jerald C; Billings, Erik A; Rao, Mangala; Robb, Merlin L; Kim, Jerome H; Marovich, Mary A; Goudsmit, Jaap; Michael, Nelson L

2012-01-04

Preclinical studies of human immunodeficiency virus type 1 (HIV-1) vaccine candidates have typically shown post-infection virological control, but protection against acquisition of infection has previously only been reported against neutralization-sensitive virus challenges. Here we demonstrate vaccine protection against acquisition of fully heterologous, neutralization-resistant simian immunodeficiency virus (SIV) challenges in rhesus monkeys. Adenovirus/poxvirus and adenovirus/adenovirus-vector-based vaccines expressing SIV(SME543) Gag, Pol and Env antigens resulted in an 80% or greater reduction in the per-exposure probability of infection against repetitive, intrarectal SIV(MAC251) challenges in rhesus monkeys. Protection against acquisition of infection showed distinct immunological correlates compared with post-infection virological control and required the inclusion of Env in the vaccine regimen. These data demonstrate the proof-of-concept that optimized HIV-1 vaccine candidates can block acquisition of stringent, heterologous, neutralization-resistant virus challenges in rhesus monkeys.

Characterization of simian T-cell leukemia virus type 1 in naturally infected Japanese macaques as a model of HTLV-1 infection

PubMed Central

2013-01-01

Background Human T-cell leukemia virus type 1 (HTLV-1) causes chronic infection leading to development of adult T-cell leukemia (ATL) and inflammatory diseases. Non-human primates infected with simian T-cell leukemia virus type 1 (STLV-1) are considered to constitute a suitable animal model for HTLV-1 research. However, the function of the regulatory and accessory genes of STLV-1 has not been analyzed in detail. In this study, STLV-1 in naturally infected Japanese macaques was analyzed. Results We identified spliced transcripts of STLV-1 corresponding to HTLV-1 tax and HTLV-1 bZIP factor (HBZ). STLV-1 Tax activated the NFAT, AP-1 and NF-κB signaling pathways, whereas STLV-1 bZIP factor (SBZ) suppressed them. Conversely, SBZ enhanced TGF-β signaling and induced Foxp3 expression. Furthermore, STLV-1 Tax activated the canonical Wnt pathway while SBZ suppressed it. STLV-1 Tax enhanced the viral promoter activity while SBZ suppressed its activation. Then we addressed the clonal proliferation of STLV-1+ cells by massively sequencing the provirus integration sites. Some clones proliferated distinctively in monkeys with higher STLV-1 proviral loads. Notably, one of the monkeys surveyed in this study developed T-cell lymphoma in the brain; STLV-1 provirus was integrated in the lymphoma cell genome. When anti-CCR4 antibody, mogamulizumab, was administered into STLV-1-infected monkeys, the proviral load decreased dramatically within 2 weeks. We observed that some abundant clones recovered after discontinuation of mogamulizumab administration. Conclusions STLV-1 Tax and SBZ have functions similar to those of their counterparts in HTLV-1. This study demonstrates that Japanese macaques naturally infected with STLV-1 resemble HTLV-1 carriers and are a suitable model for the investigation of persistent HTLV-1 infection and asymptomatic HTLV-1 carrier state. Using these animals, we verified that mogamulizumab, which is currently used as a drug for relapsed ATL, is also effective in reducing the proviral load in asymptomatic individuals. PMID:24156738

Cross-species transmission of a novel adenovirus associated with a fulminant pneumonia outbreak in a new world monkey colony.

PubMed

Chen, Eunice C; Yagi, Shigeo; Kelly, Kristi R; Mendoza, Sally P; Tarara, Ross P; Canfield, Don R; Maninger, Nicole; Rosenthal, Ann; Spinner, Abigail; Bales, Karen L; Schnurr, David P; Lerche, Nicholas W; Chiu, Charles Y

2011-07-01

Adenoviruses are DNA viruses that naturally infect many vertebrates, including humans and monkeys, and cause a wide range of clinical illnesses in humans. Infection from individual strains has conventionally been thought to be species-specific. Here we applied the Virochip, a pan-viral microarray, to identify a novel adenovirus (TMAdV, titi monkey adenovirus) as the cause of a deadly outbreak in a closed colony of New World monkeys (titi monkeys; Callicebus cupreus) at the California National Primate Research Center (CNPRC). Among 65 titi monkeys housed in a building, 23 (34%) developed upper respiratory symptoms that progressed to fulminant pneumonia and hepatitis, and 19 of 23 monkeys, or 83% of those infected, died or were humanely euthanized. Whole-genome sequencing of TMAdV revealed that this adenovirus is a new species and highly divergent, sharing <57% pairwise nucleotide identity with other adenoviruses. Cultivation of TMAdV was successful in a human A549 lung adenocarcinoma cell line, but not in primary or established monkey kidney cells. At the onset of the outbreak, the researcher in closest contact with the monkeys developed an acute respiratory illness, with symptoms persisting for 4 weeks, and had a convalescent serum sample seropositive for TMAdV. A clinically ill family member, despite having no contact with the CNPRC, also tested positive, and screening of a set of 81 random adult blood donors from the Western United States detected TMAdV-specific neutralizing antibodies in 2 individuals (2/81, or 2.5%). These findings raise the possibility of zoonotic infection by TMAdV and human-to-human transmission of the virus in the population. Given the unusually high case fatality rate from the outbreak (83%), it is unlikely that titi monkeys are the native host species for TMAdV, and the natural reservoir of the virus is still unknown. The discovery of TMAdV, a novel adenovirus with the capacity to infect both monkeys and humans, suggests that adenoviruses should be monitored closely as potential causes of cross-species outbreaks.

Mycobacterium marinum infection from sea monkeys.

PubMed

Leblanc, Jaclyn; Webster, Duncan; Tyrrell, Gregory J; Chiu, Isabelle

2012-01-01

A case of cutaneous Mycobacterium marinum infection acquired from Artemia nyos (sea monkeys) is presented. The infection was unresponsive to initial antimicrobial therapies. A biopsy of a lesion revealed granulomatous inflammation with cultures that subsequently grew M marinum. A three-month course of clarithromycin provided complete resolution.

A survey for Cyclospora spp. in Kenyan primates, with some notes on its biology.

PubMed

Eberhard, M L; Njenga, M N; DaSilva, A J; Owino, D; Nace, E K; Won, K Y; Mwenda, J M

2001-12-01

From March 1999 through August 2000, 511 stool samples collected from 11 different primate species in 10 geographically distinct locations in Kenya, East Africa, were screened for the presence of Cyclospora spp. oocysts. Positive samples (43/102, 42%) were identified in vervet monkeys (Cercopithecus aethiops) in 4 of 4 locations; 19/206 (9%) in yellow and olive baboons (Papio cynocephalus, P. anubis, respectively) in 5 of 5 locations; and 19/76 (25%) in black and white colobus monkeys (Colobus angolensis, C. guereza, respectively) from 2 of 3 locations. DNA sequences obtained from 18 S rRNA coding regions from respective subsets of these positive samples were typed as Cyclospora cercopitheci (samples from Cercopithecus aethiops). Cyclospora papionis (samples from Papio cynocephalus and P. anubis), and Cyclospora colobi (samples from Colobus angolensis and C. guereza). Cyclospora oocysts were not detected in samples collected from patas, highland sykes, lowland sykes, blue sykes, DeBrazza, or red-tailed monkeys. A coded map showing the geographic location of the collected samples is given. Stool samples from 1 troop of vervet monkeys were collected over a 12-mo period. Positive samples ranged between 21 and 63%. These results suggest that there is no strongly marked seasonality evident in Cyclospora infection in monkeys as has been noted in human infection. This is further confirmed by the recovery of positive samples collected from vervet monkeys, baboons, and colobus monkeys at all times of the year during this survey. This absence of seasonality in infection is especially notable because of the extreme weather patterns typical of Kenya, where marked rainy and dry seasons occur. A second noteworthy observation is that the striking host specificity of the Cyclospora species initially described was confirmed in this survey. Baboons were only infected with C. papionis, vervet monkeys with C. cercopitheci, and colobus monkeys with C. colobi, despite geographic overlaps of both the monkey and parasite species and wide geographic distribution of each parasite and monkey host.

Schistosoma mansoni and other intestinal parasitic infections in schoolchildren and vervet monkeys in Lake Ziway area, Ethiopia.

PubMed

Teklemariam, Dejene; Legesse, Mengistu; Degarege, Abraham; Liang, Song; Erko, Berhanu

2018-02-20

To assess Schistosoma mansoni and other intestinal parasitic infections in schoolchildren and vervet monkeys (Chlorocebus aethiops) in Bochessa Village, Ziway, Ethiopia. Fecal specimens from selected schoolchildren and droppings of the vervet monkeys were collected and microscopically examined for intestinal parasites using the Kato-Katz thick smear and formol-ether concentration techniques. The prevalences of S. mansoni, Trichuris trichiura, Ascaris lumbricoides, Enterobius vermicularis, hookworms, Hymenolepis nana and Taenia species among the children were 35.7, 26.9, 24.1, 2.1, 2.1, 1.07 and 2.1%, respectively (by Kato-Katz) and 39.3, 36.1, 35.6, 2.9, 10.0, 4.3, and 2.9%, respectively (by formol-ether concentration). Prevalence of S. mansoni in vervet monkeys ranged from 10 to 20%. B. pfeifferi snails were exposed to S. mansoni miracidia from vervet origin, shed cercariae were then used to infect lab-bred albino mice. Adult worms were harvested from the mice 5 weeks post-exposure to cercariae to establish the schistosome life cycle and confirm the infection in the vervet monkeys. The natural infection of S. mansoni in vervet monkeys suggests that the non-human primate is likely to be implicated in the local transmission of schistosomiasis. Further epidemiological and molecular studies are needed to fully elucidate zoonotic role of non-human primate in the area.

Induction of immune response in macaque monkeys infected with simian-human immunodeficiency virus having the TNF-{alpha} gene at an early stage of infection

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shimizu, Yuya; Miyazaki, Yasuyuki; Ibuki, Kentaro

2005-12-20

TNF-{alpha} has been implicated in the pathogenesis of, and the immune response against, HIV-1 infection. To clarify the roles of TNF-{alpha} against HIV-1-related virus infection in an SHIV-macaque model, we genetically engineered an SHIV to express the TNF-{alpha} gene (SHIV-TNF) and characterized the virus's properties in vivo. After the acute viremic stage, the plasma viral loads declined earlier in the SHIV-TNF-inoculated monkeys than in the parental SHIV (SHIV-NI)-inoculated monkeys. SHIV-TNF induced cell death in the lymph nodes without depletion of circulating CD4{sup +} T cells. SHIV-TNF provided some immunity in monkeys by increasing the production of the chemokine RANTES andmore » by inducing an antigen-specific proliferation of lymphocytes. The monkeys immunized with SHIV-TNF were partly protected against a pathogenic SHIV (SHIV-C2/1) challenge. These findings suggest that TNF-{alpha} contributes to the induction of an effective immune response against HIV-1 rather than to the progression of disease at the early stage of infection.« less

THE COURSE OF ACUTE INTESTINAL INFECTIONS IN MONKEYS DURING THE ACTION OF IONISING RADIATION (in Russian)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Stasilevich, Z.K.

1963-04-01

The influence of sublethal x irradiation on the susceptibility of monkeys to acute intestinal infections (paratyphoid B fever, Heidelberg's salmonellosis and colienteritis) was studied. Experiments were carried out on 46 macaque monkeys, aged 2 1/2 to 3 yr. In monkeys subjected to a dose of 300 r there was an elevated susceptibility to paratyphoid B fever; however, the infectious process was not aggravated. Irradiation of animals with a similar dose aggravated the infectious process in Heidelberg's salmonellosis. In monkeys with colienteritis the above dose did not influence the natural immunity of animals to this disease. A clinically marked disease (colienteritis),more » with a lethal outcome was induced in monkeys irradiated with a dose of 445 r. (auth)« less

Protective efficacy of recombinant BCG Tokyo (Ag85A) in rhesus monkeys (Macaca mulatta) infected intratracheally with H37Rv Mycobacterium tuberculosis.

PubMed

Sugawara, I; Sun, L; Mizuno, S; Taniyama, T

2009-01-01

We have reported previously that recombinant BCG Tokyo (Ag85A) (rBCG-Ag85A[Tokyo]) shows promise as a tuberculosis vaccine, demonstrating protective efficacy in cynomolgus monkeys. As a next step, rhesus monkeys were utilized because they are also susceptible to Mycobacterium tuberculosis and show a continuous course of infection resembling human tuberculosis. The recombinant BCG vaccine (5x10(5) CFU per monkey) was administered once intradermally into the back skin to three groups of rhesus monkeys, and its protective efficacy was compared for 4months with that of its parental BCG Tokyo strain. Eight week vaccination of the monkeys with rBCG-Ag85A[Tokyo] resulted in a reduction of tubercle bacilli CFU (p<0.01) and lung pathology in animals infected intratracheally with 3000 CFU H37Rv M. tuberculosis. Vaccination prevented an increase in the old tuberculin test after challenge with M. tuberculosis and reaction of M. tuberculosis-derived antigen. Thus, it was shown that even in rhesus monkeys rBCG-Ag85A[Tokyo] induced higher protective efficacy than BCG Tokyo.

Antibody-Dependent Cell-Mediated Viral Inhibition Emerges after Simian Immunodeficiency Virus SIVmac251 Infection of Rhesus Monkeys Coincident with gp140-Binding Antibodies and Is Effective against Neutralization-Resistant Viruses▿

PubMed Central

Asmal, Mohammed; Sun, Yue; Lane, Sophie; Yeh, Wendy; Schmidt, Stephen D.; Mascola, John R.; Letvin, Norman L.

2011-01-01

Antibody-dependent cell-mediated viral inhibition (ADCVI) is an attractive target for vaccination because it takes advantage of both the anamnestic properties of an adaptive immune response and the rapid early response characteristics of an innate immune response. Effective utilization of ADCVI in vaccine strategies will depend on an understanding of the natural history of ADCVI during acute and chronic human immunodeficiency virus type 1 (HIV-1) infection. We used the simian immunodeficiency virus (SIV)-infected rhesus monkey as a model to study the kinetics of ADCVI in early infection, the durability of ADCVI through the course of infection, and the effectiveness of ADCVI against viruses with envelope mutations that are known to confer escape from antibody neutralization. We demonstrate the development of ADCVI, capable of inhibiting viral replication 100-fold, within 3 weeks of infection, preceding the development of a comparable-titer neutralizing antibody response by weeks to months. The emergence of ADCVI was temporally associated with the emergence of gp140-binding antibodies, and in most animals, ADCVI persisted through the course of infection. Highly evolved viral envelopes from viruses isolated at late time points following infection that were resistant to plasma neutralization remained susceptible to ADCVI, suggesting that the epitope determinants of neutralization escape are not shared by antibodies that mediate ADCVI. These findings suggest that despite the ability of SIV to mutate and adapt to multiple immunologic pressures during the course of infection, SIV envelope may not escape the binding of autologous antibodies that mediate ADCVI. PMID:21450829

Use of a Recombinant Gamma-2 Herpesvirus Vaccine Vector against Dengue Virus in Rhesus Monkeys.

PubMed

Bischof, Georg F; Magnani, Diogo M; Ricciardi, Michael; Shin, Young C; Domingues, Aline; Bailey, Varian K; Gonzalez-Nieto, Lucas; Rakasz, Eva G; Watkins, David I; Desrosiers, Ronald C

2017-08-15

Research on vaccine approaches that can provide long-term protection against dengue virus infection is needed. Here we describe the construction, immunogenicity, and preliminary information on the protective capacity of recombinant, replication-competent rhesus monkey rhadinovirus (RRV), a persisting herpesvirus. One RRV construct expressed nonstructural protein 5 (NS5), while a second recombinant expressed a soluble variant of the E protein (E85) of dengue virus 2 (DENV2). Four rhesus macaques received a single vaccination with a mixture of both recombinant RRVs and were subsequently challenged 19 weeks later with 1 × 10 5 PFU of DENV2. During the vaccine phase, plasma of all vaccinated monkeys showed neutralizing activity against DENV2. Cellular immune responses against NS5 were also elicited, as evidenced by major histocompatibility complex class I (MHC-I) tetramer staining in the one vaccinated monkey that was Mamu-A*01 positive. Unlike two of two unvaccinated controls, two of the four vaccinated monkeys showed no detectable viral RNA sequences in plasma after challenge. One of these two monkeys also showed no anamnestic increases in antibody levels following challenge and thus appeared to be protected against the acquisition of DENV2 following high-dose challenge. Continued study will be needed to evaluate the performance of herpesviral and other persisting vectors for achieving long-term protection against dengue virus infection. IMPORTANCE Continuing studies of vaccine approaches against dengue virus (DENV) infection are warranted, particularly ones that may provide long-term immunity against all four serotypes. Here we investigated whether recombinant rhesus monkey rhadinovirus (RRV) could be used as a vaccine against DENV2 infection in rhesus monkeys. Upon vaccination, all animals generated antibodies capable of neutralizing DENV2. Two of four vaccinated monkeys showed no detectable viral RNA after subsequent high-dose DENV2 challenge at 19 weeks postvaccination. Furthermore, one of these vaccinated monkeys appeared to be protected against the acquisition of DENV2 infection on the basis of undetectable viral loads and the lack of an anamnestic antibody response. These findings underscore the potential utility of recombinant herpesviruses as vaccine vectors. Copyright © 2017 American Society for Microbiology.

Species-specific inflammatory responses as a primary component for the development of glomerular lesions in mice and monkeys following chronic administration of a second-generation antisense oligonucleotide.

PubMed

Frazier, Kendall S; Sobry, Cécile; Derr, Victoria; Adams, Mike J; Besten, Cathaline Den; De Kimpe, Sjef; Francis, Ian; Gales, Tracy L; Haworth, Richard; Maguire, Shaun R; Mirabile, Rosanna C; Mullins, David; Palate, Bernard; Doorten, Yolanda Ponstein-Simarro; Ridings, James E; Scicchitano, Marshall S; Silvano, Jérémy; Woodfine, Jennie

2014-07-01

Chronic administration of drisapersen, a 2'-OMe phosphorothioate antisense oligonucleotide (AON) to mice and monkeys resulted in renal tubular accumulation, with secondary tubular degeneration. Glomerulopathy occurred in both species with species-specific characteristics. Glomerular lesions in mice were characterized by progressive hyaline matrix accumulation, accompanied by the presence of renal amyloid and with subsequent papillary necrosis. Early changes involved glomerular endothelial hypertrophy and degeneration, but the chronic glomerular amyloid and hyaline alterations in mice appeared to be species specific. An immune-mediated mechanism for the glomerular lesions in mice was supported by early inflammatory changes including increased expression of inflammatory cytokines and other immunomodulatory genes within the renal cortex, increased stimulation of CD68 protein, and systemic elevation of monocyte chemotactic protein 1. In contrast, kidneys from monkeys given drisapersen chronically showed less severe glomerular changes characterized by increased mesangial and inflammatory cells, endothelial cell hypertrophy, and subepithelial and membranous electron-dense deposits, with ultrastructural and immunohistochemical characteristics of complement and complement-related fragments. Lesions in monkeys resembled typical features of C3 glomerulopathy, a condition described in man and experimental animals to be linked to dysregulation of the alternative complement pathway. Thus, inflammatory/immune mechanisms appear critical to glomerular injury with species-specific sensitivities for mouse and monkey. The lower observed proinflammatory activity in humans as compared to mice and monkeys may reflect a lower risk of glomerular injury in patients receiving AON therapy. © 2014 by The Author(s).

Selective induction of cell-mediated immunity and protection of rhesus macaques from chronic SHIV{sub KU2} infection by prophylactic vaccination with a conserved HIV-1 envelope peptide-cocktail

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nehete, Pramod N.; Nehete, Bharti P.; Hill, Lori

2008-01-05

Infection of Indian-origin rhesus macaques by the simian human immunodeficiency virus (SHIV) is considered to be a suitable preclinical model for directly testing efficacy of vaccine candidates based on the HIV-1 envelope. We used this model for prophylactic vaccination with a peptide-cocktail comprised of highly conserved HIV-1 envelope sequences immunogenic/antigenic in macaques and humans. Separate groups of macaques were immunized with the peptide-cocktail by intravenous and subcutaneous routes using autologous dendritic cells (DC) and Freund's adjuvant, respectively. The vaccine elicited antigen specific IFN-{gamma}-producing cells and T-cell proliferation, but not HIV-neutralizing antibodies. The vaccinated animals also exhibited efficient cross-clade cytolytic activitymore » against target cells expressing envelope proteins corresponding to HIV-1 strains representative of multiple clades that increased after intravenous challenge with pathogenic SHIV{sub KU2}. Virus-neutralizing antibodies were either undetectable or present only transiently at low levels in the control as well as vaccinated monkeys after infection. Significant control of plasma viremia leading to undetectable levels was achieved in majority of vaccinated monkeys compared to mock-vaccinated controls. Monkeys vaccinated with the peptide-cocktail using autologous DC, compared to Freund's adjuvant, and the mock-vaccinated animals, showed significantly higher IFN-{gamma} production, higher levels of vaccine-specific IFN-{gamma} producing CD4{sup +} cells and significant control of plasma viremia. These results support DC-based vaccine delivery and the utility of the conserved HIV-1 envelope peptide-cocktail, capable of priming strong cell-mediated immunity, for potential inclusion in HIV vaccination strategies.« less

Enterovirus 71 pathogenicity in monkeys and cotton rats.

PubMed

Koroleva, Galina A; Karmysheva, Valentina Ya; Lukashev, Alexander N

2014-05-01

Enterovirus 71 (EV71) is a neurovirulent non-polio enterovirus that can cause severe central nervous system (CNS) infection in infants. Vervet monkeys infected intracerebrally or intramuscularly with EV71 isolates from the Bulgarian outbreak of 1975 developed clinical manifestations and pathological signs of encephalomyelitis and spinal poliomyelitis that were similar to EV71 neuroinfection in children. In addition, vervet monkeys with encephalomyelitis had severe alterations in the choroid plexus. EV71 neuroinfection could also be reproduced in young (3- to 4-week old) cotton rats with clinical and pathological signs comparable with those observed in vervet monkeys.

EFFECTS OF PCB (AROCLORR 1254) ON NON-SPECIFIC IMMUNE PARAMETERS IN RHESUS (MACACA MULATA) MONKEYS.

EPA Science Inventory

The effects of low level chronic polychlorinated biphenyl - Aroclor 1254 - (PCB) exposure were investigated on nonspecific immune parameters in female rhesus (Macaca mulatta) monkeys. Five groups of monkeys were orally administered PCB at concentrations of 0, 5, 20, 40, or 80 ug/...

Serological evidence for hepatitis e virus infection in laboratory monkeys and pigs in animal facilities in Japan.

PubMed

Yamamoto, Hiroshi; Li, Tian-Cheng; Koshimoto, Chihiro; Ito, Kaori; Kita, Masakazu; Miyashita, Nobumoto; Arikawa, Jiro; Yagami, Kenichi; Asano, Masahide; Tezuka, Hideo; Suzuki, Noboru; Kurosawa, Tsutomu; Shibahara, Toshiyuki; Furuya, Masato; Mohri, Shirou; Sato, Hiroshi; Ohsawa, Kazutaka; Ibuki, Kentaro; Takeda, Naokazu

2008-07-01

In laboratory animal facilities, monkeys and pigs are used for animal experiments, but the details of hepatitis E virus (HEV) infection in these animals are unknown. The risk of infection from laboratory animals to humans has become a concern; therefore, much attention should be paid to the handling of these animals during their care and use, including surgical procedures performed on infected animals. In this connection, serum samples collected from 916 monkeys and 77 pigs kept in 23 animal facilities belonging to the Japanese Association of Laboratory Animal Facilities of National University Corporations (JALAN) and the Japanese Association of Laboratory Animal Facilities of Public and Private Universities (JALAP) in Japan were examined for the purpose of detecting antibodies to HEV and HEV RNA by using ELISA and RT-PCR, respectively. One hundred and seven serum samples of 916 (11.7%) monkeys were positive for anti-HEV IgG, and 7 and 17 serum samples of 916 (0.8% and 5.3%) monkeys were positive for anti-HEV IgM and IgA, respectively. Thirty-six samples from 62 (58.1%) farm pigs were positive for anti-HEV IgG, whereas all samples tested from miniature pigs were negative (0/15, 0%). Seven samples from 62 (9.1%) farm pigs and 7 samples from 916 (0.8%) monkeys were positive for IgM antibody, but these HEV-IgM antibody positive serum samples were HEV-RNA negative by RT-PCR. The IgM antibody positive rate (9.1%) of farm pigs was much higher than that of monkeys (0.8%). These results suggest the relative levels of risk of HEV infection from these animals to animal handlers and researchers who work with them in laboratory animal facilities.

Infection of Aotus azarae boliviensis monkeys with different strains of Plasmodium falciparum.

PubMed

Collins, W E; Skinner, J C; Broderson, J R; Huong, A Y; Mehaffey, P C; Stanfill, P S; Sutton, B B

1986-08-01

Eleven strains of Plasmodium falciparum from Asia, Africa, and Central America were inoculated into a total of 58 splenectomized Aotus azarae boliviensis monkeys. Eight of the strains produced high-level parasitemias, whereas 3 (2 from Honduras and 1 from Zaire) produced only low-level parasitemias. Mosquito infections were only obtained during the first 2 linear passages of the Santa Lucia strain from El Salvador. The results indicate that this species of Aotus monkey is highly susceptible to infection with strains of P. falciparum from different geographic areas, and therefore may be useful for a number of chemotherapeutic or immunologic studies. Its usefulness for mosquito infection studies is very limited.

Chronic Nicotine Treatment Increases nAChRs and Microglial Expression in Monkey Substantia Nigra after Nigrostriatal Damage

PubMed Central

Campos, Carla; Parameswaran, Neeraja; William Langston, J.; Michael McIntosh, J.; Yeluashvili, Michael

2010-01-01

Our previous work had shown that long-term nicotine administration improved dopaminergic markers and nicotinic receptors (nAChRs) in the striatum of monkeys with nigrostriatal damage. The present experiments were done to determine whether nicotine treatment also led to changes in the substantia nigra, the region containing dopaminergic cell bodies. Monkeys were chronically treated with nicotine in the drinking water for 6 months after which they were injected with low dose MPTP for a further 6-month period. Nicotine was administered until the monkeys were euthanized 2 months after the last MPTP injection. Nicotine treatment did not affect the dopamine transporter or the number of tyrosine hydroxylase positive cells in the substantia nigra of lesioned monkeys. However, nicotine administration did lead to a greater increase in α3/α6β2* and α4β2* nAChRs in lesioned monkeys compared to controls. Nicotine also significantly elevated microglia and reduced the number of extracellular neuromelanin deposits in the substantia nigra of MPTP-lesioned monkeys. These findings indicate that long-term nicotine treatment modulates expression of several molecular measures in monkey substantia nigra that may result in an improvement in nigral integrity and/or function. These observations may have therapeutic implications for Parkinson’s disease. PMID:19685015

Characterization of ovarian aging and reproductive senescence in vervet monkeys (Chlorocebus aethiops sabaeus).

PubMed

Atkins, Hannah M; Willson, Cynthia J; Silverstein, Marnie; Jorgensen, Matthew; Floyd, Edison; Kaplan, Jay R; Appt, Susan E

2014-02-01

Female vervet monkeys (Chlorocebus aethiops sabaeus) are used as an experimental model for chronic diseases relevant to women's health. However, reproductive senescence (menopause) has not yet been characterized for vervet monkeys. Here we describe the histologic, hormonal, and menstrual markers of reproductive senescence in vervet monkeys from the Wake Forest Vervet Research Colony. Ovaries from monkeys (age, 0 to 27 y) were serially sectioned (5 μm), stained, and photographed. In every 100th section, the numbers of primordial, primary, and secondary follicles were determined, and triplicate measurements were used to calculate mean numbers of follicles per ovary. Antimüllerian hormone (AMH), follicle stimulating hormone, and menstrual cycle length were measured in additional monkeys. Primordial follicles and AMH decreased significantly with age, and significant correlations between numbers of primordial and primary follicles and between numbers of primary and secondary follicles were noted. Histologic evaluation revealed that ovaries from 4 aged monkeys (older than 23 y) were senescent. One aged monkey transitioned to menopause, experiencing cycle irregularity over 4 y, eventual cessation of menses, and plasma AMH below the level of detection. Finally, with increasing age, the percentage of female vervets with offspring declined significantly. The present study provides insight into ovarian aging and reproductive senescence in vervet monkeys. Results highlight the importance of considering this nonhuman primate as a model to investigate the relationships between ovarian aging and chronic disease risk.

Monkey bites among US military members, Afghanistan, 2011.

PubMed

Mease, Luke E; Baker, Katheryn A

2012-10-01

Bites from Macaca mulatta monkeys, native to Afghanistan, can cause serious infections. To determine risk for US military members in Afghanistan, we reviewed records for September-December 2011. Among 126 animal bites and exposures, 10 were monkey bites. Command emphasis is vital for preventing monkey bites; provider training and bite reporting promote postexposure treatment.

LATENT INFECTIONS IN MONKEYS WITH RADIATION SICKNESS INDUCED BY FRACTIONAL IRRADIATION (in Russian)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dzhikidze, E.K.; Aksenova, A.S.

1962-03-01

ABS>Work was carried out on 29 monkeys, most of them carriers of dysentery bacteria, subjected to multifold action of roentgen (12 monkeys) and gamma rays (l7 monkeys) in daily doses of 16-26 and 34 r. A very early appearance of symptoms of radiation sickness was observed, which by clinical and morphological manifestations resembled an acute radiation process. 26 out of 29 morkeys died in periods of 27 to 95 days from the start of the experiments, the total doses ranging from 450 to 1699 r, At different periods after the irradiation 25 monkeys developed infectious complications, in the majority ofmore » cases associated with activation of latent dysenteric infection (18 monkeys). The course of infectious processes against the background of radiation sickness was frequently of an atypical nature with scarce manifestations of the main symptoms of the disease. (auth)« less

Pentatrichomonas hominis: prevalence and molecular characterization in humans, dogs, and monkeys in Northern China.

PubMed

Li, Wen-Chao; Ying, Meng; Gong, Peng-Tao; Li, Jian-Hua; Yang, Ju; Li, He; Zhang, Xi-Chen

2016-02-01

Pentatrichomonas hominis is an anaerobic amitochondrial flagellated protist that primarily colonizes the large intestines of a number of species, including cats, dogs, nonhuman primates, and humans. The prevalence of this parasite in dogs, monkeys, and humans is, however, poorly understood. In this study, a total of 362 fecal samples including 252 dogs, 60 monkeys, and 50 humans from northern China were collected for an epidemiological survey of P. hominis infection.The average prevalence of P. hominis infection determined by nested PCR was 27.38% (69/252), 4.00% (2/50), and 46.67% (28/60) in dogs, humans, and monkeys, respectively. The prevalence was significantly higher in 6-month-old dogs (41.53%) and children (7.69%) than in older dogs (14.39%) and adults (0%) (P < 0.05). Sequencing of amplicons revealed that four variable positions separated sequences into three types, called CC1-3. CC1 was the most prevalent in the study population. This study determined that P. hominis infection is common in dogs, monkeys, and humans, especially in children and young dogs. Given the infection prevalence, P. hominis may pose a risk of zoonotic and anthroponotic transmission.

Fetal Neuropathology in Zika Virus-Infected Pregnant Female Rhesus Monkeys.

PubMed

Martinot, Amanda J; Abbink, Peter; Afacan, Onur; Prohl, Anna K; Bronson, Roderick; Hecht, Jonathan L; Borducchi, Erica N; Larocca, Rafael A; Peterson, Rebecca L; Rinaldi, William; Ferguson, Melissa; Didier, Peter J; Weiss, Deborah; Lewis, Mark G; De La Barrera, Rafael A; Yang, Edward; Warfield, Simon K; Barouch, Dan H

2018-05-17

The development of interventions to prevent congenital Zika syndrome (CZS) has been limited by the lack of an established nonhuman primate model. Here we show that infection of female rhesus monkeys early in pregnancy with Zika virus (ZIKV) recapitulates many features of CZS in humans. We infected 9 pregnant monkeys with ZIKV, 6 early in pregnancy (weeks 6-7 of gestation) and 3 later in pregnancy (weeks 12-14 of gestation), and compared findings with uninfected controls. 100% (6 of 6) of monkeys infected early in pregnancy exhibited prolonged maternal viremia and fetal neuropathology, including fetal loss, smaller brain size, and histopathologic brain lesions, including microcalcifications, hemorrhage, necrosis, vasculitis, gliosis, and apoptosis of neuroprogenitor cells. High-resolution MRI demonstrated concordant lesions indicative of deep gray matter injury. We also observed spinal, ocular, and neuromuscular pathology. Our data show that vascular compromise and neuroprogenitor cell dysfunction are hallmarks of CZS pathogenesis, suggesting novel strategies to prevent and to treat this disease. Copyright © 2018 Elsevier Inc. All rights reserved.

Naturally transmitted herpesvirus papio-2 infection in a black and white colobus monkey.

PubMed

Troan, Brigid V; Perelygina, Ludmila; Patrusheva, Irina; Wettere, Arnaud J van; Hilliard, Julia K; Loomis, Michael R; Voe, Ryan S De

2007-12-15

A 6.5-year-old female eastern black and white colobus monkey (Colobus guereza) was evaluated after acute onset of ataxia and inappetence. The monkey was ataxic and lethargic, but no other abnormalities were detected via physical examination, radiography, or clinicopathologic analyses. During the next 2 days, the monkey's clinical condition deteriorated, and its WBC count decreased dramatically. Cytologic examination of a CSF sample revealed marked lymphohistiocytic inflammation. Despite supportive care, the monkey became apneic; after 20 hours of mechanical ventilation, fatal cardiac arrest occurred. At necropsy, numerous petechiae were detected within the white matter tracts of the brain; microscopic lesions of multifocal necrosis and hemorrhage with intranuclear inclusions identified in the brain and adrenal glands were consistent with an acute herpesvirus infection. A specific diagnosis of herpesvirus papio-2 (HVP-2) infection was made on the basis of results of serologic testing; PCR assay of tissue specimens; live virus isolation from the lungs; and immunohistochemical identification of the virus within brain, spinal cord, and adrenal gland lesions. Via phylogenetic tree analysis, the colobus HVP-2 isolate was grouped with neuroinvasive strains of the virus. The virus was most likely transmitted to the colobus monkey through toys shared with a nearby colony of baboons (the natural host of HVP-2). To the authors' knowledge, this is the first reported case of natural transmission of HVP-2 to a nonhost species. Infection with HVP-2 should be a differential diagnosis for acute encephalopathy in primate monkeys and humans, particularly following exposure to baboons.

Monkey Bites among US Military Members, Afghanistan, 2011

PubMed Central

Baker, Katheryn A.

2012-01-01

Bites from Macaca mulatta monkeys, native to Afghanistan, can cause serious infections. To determine risk for US military members in Afghanistan, we reviewed records for September–December 2011. Among 126 animal bites and exposures, 10 were monkey bites. Command emphasis is vital for preventing monkey bites; provider training and bite reporting promote postexposure treatment. PMID:23017939

Evidence of possible natural infections of man with Brugia pahangi in South Kalimantan (Borneo), Indonesia.

PubMed

Palmieri, J R; Ratiwayanto, S; Masbar, S; Tirtokusumo, S; Rusch, J; Marwoto, H A

1985-09-01

Blood from 9 humans, 6 domestic cats (Felis domesticus), and 5 silvered leaf monkeys (Presbytis cristatus) from South Kalimantan (Borneo), Indonesia, with known filarial infections was examined for determination ofacid phosphatase activity of the microfilarae (mff). The findings suggest 1) that Brugia parasites from domestic cats and silvered leaf monkeys can be speciated by acid phosphatase activity and that speciation by acid phosphatase assay corresponds to that based upon adult worm morphology and 2) that Brugia mff from humans have acid phosphatase activity characteristic of that of B. pahangi microfilariae from cat and monkey. Thus B. pahangi may infect man in South Kalimantan.

Canine distemper virus isolated from a monkey efficiently replicates on Vero cells expressing non-human primate SLAM receptors but not human SLAM receptor.

PubMed

Feng, Na; Liu, Yuxiu; Wang, Jianzhong; Xu, Weiwei; Li, Tiansong; Wang, Tiecheng; Wang, Lei; Yu, Yicong; Wang, Hualei; Zhao, Yongkun; Yang, Songtao; Gao, Yuwei; Hu, Guixue; Xia, Xianzhu

2016-08-02

In 2008, an outbreak of canine distemper virus (CDV) infection in monkeys was reported in China. We isolated CDV strain (subsequently named Monkey-BJ01-DV) from lung tissue obtained from a rhesus monkey that died in this outbreak. We evaluated the ability of this virus on Vero cells expressing SLAM receptors from dog, monkey and human origin, and analyzed the H gene of Monkey-BJ01-DV with other strains. The Monkey-BJ01-DV isolate replicated to the highest titer on Vero cells expressing dog-origin SLAM (10(5.2±0.2) TCID50/ml) and monkey-origin SLAM (10(5.4±0.1) TCID50/ml), but achieved markedly lower titers on human-origin SLAM cells (10(3.3±0.3) TCID50/ml). Phylogenetic analysis of the full-length H gene showed that Monkey-BJ01-DV was highly related to other CDV strains obtained during recent CDV epidemics among species of the Canidae family in China, and these Monkey strains CDV (Monkey-BJ01-DV, CYN07-dV, Monkey-KM-01) possessed a number of amino acid specific substitutions (E276V, Q392R, D435Y and I542F) compared to the H protein of CDV epidemic in other animals at the same period. Our results suggested that the monkey origin-CDV-H protein could possess specific substitutions to adapt to the new host. Monkey-BJ01-DV can efficiently use monkey- and dog-origin SLAM to infect and replicate in host cells, but further adaptation may be required for efficient replication in host cells expressing the human SLAM receptor.

Infection and persistence of rhesus monkey rhadinovirus in immortalized B-cell lines.

PubMed

Bilello, John P; Lang, Sabine M; Wang, Fred; Aster, Jon C; Desrosiers, Ronald C

2006-04-01

Similar to its close relative human herpesvirus 8, rhesus monkey rhadinovirus (RRV) persists predominantly in B cells of its natural host. Rhesus monkey B-cell lines immortalized by the Epstein-Barr-related virus from rhesus monkeys (rhEBV) were used as targets for infection by RRV. These cultured B cells were susceptible to infection by RRV and continued to produce low titers of RRV for months of continuous culture. Infection by RRV did not detectably alter the growth rates of these B-cell lines when it was measured at standard or reduced serum concentrations. Depending on the cell line, 5 to 40% of the B cells stained positive for the RRV genome by fluorescence in situ hybridization (FISH). Most RRV-positive cells showed a fine punctate nuclear staining pattern consistent with latent infection, while a small minority of cells (0.2 to 1%) contained large, intensely staining nuclear foci consistent with productive, replicative infection. Greater than 90% of the cells were rhEBV genome positive in a pattern consistent with latent infection, and again only a small minority of cells showed a productive, replicative staining pattern. Dual, two-color FISH staining revealed coinfection of numerous cells with both RRV and rhEBV, but productive replication of RRV and rhEBV was always observed in separate cells, never in the same cell. Thus, productive replication of RRV is unlinked to that of rhEBV; factors that influence activation to productive replication act separately on RRV and rhEBV, even within the same cell. The percentage of B cells expressing green fluorescent protein (GFP) early after infection with a recombinant RRV containing a GFP reporter gene was dose dependent and at a low multiplicity of infection increased progressively over time until 14 to 17 days after infection. These results establish a naturalistic cell culture system for the study of infection and persistence by RRV in rhesus monkey B cells.

Persistent rhinitis and epithelial remodeling induced by cyclic ozone exposure in the nasal airways of infant monkeys

PubMed Central

Ballinger, Carol A.; Plopper, Charles G.; McDonald, Ruth J.; Bartolucci, Alfred A.; Postlethwait, Edward M.; Harkema, Jack R.

2011-01-01

Children chronically exposed to high levels of ozone (O3), the principal oxidant pollutant in photochemical smog, are more vulnerable to respiratory illness and infections. The specific factors underlying this differential susceptibility are unknown but may be related to air pollutant-induced nasal alterations during postnatal development that impair the normal physiological functions (e.g., filtration and mucociliary clearance) serving to protect the more distal airways from inhaled xenobiotics. In adult animal models, chronic ozone exposure is associated with adaptations leading to a decrease in airway injury. The purpose of our study was to determine whether cyclic ozone exposure induces persistent morphological and biochemical effects on the developing nasal airways of infant monkeys early in life. Infant (180-day-old) rhesus macaques were exposed to 5 consecutive days of O3 [0.5 parts per million (ppm), 8 h/day; “1-cycle”] or filtered air (FA) or 11 biweekly cycles of O3 (FA days 1–9; 0.5 ppm, 8 h/day on days 10–14; “11-cycle”). The left nasal passage was processed for light microscopy and morphometric analysis. Mucosal samples from the right nasal passage were processed for GSH, GSSG, ascorbate (AH2), and uric acid (UA) concentration. Eleven-cycle O3 induced persistent rhinitis, squamous metaplasia, and epithelial hyperplasia in the anterior nasal airways of infant monkeys, resulting in a 39% increase in the numeric density of epithelial cells. Eleven-cycle O3 also induced a 65% increase in GSH concentrations at this site. The persistence of epithelial hyperplasia was positively correlated with changes in GSH. These results indicate that early life ozone exposure causes persistent nasal epithelial alterations in infant monkeys and provide a potential mechanism for the increased susceptibility to respiratory illness exhibited by children in polluted environments. PMID:21131400

An outbreak of toxoplasmosis in squirrel monkeys (Saimiri sciureus) in South Korea.

PubMed

Oh, Hanseul; Eo, Kyung-Yeon; Gumber, Sanjeev; Hong, Jung Joo; Kim, C-Yoon; Lee, Hyun-Ho; Jung, Young-Mok; Kim, Jin; Whang, Gyu-Whan; Lee, Ji-Min; Yeo, Yong-Gu; Ryu, Bokyeong; Ryu, Ji-Sook; Lee, Seul-Kee; Kim, Ukjin; Kang, Sin-Geun; Park, Jae-Hak

2018-04-30

Toxoplasma gondii (T. gondii) is an intracellular protozoan parasite that can infect warm-blooded animals including humans. New World monkeys, such as squirrel monkeys, are more susceptible to T. gondii than Old World monkeys, often developing fatal disease. In this study, seven of thirteen dead squirrel monkeys at Seoul Grand Park were tested to find the cause of sudden death. The main histopathological findings included interstitial pneumonia, necrotizing hepatitis, and splenitis. Periodic acid-Schiff staining of liver, spleen, and lung revealed cyst structures consistent with bradyzoites. Amplification of the B1 gene was detected in the liver or spleen of all monkeys. Additionally, a restriction fragment length polymorphism assay and phylogenetic analysis of the GRA6 amplicon revealed a consistent clustering with the type II strain of T. gondii. This study is the first report of T. gondii infection of squirrel monkeys in Korea, and the first report of type II T. gondii based on GRA6 analysis in Korea. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Experimental Zika Virus Infection in the Pregnant Common Marmoset Induces Spontaneous Fetal Loss and Neurodevelopmental Abnormalities.

PubMed

Seferovic, Maxim; Martín, Claudia Sánchez-San; Tardif, Suzette D; Rutherford, Julienne; Castro, Eumenia C C; Li, Tony; Hodara, Vida L; Parodi, Laura M; Giavedoni, Luis; Layne-Colon, Donna; Tamhankar, Manasi; Yagi, Shigeo; Martyn, Calla; Reyes, Kevin; Suter, Melissa A; Aagaard, Kjersti M; Chiu, Charles Y; Patterson, Jean L

2018-05-01

During its most recent outbreak across the Americas, Zika virus (ZIKV) was surprisingly shown to cause fetal loss and congenital malformations in acutely and chronically infected pregnant women. However, understanding the underlying pathogenesis of ZIKV congenital disease has been hampered by a lack of relevant in vivo experimental models. Here we present a candidate New World monkey model of ZIKV infection in pregnant marmosets that faithfully recapitulates human disease. ZIKV inoculation at the human-equivalent of early gestation caused an asymptomatic seroconversion, induction of type I/II interferon-associated genes and proinflammatory cytokines, and persistent viremia and viruria. Spontaneous pregnancy loss was observed 16-18 days post-infection, with extensive active placental viral replication and fetal neurocellular disorganization similar to that seen in humans. These findings underscore the key role of the placenta as a conduit for fetal infection, and demonstrate the utility of marmosets as a highly relevant model for studying congenital ZIKV disease and pregnancy loss.

Evaluation of an intragastric challenge model for Shigella dysenteriae 1 in rhesus monkeys (Macaca mulatta) for the pre-clinical assessment of Shigella vaccine formulations

PubMed Central

Islam, Dilara; Ruamsap, Nattaya; Khantapura, Patchariya; Aksomboon, Ajchara; Srijan, Apichai; Wongstitwilairoong, Boonchai; Bodhidatta, Ladaporn; Gettayacamin, Montip; Venkatesan, Malabi M; Mason, Carl J

2014-01-01

Shigellosis is a worldwide disease, characterized by abdominal pain, fever, vomiting, and the passage of blood- and mucus-streaked stools. Rhesus monkeys and other primates are the only animals that are naturally susceptible to shigellosis. A suitable animal model is required for the pre-clinical evaluation of vaccines candidates. In this study, the minimal dose of Shigella dysenteriae1 1617 strain required to produce dysentery in four of five (80% attack rate) monkeys using an escalating dose range for three groups [2 × 108, 2 × 109 and 2 × 1010 colony forming unit (CFU)] was determined. In addition, the monkeys were re-infected. The identified optimal challenge dose was 2 × 109 CFU; this dose elicited 60% protection in monkeys when they were re-challenged with a one log higher dose (2 × 1010 CFU). The challenge dose, 2 × 1010 CFU, produced severe dysentery in all monkeys, with one monkey dying within 24 h, elicited 100% protection when re-challenged with the same dose. All monkeys exhibited immune responses. This study concludes that the rhesus monkey model closely mimics the disease and immune response seen in humans and is a suitable animal model for the pre-clinical evaluation of Shigella vaccine candidates. Prior infection with the 1617 strain can protect monkeys against subsequent re-challenges with homologous strains. PMID:24028276

Safety, Pharmacokinetic, and Efficacy Studies of Oral DB868 in a First Stage Vervet Monkey Model of Human African Trypanosomiasis

PubMed Central

Thuita, John K.; Wolf, Kristina K.; Murilla, Grace A.; Liu, Qiang; Mutuku, James N.; Chen, Yao; Bridges, Arlene S.; Mdachi, Raymond E.; Ismail, Mohamed A.; Ching, Shelley; Boykin, David W.; Hall, James Edwin; Tidwell, Richard R.; Paine, Mary F.; Brun, Reto; Wang, Michael Zhuo

2013-01-01

There are no oral drugs for human African trypanosomiasis (HAT, sleeping sickness). A successful oral drug would have the potential to reduce or eliminate the need for patient hospitalization, thus reducing healthcare costs of HAT. The development of oral medications is a key objective of the Consortium for Parasitic Drug Development (CPDD). In this study, we investigated the safety, pharmacokinetics, and efficacy of a new orally administered CPDD diamidine prodrug, 2,5-bis[5-(N-methoxyamidino)-2-pyridyl]furan (DB868; CPD-007-10), in the vervet monkey model of first stage HAT. DB868 was well tolerated at a dose up to 30 mg/kg/day for 10 days, a cumulative dose of 300 mg/kg. Mean plasma levels of biomarkers indicative of liver injury (alanine aminotransferase, aspartate aminotransferase) were not significantly altered by drug administration. In addition, no kidney-mediated alterations in creatinine and urea concentrations were detected. Pharmacokinetic analysis of plasma confirmed that DB868 was orally available and was converted to the active compound DB829 in both uninfected and infected monkeys. Treatment of infected monkeys with DB868 began 7 days post-infection. In the infected monkeys, DB829 attained a median Cmax (dosing regimen) that was 12-fold (3 mg/kg/day for 7 days), 15-fold (10 mg/kg/day for 7 days), and 31-fold (20 mg/kg/day for 5 days) greater than the IC50 (14 nmol/L) against T. b. rhodesiense STIB900. DB868 cured all infected monkeys, even at the lowest dose tested. In conclusion, oral DB868 cured monkeys with first stage HAT at a cumulative dose 14-fold lower than the maximum tolerated dose and should be considered a lead preclinical candidate in efforts to develop a safe, short course (5–7 days), oral regimen for first stage HAT. PMID:23755309

Arteriviruses, Pegiviruses, and Lentiviruses Are Common among Wild African Monkeys.

PubMed

Bailey, Adam L; Lauck, Michael; Ghai, Ria R; Nelson, Chase W; Heimbruch, Katelyn; Hughes, Austin L; Goldberg, Tony L; Kuhn, Jens H; Jasinska, Anna J; Freimer, Nelson B; Apetrei, Cristian; O'Connor, David H

2016-08-01

Nonhuman primates (NHPs) are a historically important source of zoonotic viruses and are a gold-standard model for research on many human pathogens. However, with the exception of simian immunodeficiency virus (SIV) (family Retroviridae), the blood-borne viruses harbored by these animals in the wild remain incompletely characterized. Here, we report the discovery and characterization of two novel simian pegiviruses (family Flaviviridae) and two novel simian arteriviruses (family Arteriviridae) in wild African green monkeys from Zambia (malbroucks [Chlorocebus cynosuros]) and South Africa (vervet monkeys [Chlorocebus pygerythrus]). We examine several aspects of infection, including viral load, genetic diversity, evolution, and geographic distribution, as well as host factors such as age, sex, and plasma cytokines. In combination with previous efforts to characterize blood-borne RNA viruses in wild primates across sub-Saharan Africa, these discoveries demonstrate that in addition to SIV, simian pegiviruses and simian arteriviruses are widespread and prevalent among many African cercopithecoid (i.e., Old World) monkeys. Primates are an important source of viruses that infect humans and serve as an important laboratory model of human virus infection. Here, we discover two new viruses in African green monkeys from Zambia and South Africa. In combination with previous virus discovery efforts, this finding suggests that these virus types are widespread among African monkeys. Our analysis suggests that one of these virus types, the simian arteriviruses, may have the potential to jump between different primate species and cause disease. In contrast, the other virus type, the pegiviruses, are thought to reduce the disease caused by human immunodeficiency virus (HIV) in humans. However, we did not observe a similar protective effect in SIV-infected African monkeys coinfected with pegiviruses, possibly because SIV causes little to no disease in these hosts. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Arteriviruses, Pegiviruses, and Lentiviruses Are Common among Wild African Monkeys

PubMed Central

Bailey, Adam L.; Lauck, Michael; Ghai, Ria R.; Nelson, Chase W.; Heimbruch, Katelyn; Hughes, Austin L.; Goldberg, Tony L.; Jasinska, Anna J.; Freimer, Nelson B.; Apetrei, Cristian

2016-01-01

ABSTRACT Nonhuman primates (NHPs) are a historically important source of zoonotic viruses and are a gold-standard model for research on many human pathogens. However, with the exception of simian immunodeficiency virus (SIV) (family Retroviridae), the blood-borne viruses harbored by these animals in the wild remain incompletely characterized. Here, we report the discovery and characterization of two novel simian pegiviruses (family Flaviviridae) and two novel simian arteriviruses (family Arteriviridae) in wild African green monkeys from Zambia (malbroucks [Chlorocebus cynosuros]) and South Africa (vervet monkeys [Chlorocebus pygerythrus]). We examine several aspects of infection, including viral load, genetic diversity, evolution, and geographic distribution, as well as host factors such as age, sex, and plasma cytokines. In combination with previous efforts to characterize blood-borne RNA viruses in wild primates across sub-Saharan Africa, these discoveries demonstrate that in addition to SIV, simian pegiviruses and simian arteriviruses are widespread and prevalent among many African cercopithecoid (i.e., Old World) monkeys. IMPORTANCE Primates are an important source of viruses that infect humans and serve as an important laboratory model of human virus infection. Here, we discover two new viruses in African green monkeys from Zambia and South Africa. In combination with previous virus discovery efforts, this finding suggests that these virus types are widespread among African monkeys. Our analysis suggests that one of these virus types, the simian arteriviruses, may have the potential to jump between different primate species and cause disease. In contrast, the other virus type, the pegiviruses, are thought to reduce the disease caused by human immunodeficiency virus (HIV) in humans. However, we did not observe a similar protective effect in SIV-infected African monkeys coinfected with pegiviruses, possibly because SIV causes little to no disease in these hosts. PMID:27170760

A brief history of the discovery of natural simian immunodeficiency virus (SIV) infections in captive sooty mangabey monkeys.

PubMed

Gormus, Bobby J; Martin, Louis N; Baskin, Gary B

2004-01-01

Experimental leprosy studies using Mycobacterium leprae inoculum isolated from a sooty mangabey monkey (SMM) resulted in the accidental discovery that SMM's asymptomatically carry simian immunodeficiency virus (SIV) that is pathogenic in macaques. We showed that the SMM virus, SIVDelta, was antigenically related to SIVmac, which had been identified in macaques, and to the human immunodeficiency virus (HIV). Similar asymptomatic natural SIV infections had been reported in African green monkeys (AGM). Our results together with observations of others led us to propose that both SIVmac and SIVDelta originated in SMM and that SIV emerged in humans as a result of early African nonhuman primate SIV trans-species infections in humans.

Immunophenotypic characterization of the cutaneous exanthem of SIV-infected rhesus monkeys. Apposition of degenerative Langerhans cells and cytotoxic lymphocytes during the development of acquired immunodeficiency syndrome.

PubMed Central

Ringler, D. J.; Hancock, W. W.; King, N. W.; Letvin, N. L.; Daniel, M. D.; Desrosiers, R. C.; Murphy, G. F.

1987-01-01

A T-cell tropic retrovirus, simian immunodeficiency virus (SIV), has recently been isolated from immunodeficient rhesus monkeys. This virus has remarkable similarities to human immunodeficiency virus (HIV), the etiologic agent of acquired immunodeficiency syndrome. Subsequent studies of simian infection with SIV have shown it to be a relevant animal model for studying the pathogenesis of AIDS in man. In both HIV-infected humans and SIV-infected monkeys, a cutaneous maculopapular eruption has been described. To date, the pathogenesis and possible relationship of these exanthema to the evolution of systemic immunosuppression have remained obscure. In this study, the mononuclear cell infiltrates that characterize skin rashes of SIV-infected rhesus monkeys were found to be composed predominantly of cells with phenotypic characteristics of cytotoxic/suppressor (T8+) lymphocytes and natural killer cells. Many of these cells expressed membrane-bound interleukin-2 receptor molecules. Double labeling and immunoelectron microscopy revealed these cells in direct contact with degenerative Langerhans cells within the epidermis and dermis. These observations suggest that the cutaneous rash associated with SIV infection may be the consequence of target cell injury of Langerhans cells by effector cells with cytotoxic potential. Images Figure 1 Figure 2 Figure 3 PMID:3030113

Experimental Cross-Species Infection of Common Marmosets by Titi Monkey Adenovirus

PubMed Central

Chen, Eunice C.; Liu, Maria; Brasky, Kathleen M.; Lanford, Robert E.; Kelly, Kristi R.; Bales, Karen L.; Schnurr, David P.; Canfield, Don R.; Patterson, Jean L.; Chiu, Charles Y.

2013-01-01

Adenoviruses are DNA viruses that infect a number of vertebrate hosts and are associated with both sporadic and epidemic disease in humans. We previously identified a novel adenovirus, titi monkey adenovirus (TMAdV), as the cause of a fulminant pneumonia outbreak in a colony of titi monkeys (Callicebus cupreus) at a national primate center in 2009. Serological evidence of infection by TMAdV was also found in a human researcher at the facility and household family member, raising concerns for potential cross-species transmission of the virus. Here we present experimental evidence of cross-species TMAdV infection in common marmosets (Callithrix jacchus). Nasal inoculation of a cell cultured-adapted TMAdV strain into three marmosets produced an acute, mild respiratory illness characterized by low-grade fever, reduced activity, anorexia, and sneezing. An increase in virus-specific neutralization antibody titers accompanied the development of clinical signs. Although serially collected nasal swabs were positive for TMAdV for at least 8 days, all 3 infected marmosets spontaneously recovered by day 12 post-inoculation, and persistence of the virus in tissues could not be established. Thus, the pathogenesis of experimental inoculation of TMAdV in common marmosets resembled the mild, self-limiting respiratory infection typically seen in immunocompetent human hosts rather than the rapidly progressive, fatal pneumonia observed in 19 of 23 titi monkeys during the prior 2009 outbreak. These findings further establish the potential for adenovirus cross-species transmission and provide the basis for development of a monkey model useful for assessing the zoonotic potential of adenoviruses. PMID:23894316

Canine distemper outbreak in rhesus monkeys, China.

PubMed

Qiu, Wei; Zheng, Ying; Zhang, Shoufeng; Fan, Quanshui; Liu, Hua; Zhang, Fuqiang; Wang, Wei; Liao, Guoyang; Hu, Rongliang

2011-08-01

Since 2006, canine distemper outbreaks have occurred in rhesus monkeys at a breeding farm in Guangxi, People's Republic of China. Approximately 10,000 animals were infected (25%-60% disease incidence); 5%-30% of infected animals died. The epidemic was controlled by vaccination. Amino acid sequence analysis of the virus indicated a unique strain.

Chronic preclinical safety evaluation of EPO-018B, a pegylated peptidic erythropoiesis-stimulating agent in monkeys and rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gong, Xue-Lian; Gu, Xiao-Lei

EPO-018B, a synthetic peptide-based erythropoiesis stimulating agent (ESA), is mainly designed for treatment of anemia caused by chronic renal failure and chemotherapy against cancer. It overcomes the deficiencies of currently approved ESA, including the frequent administration of temperature-sensitive recombinant protein and anti-EPO antibody-mediated pure red cell aplasia (PRCA). This study was designed to evaluate the potential chronic toxicity of EPO-018B. Subcutaneous administration doses were designed as 0, 0.2, 1 and 10 mg/kg for six months for 160 rats (20/gender/group) and 0, 0.3, 3 and 20 mg/kg for nine months for 32 monkeys (4/gender/group) once every three weeks. The vehicles receivedmore » the same volume of physiological saline injection. All animals survived to the scheduled necropsies after six weeks (for rats) and fourteen weeks (for monkeys) recovery period, except for the two high-dose female rats and two high-dose male monkeys, which were considered related to the increased RBCs, chronic blood hyperviscosity and chronic cardiac injury. EPO-018B is supposed to be subcutaneously injected once every month and the intended human therapeutic dose is 0.025 mg/kg. The study findings at 0.2 mg/kg for rats and 0.3 mg/kg for monkeys were considered to be the study NOAEL (the no observed adverse effect level), which were more than ten times the intended human therapeutic dose. Higher doses caused adverse effects related to the liver toxicity, cardiotoxicity, appearance of neutralizing antibodies of EPO-018B and the decrease of serum glucose and cholesterol. Most treatment-induced effects were reversible or revealed ongoing recovery upon the discontinuation of treatment. The sequelae occurred in rats and monkeys were considered secondary to exaggerated pharmacology and would less likely occur in the intended patient population. As to the differences between human beings and animals, the safety of EPO-018B need to be further confirmed in the future clinical studies. - Highlights: • EPO-018B is a newly developed synthetic peptide-based ESA. • The evaluation contained studies of 6 months in rats and 9 months in monkeys. • The safety studies provided further evidences in future clinical trials. • Most toxic effects were reversible and need more evidences in clinical studies.« less

A quantitative approach to developing Parkinsonian monkeys (Macaca fascicularis) with intracerebroventricular 1-methyl-4-phenylpyridinium injections.

PubMed

Li, Hao; Lei, Xiaoguang; Huang, Baihui; Rizak, Joshua D; Yang, Lichuan; Yang, Shangchuan; Wu, Jing; Lü, Longbao; Wang, Jianhong; Yan, Ting; Li, Hongwei; Wang, Zhengbo; Hu, Yingzhou; Le, Weidong; Deng, Xingli; Li, Jiali; Xu, Lin; Zhang, Baorong; Hu, Xintian

2015-08-15

Non-human primate Parkinson's disease (PD) models are essential for PD research. The most extensively used PD monkey models are induced with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). However, the modeling processes of developing PD monkeys cannot be quantitatively controlled with MPTP. Therefore, a new approach to quantitatively develop chronic PD monkey models will help to advance the goals of "reduction, replacement and refinement" in animal experiments. A novel chronic PD monkey models was reported using the intracerebroventricular administration of 1-methyl-4-phenylpyridinium (MPP(+)) in Cynomolgus monkeys (Macaca fascicularis). This approach successfully produced stable and consistent PD monkeys with typical motor symptoms and pathological changes. More importantly, a sigmoidal relationship (Y=8.15801e(-0.245/x); R=0.73) was discovered between PD score (Y) and cumulative dose of MPP(+) (X). This relationship was then used to develop two additional PD monkeys under a specific time schedule (4 weeks), with planned PD scores (7) by controlling the dose and frequency of the MPP(+) administration as an independent validation of the formula. We developed Parkinsonian monkeys within controlled time frames by regulating the accumulated dose of MPP(+) intracerebroventricular administered, while limiting side effects often witnessed in models developed with the peripheral administration of MPTP, makes this model highly suitable for treatment development. This novel approach provides an edge in evaluating the mechanisms of PD pathology associated with environmental toxins and novel treatment approaches as the formula developed provides a "map" to control and predict the modeling processes. Copyright © 2015 Elsevier B.V. All rights reserved.

STUDIES ON YELLOW FEVER IN SOUTH AMERICA

PubMed Central

Davis, Nelson C.; Shannon, Raymond C.

1929-01-01

1. Batches of Aëdes (Stegomyia) aegypti which had fed on monkeys in the early febrile stage of yellow fever and which has subsequently passed the usually accepted extrinsic incubation period for the virus, failed to transmit the disease to normal monkeys in approximately fifty per cent of the experiments. During the same time over eighty per cent of blood transfers were successful. 2. The monkeys which failed to show fever following mosquito bites later proved resistant to the inoculation of blood or tissues containing virus. 3. The incubation, or afebrile, period in monkeys following the bites of infected mosquitoes varied from less than twenty-four hours to fifteen days. It averaged somewhat longer in non-fatal than in fatal infections. PMID:19869665

Evaluation of a killed Rocky Mountain spotted fever vaccine in cynomolgus monkeys.

PubMed Central

Gonder, J C; Kenyon, R H; Pedersen, C E

1979-01-01

A nonhuman primate model of Rocky Mountain spotted fever infection was developed in cynomolgus monkeys (Macaca fascicularis) infected by the subcutaneous route or by aerosol. Clinical responses, hematology and serum chemistry values, and pathological findings were similar to those found in humans ill with Rocky Mountain spotted fever. The clinical model was then used to test the efficacy of a killed Rocky Mountain spotted fever vaccine grown in chicken embryo cells. Monkeys were immunized with varying dilutions of the vaccine with a two-dose schedule and then challenged at 2 months with virulent Rickettsia rickettsii by the subcutaneous route or by aerosol. The undiluted vaccine totally protected monkeys against both challenges, even at extremely high doses. PMID:120877

Vesicoureteral reflux in the primate IV: does reflux harm the kidney

DOE Office of Scientific and Technical Information (OSTI.GOV)

Roberts, J.A.; Fischman, N.H.; Thomas, R.

1982-09-01

It has been said that vesicoureteral reflux causes renal scarring because of intrarenal reflux. We studied reflux in the monkey because of its similarity to man, especially in regard to the incidence of vesicoureteral reflux and chronic pyelonephritis. High pressure moderate grade reflux was produced and renal function followed by means of quantitative renal camera studies using /sup 131/I hippuran. There was no change in renal function from sterile reflux even when intrarenal reflux occurred. When, however, infection was introduced, renal function decreased. We concluded that sterile moderate vesicoureteral or intrarenal reflux does not harm the kidney.

Immunization with Recombinant Helicobacter pylori Urease in Specific-Pathogen-Free Rhesus Monkeys (Macaca mulatta)

PubMed Central

Solnick, Jay V.; Canfield, Don R.; Hansen, Lori M.; Torabian, Sima Z.

2000-01-01

Immunization with urease can protect mice from challenge with Helicobacter pylori, though results vary depending on the particular vaccine, challenge strain, and method of evaluation. Unlike mice, rhesus monkeys are naturally colonized with H. pylori and so may provide a better estimate of vaccine efficacy in humans. The purpose of this study was to examine the effectiveness of H. pylori urease as a vaccine in specific-pathogen (H. pylori)-free rhesus monkeys. Monkeys raised from birth and documented to be free of H. pylori were vaccinated with orogastric (n = 4) or intramuscular (n = 5) urease. Two control monkeys were sham vaccinated. All monkeys were challenged with a rhesus monkey-derived strain of H. pylori, and the effects of vaccination were evaluated by use of quantitative cultures of gastric tissue, histology, and measurement of serum immunoglobulin G (IgG) and salivary IgA. Despite a humoral immune response, all monkeys were infected after H. pylori challenge, and there were no differences in the density of colonization. Immunization with urease therefore does not fully protect against challenge with H. pylori. An effective vaccine to prevent H. pylori infection will require different or more likely additional antigens, as well as improvements in the stimulation of the host immune response. PMID:10768944

Molecular characterization of Blastocystis isolates from children and rhesus monkeys in Kathmandu, Nepal.

PubMed

Yoshikawa, Hisao; Wu, Zhiliang; Pandey, Kishor; Pandey, Basu Dev; Sherchand, Jeevan Bahadur; Yanagi, Tetsuo; Kanbara, Hiroji

2009-03-23

To investigate the possible transmission of Blastocystis organisms between local rhesus monkeys and children in Kathmandu, Nepal, we compared the subtype (ST) and sequence of Blastocystis isolates from children with gastrointestinal symptoms and local rhesus monkeys. Twenty and 10 Blastocystis isolates were established from 82 and 10 fecal samples obtained from children and monkeys, respectively. Subtype analysis with seven sequence-tagged site (STS) primers indicated that the prevalence of Blastocystis sp. ST1, ST2 and ST3 was 20%, 20% and 60% in the child isolates, respectively. In contrast to human isolates, ST3 was not found in monkey isolates and the prevalence of ST1 and ST2 was 50% and 70%, respectively, including three mixed STs1 and 2 and one isolate not amplified by any STS primers, respectively. Since Blastocystis sp. ST2 has been reported as the most dominant genotype in the survey of Blastocystis infection among the various monkey species, sequence comparison of the 150bp variable region of the small subunit rRNA (SSU rRNA) gene was conducted among ST2 isolates of humans and monkeys. Sequence alignment of 24 clones developed from ST2 isolates of 4 humans and 4 monkeys showed three distinct subgroups, defined as ST2A, ST2B and ST2C. These three subgroups were shared between the child and monkey isolates. These results suggest that the local rhesus monkeys are a possible source of Blastocystis sp. ST2 infection of humans in Kathmandu.

Evaluation of an intragastric challenge model for Shigella dysenteriae 1 in rhesus monkeys (Macaca mulatta) for the pre-clinical assessment of Shigella vaccine formulations.

PubMed

Islam, Dilara; Ruamsap, Nattaya; Khantapura, Patchariya; Aksomboon, Ajchara; Srijan, Apichai; Wongstitwilairoong, Boonchai; Bodhidatta, Ladaporn; Gettayacamin, Montip; Venkatesan, Malabi M; Mason, Carl J

2014-06-01

Shigellosis is a worldwide disease, characterized by abdominal pain, fever, vomiting, and the passage of blood- and mucus-streaked stools. Rhesus monkeys and other primates are the only animals that are naturally susceptible to shigellosis. A suitable animal model is required for the pre-clinical evaluation of vaccines candidates. In this study, the minimal dose of Shigella dysenteriae1 1617 strain required to produce dysentery in four of five (80% attack rate) monkeys using an escalating dose range for three groups [2 × 10(8) , 2 × 10(9) and 2 × 10(10) colony forming unit (CFU)] was determined. In addition, the monkeys were re-infected. The identified optimal challenge dose was 2 × 10(9) CFU; this dose elicited 60% protection in monkeys when they were re-challenged with a one log higher dose (2 × 10(10) CFU). The challenge dose, 2 × 10(10) CFU, produced severe dysentery in all monkeys, with one monkey dying within 24 h, elicited 100% protection when re-challenged with the same dose. All monkeys exhibited immune responses. This study concludes that the rhesus monkey model closely mimics the disease and immune response seen in humans and is a suitable animal model for the pre-clinical evaluation of Shigella vaccine candidates. Prior infection with the 1617 strain can protect monkeys against subsequent re-challenges with homologous strains. © 2013 The Authors. APMIS published by John Wiley & Sons Ltd.

Canine Distemper Outbreak in Rhesus Monkeys, China

PubMed Central

Qiu, Wei; Zheng, Ying; Zhang, Shoufeng; Fan, Quanshui; Liu, Hua; Zhang, Fuqiang; Wang, Wei; Liao, Guoyang

2011-01-01

Since 2006, canine distemper outbreaks have occurred in rhesus monkeys at a breeding farm in Guangxi, People’s Republic of China. Approximately 10,000 animals were infected (25%–60% disease incidence); 5%–30% of infected animals died. The epidemic was controlled by vaccination. Amino acid sequence analysis of the virus indicated a unique strain. PMID:21801646

Lung fluke (Paragonimus africanus) infects Nigerian red-capped mangabeys and causes respiratory disease

PubMed Central

Friant, Sagan; Brown, Kelsey; Saari, Mason T.; Segel, Nicholas H.; Slezak, Julia; Goldberg, Tony L.

2015-01-01

Eggs of the lung fluke genus Paragonimus were detected in red-capped mangabeys (Cercocebus torquatus) in Nigeria. We assess the role of these primates as potential sylvatic hosts and the clinical effects of the parasite on monkeys. DNA sequenced from eggs in feces were 100% identical in the ITS2 region to Paragonimus africanus sequences from humans in Cameroon. Paragonimus-positive monkeys coughed more than uninfected monkeys. Experimental de-worming led to reduction in parasite intensity and a corresponding reduction of coughing to baseline levels in infected monkeys. This report provides the first evidence of Paragonimus sp. in C. torquatus, of P. africanus in Nigerian wildlife, and the first molecular evidence of the parasite in African wildlife. Coughing, sometimes interpreted as a communication behavior in primates, can actually indicate infection with lung parasites. Observations of coughing in primates may, in turn, provide a useful mechanism for surveillance of Paragonimus spp, which are re-emerging human pathogens, in wildlife reservoirs. PMID:26543803

Lung fluke (Paragonimus africanus) infects Nigerian red-capped mangabeys and causes respiratory disease.

PubMed

Friant, Sagan; Brown, Kelsey; Saari, Mason T; Segel, Nicholas H; Slezak, Julia; Goldberg, Tony L

2015-12-01

Eggs of the lung fluke genus Paragonimus were detected in red-capped mangabeys (Cercocebus torquatus) in Nigeria. We assess the role of these primates as potential sylvatic hosts and the clinical effects of the parasite on monkeys. DNA sequenced from eggs in feces were 100% identical in the ITS2 region to Paragonimus africanus sequences from humans in Cameroon. Paragonimus-positive monkeys coughed more than uninfected monkeys. Experimental de-worming led to reduction in parasite intensity and a corresponding reduction of coughing to baseline levels in infected monkeys. This report provides the first evidence of Paragonimus sp. in C. torquatus, of P. africanus in Nigerian wildlife, and the first molecular evidence of the parasite in African wildlife. Coughing, sometimes interpreted as a communication behavior in primates, can actually indicate infection with lung parasites. Observations of coughing in primates may, in turn, provide a useful mechanism for surveillance of Paragonimus spp, which are re-emerging human pathogens, in wildlife reservoirs.

An alert of Mycobacterium tuberculosis infection of rhesus macaques in a wild zoo in China.

PubMed

Gong, Wenping; Yang, Yourong; Luo, Yi; Li, Ning; Bai, Xuejuan; Liu, Yinping; Zhang, Junxian; Chen, Ming; Zhang, Chenglin; Wu, Xueqiong

2017-10-30

Mycobacterium tuberculosis, the pathogen that causes tuberculosis (TB), is becoming increasingly recognized as an important cause of fatal chronic illnesses in China. In this study, we report an infectious disease among 84 rhesus macaques at a Chinese zoo. Their clinical signs and symptoms were very similar with the manifestations of TB in humans. To determine the potential pathogens of this outbreak, many methods were used. First, tuberculin skin tests showed that none of the monkeys displayed significant skin reactions. Subsequently, the sera were tested for specific antibody IgG; 29 (34.5%) and 39 (46.4%) blood samples tested positive by TB-IgG and TB-DOT, respectively. Radiographic examination showed characteristic imageology changes in 14 (16.7%) monkeys. One individual determined as positive by the above three methods was euthanized, and histopathological analysis demonstrated typical granulomas and caseous necrosis in the lung, liver, spleen, and intestine. Furthermore, the pathogenic mycobacteria were isolated from lung lobe, cultured on acidic Lowenstein-Jensen culture medium, and identified as M. tuberculosis by real-time PCR and DNA sequencing. Nevertheless, the origin of the infection remained unknown. These findings emphasize the need to strengthen the management and training of staff, especially those working at animal shelters.

An alert of Mycobacterium tuberculosis infection of rhesus macaques in a wild zoo in China

PubMed Central

Gong, Wenping; Yang, Yourong; Luo, Yi; Li, Ning; Bai, Xuejuan; Liu, Yinping; Zhang, Junxian; Chen, Ming; Zhang, Chenglin; Wu, Xueqiong

2017-01-01

Mycobacterium tuberculosis, the pathogen that causes tuberculosis (TB), is becoming increasingly recognized as an important cause of fatal chronic illnesses in China. In this study, we report an infectious disease among 84 rhesus macaques at a Chinese zoo. Their clinical signs and symptoms were very similar with the manifestations of TB in humans. To determine the potential pathogens of this outbreak, many methods were used. First, tuberculin skin tests showed that none of the monkeys displayed significant skin reactions. Subsequently, the sera were tested for specific antibody IgG; 29 (34.5%) and 39 (46.4%) blood samples tested positive by TB-IgG and TB-DOT, respectively. Radiographic examination showed characteristic imageology changes in 14 (16.7%) monkeys. One individual determined as positive by the above three methods was euthanized, and histopathological analysis demonstrated typical granulomas and caseous necrosis in the lung, liver, spleen, and intestine. Furthermore, the pathogenic mycobacteria were isolated from lung lobe, cultured on acidic Lowenstein-Jensen culture medium, and identified as M. tuberculosis by real-time PCR and DNA sequencing. Nevertheless, the origin of the infection remained unknown. These findings emphasize the need to strengthen the management and training of staff, especially those working at animal shelters. PMID:28659540

Seroprevalence of Zika Virus in Wild African Green Monkeys and Baboons.

PubMed

Buechler, Connor R; Bailey, Adam L; Weiler, Andrea M; Barry, Gabrielle L; Breitbach, Meghan E; Stewart, Laurel M; Jasinska, Anna J; Freimer, Nelson B; Apetrei, Cristian; Phillips-Conroy, Jane E; Jolly, Clifford J; Rogers, Jeffrey; Friedrich, Thomas C; O'Connor, David H

2017-01-01

Zika virus (ZIKV) has recently spread through the Americas and has been associated with a range of health effects, including birth defects in children born to women infected during pregnancy. Although the natural reservoir of ZIKV remains poorly defined, the virus was first identified in a captive "sentinel" macaque monkey in Africa in 1947. However, the virus has not been reported in humans or nonhuman primates (NHPs) in Africa outside Gabon in over a decade. Here, we examine ZIKV infection in 239 wild baboons and African green monkeys from South Africa, the Gambia, Tanzania, and Zambia using combinations of unbiased deep sequencing, quantitative reverse transcription-PCR (qRT-PCR), and an antibody capture assay that we optimized using serum collected from captive macaque monkeys exposed to ZIKV, dengue virus, and yellow fever virus. While we did not find evidence of active ZIKV infection in wild NHPs in Africa, we found variable ZIKV seropositivity of up to 16% in some of the NHP populations sampled. We anticipate that these results and the methodology described within will help in continued efforts to determine the prevalence, natural reservoir, and transmission dynamics of ZIKV in Africa and elsewhere. IMPORTANCE Zika virus (ZIKV) is a mosquito-borne virus originally discovered in a captive monkey living in the Zika Forest of Uganda, Africa, in 1947. Recently, an outbreak in South America has shown that ZIKV infection can cause myriad health effects, including birth defects in the children of women infected during pregnancy. Here, we sought to investigate ZIKV infection in wild African primates to better understand its emergence and spread, looking for evidence of active or prior infection. Our results suggest that up to 16% of some populations of nonhuman primate were, at some point, exposed to ZIKV. We anticipate that this study will be useful for future studies that examine the spread of infections from wild animals to humans in general and those studying ZIKV in primates in particular.

THE TRANSMISSION OF YELLOW FEVER

PubMed Central

Davis, Nelson C.

1930-01-01

1. Saimiri sciureus has been infected with yellow fever virus, both by the inoculation of infectious blood and by the bites of infective mosquitoes. Some of the monkeys have died, showing lesions, including hepatic necrosis, suggesting yellow fever as seen in human beings and in rhesus monkeys. Virus has been transferred back to M. rhesus from infected Saimiri both by blood inoculation and by mosquito bites. The virus undoubtedly has been maintained through four direct passages in Saimiri. Reinoculations of infectious material into recovered monkeys have not given rise to invasion of the blood stream by virus. Sera from recovered animals have protected M. rhesus against the inoculation of virus. 2. It has been possible to pass the virus to and from Ateleus ater by the injection of blood or liver and by the bites of mosquitoes. The livers from two infected animals have shown no necrosis. The serum from one recovered monkey proved to be protective for M. rhesus. 3. Only three out of twelve Lagothrix lagotricha have reacted to yellow fever virus by a rise in temperature. Probably none have died as a result of the infection. In only one instance has the virus been transferred back to M. rhesus. The sera of recovered animals have had a protective action against yellow fever virus. PMID:19869721

Pathogenesis of Rift Valley Fever in Rhesus Monkeys: Role of Interferon Response

DTIC Science & Technology

1990-01-01

hemorrhagic fever characterized by epistaxis, petechial to purpuric cutaneous lesions, anorexia, and vomiting prior to death. The 14 remaining monkeys survived...DMI, FILE Copy Arch Virol (1990) 110: 195-212 Amhivesirology ( by Springer-Verlag 1990 00 N Pathogenesis of Rift Valley fever in rhesus monkeys: (NI...inoculated intravenously with Rift Valley fever (RVF) virus presented clinical disease syndromes similar to human cases of RVF. All 17 infected monkeys

Quantitative Comparison of Active and Latent Tuberculosis in the Cynomolgus Macaque Model▿ †

PubMed Central

Lin, Philana Ling; Rodgers, Mark; Smith, Le'kneitah; Bigbee, Matthew; Myers, Amy; Bigbee, Carolyn; Chiosea, Ion; Capuano, Saverio V.; Fuhrman, Carl; Klein, Edwin; Flynn, JoAnne L.

2009-01-01

We previously described that low-dose Mycobacterium tuberculosis infection in cynomolgus macaques results in a spectrum of disease similar to that of human infection: primary disease, latent infection, and reactivation tuberculosis (S. V. Capuano III, D. A. Croix, S. Pawar, A. Zinovik, A. Myers, P. L. Lin, S. Bissel, C. Fuhrman, E. Klein, and J. L. Flynn, Infect. Immun. 71:5831-5844, 2003). This is the only established model of latent infection, and it provides a unique opportunity to understand host and pathogen differences across of range of disease states. Here, we provide a more extensive and detailed characterization of the gross pathology, microscopic histopathology, and immunologic characteristics of monkeys in each clinical disease category. The data underscore the similarities between human and nonhuman primate M. tuberculosis infection. Furthermore, we describe novel methods of quantifying gross pathology and bacterial burden that distinguish between active disease and latent infection, and we extend the usefulness of this model for comparative studies. Early in infection, an abnormal chest X ray, M. tuberculosis growth by gastric aspirate, and increased mycobacterium-specific gamma interferon (IFN-γ) in peripheral blood mononuclear cells (PBMCs) and bronchoalveolar lavage (BAL) cells were associated with the development of active disease. At necropsy, disease was quantified with respect to pathology and bacterial numbers. Microscopically, a spectrum of granuloma types are seen and differ with disease type. At necropsy, monkeys with active disease had more lung T cells and more IFN-γ from PBMC, BAL, and mediastinal lymph nodes than monkeys with latent infection. Finally, we have observed a spectrum of disease not only in monkeys with active disease but also in those with latent infection that provides insight into human latent tuberculosis. PMID:19620341

Inactivated simian immunodeficiency virus vaccine failed to protect rhesus macaques from intravenous or genital mucosal infection but delayed disease in intravenously exposed animals

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sutjipto, S.; Pedersen, N.C.; Miller, C.J.

1990-05-01

Eight rhesus macaques were immunized four times over a period of 8 months with a psoralen-UV-light-inactivated whole simian immunodeficiency virus vaccine adjuvanted with threonyl muramyl dipeptide. Eight unvaccinated control animals received adjuvant alone. Only the vaccinated animals made antibodies before challenge exposure to the viral core and envelope as determined by Western blotting (immunoblotting) and virus-neutralizing antibodies. Ten days after the final immunization, one-half of the vaccinated and nonvaccinated monkeys were challenged exposed intravenously (i.v.) and one-half were challenge exposed via the genital mucosa with virulent simian immunodeficiency virus. All of the nonvaccinated control monkeys became persistently infected. In spitemore » of preexisting neutralizing antibodies and an anamnestic antibody response, all of the immunized monkeys also became persistently infected. However, there was evidence that the clinical course in immunized i.v. infected animals was delayed. All four mock-vaccinated i.v. challenge-exposed animals died with disease from 3 to 9 months postchallenge. In contrast, only one of four vaccinated i.v. challenge-exposed monkeys had died by 11 months postchallenge.« less

Cardiac damage induced by 2-amino-3-methyl-imidazo[4,5-f]quinoline in nonhuman primates.

PubMed Central

Thorgeirsson, U P; Farb, A; Virmani, R; Adamson, R H

1994-01-01

The heterocyclic aromatic amine 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) is a potent hepatocarcinogen in cynomolgus and rhesus monkeys. The finding of high cardiac IQ-DNA adduct levels prompted a histopathological study of perfusion-fixed hearts from 10 tumor-bearing monkeys chronically dosed with IQ at 10 mg/kg or 20 mg/kg 5 days per week for 48-80 months. Two monkeys dosed only with the vehicle for IQ, hydroxypropylcellulose, served as controls. All the monkeys had normal heart weights, and no abnormalities were observed upon gross inspection of the hearts. Microscopically, focal myocardial lesions were observed in 8 of 10 monkeys dosed with IQ. Light microscopic abnormalities included myocyte necrosis with or without chronic inflammatory infiltrates, interstitial fibrosis with myocyte hypertrophy or atrophy, and vasculitis. Electron microscopic findings included disruption of the mitochondrial architecture (i.e., mitochondrial swelling and clearing of matrix densities), myofibrillar loss, disorganization of the normal alignment of sarcomeres, and occasional myocytes showing nuclear hypertrophy or peripheral clumping of the nuclear chromatin. There was some correlation between the cumulative dose of IQ and the extent of the myocardial abnormalities. These findings suggest that chronic exposure to IQ can lead to myocardial damage in monkeys. Although focal and not associated with clinical evidence of heart failure, these abnormalities may represent the initial stages of IQ-induced toxic cardiomyopathy. Images Figure 1. A Figure 1. B Figure 1. C Figure 1. D Figure 2. A Figure 2. B Figure 3. A Figure 3. B Figure 3. C Figure 3. D Figure 4. A Figure 4. B Figure 5. A Figure 5. B PMID:8033851

Attenuation of cocaine self-administration by chronic oral phendimetrazine in rhesus monkeys.

PubMed

Czoty, P W; Blough, B E; Fennell, T R; Snyder, R W; Nader, M A

2016-06-02

Chronic treatment with the monoamine releaser d-amphetamine has been consistently shown to decrease cocaine self-administration in laboratory studies and clinical trials. However, the abuse potential of d-amphetamine is an obstacle to widespread clinical use. Approaches are needed that exploit the efficacy of the agonist approach but avoid the abuse potential associated with dopamine releasers. The present study assessed the effectiveness of chronic oral administration of phendimetrazine (PDM), a pro-drug for the monoamine releaser phenmetrazine (PM), to decrease cocaine self-administration in four rhesus monkeys. Each day, monkeys pressed a lever to receive food pellets under a 50-response fixed-ratio (FR) schedule of reinforcement and self-administered cocaine (0.003-0.56 mg/kg per injection, i.v.) under a progressive-ratio (PR) schedule in the evening. After completing a cocaine self-administration dose-response curve, sessions were suspended and PDM was administered (1.0-9.0 mg/kg, p.o., b.i.d.). Cocaine self-administration was assessed using the PR schedule once every 7 days while food-maintained responding was studied daily. When a persistent decrease in self-administration was observed, the cocaine dose-effect curve was re-determined. Daily PDM treatment decreased cocaine self-administration by 30-90% across monkeys for at least 4 weeks. In two monkeys, effects were completely selective for cocaine. Tolerance developed to initial decreases in food-maintained responding in the third monkey and in the fourth subject, fluctuations were observed that were lower in magnitude than effects on cocaine self-administration. Cocaine dose-effect curves were shifted down and/or rightward in three monkeys. These data provide further support for the use of agonist medications for cocaine abuse, and indicate that the promising effects of d-amphetamine extend to a more clinically viable pharmacotherapy. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

Effect of Prior Influenza Virus Infection on Susceptibility of AKR/J Mice and Squirrel Monkeys to Respiratory Challenge with Legionella pneumophila.

DTIC Science & Technology

1980-07-30

Infection on Susceptibility of AKR/J Mice and Squirrel Monkeys to Respiratory Challenge with Legionella pneumophila RICHARD F. BERENDT U. S. Army Medical...influenza virus and Legionella pneumophila than to either agent alone. b 3 F As knowledge of Legionnaires’ disease has accumulated, the evidence...suggests that many infections occur in individuals with underlying disease. Since Legionella pneumophila appears to spread by the airborne route (5, 6, 8, 9

T-cell tropism of simian T-cell leukaemia virus type 1 and cytokine profiles in relation to proviral load and immunological changes during chronic infection of naturally infected mandrills (Mandrillus sphinx).

PubMed

Souquière, Sandrine; Mouinga-Ondeme, Augustin; Makuwa, Maria; Beggio, Paola; Radaelli, Antonia; De Giuli Morghen, Carlo; Mortreux, Franck; Kazanji, Mirdad

2009-08-01

Although a wide variety of non-human primates are susceptible to simian T-cell leukaemia virus type 1 (STLV-1), little is known about the virological or molecular determinants of natural STLV-1 infection. We determined STLV-1 virus tropism in vivo and its relation to the immune response by evaluating cytokine production and T-cell subsets in naturally infected and uninfected mandrills. With real-time PCR methods, we found that STLV-1 in mandrills infects both CD4(+) and CD8(+) T cells; however, proviral loads were significantly higher (P = 0.01) in CD4(+) than in CD8(+) cells (mean STLV-1 copies number per 100 cells (+/- SD) was 7.8 +/- 8 in CD4(+) T cells and 3.9 +/- 4.5 in CD8(+) T cells). After culture, STLV-1 provirus was detected in enriched CD4(+) but not in enriched CD8(+) T cells. After 6 months of culture, STLV-1-transformed cell lines expressing CD3(+), CD4(+) and HLADR(+) were established, and STLV-1 proteins and tax/rex mRNA were detected. In STLV-1 infected monkeys, there was a correlation between high proviral load and elevated levels of interleukin (IL)-2, IL-6, IL-10, interferon-gamma and tumour necrosis factor-alpha. The two monkeys with the highest STLV-1 proviral load had activated CD4(+)HLADR(+) and CD8(+)HLADR(+) T-cell subsets and a high percentage of CD25(+) in CD4(+) and CD8(+) T cells. Our study provides the first cellular, immunological and virological characterization of natural STLV-1 infection in mandrills and shows that they are an appropriate animal model for further physiopathological studies of the natural history of human T-cell leukaemia viruses.

Nectin-4 Interactions Govern Measles Virus Virulence in a New Model of Pathogenesis, the Squirrel Monkey (Saimiri sciureus).

PubMed

Delpeut, Sébastien; Sawatsky, Bevan; Wong, Xiao-Xiang; Frenzke, Marie; Cattaneo, Roberto; von Messling, Veronika

2017-06-01

In addition to humans, only certain nonhuman primates are naturally susceptible to measles virus (MeV) infection. Disease severity is species dependent, ranging from mild to moderate for macaques to severe and even lethal for certain New World monkey species. To investigate if squirrel monkeys ( Saimiri sciureus ), which are reported to develop a course of disease similar to humans, may be better suited than macaques for the identification of virulence determinants or the evaluation of therapeutics, we infected them with a green fluorescent protein-expressing MeV. Compared to cynomolgus macaques ( Macaca fascicularis ) infected with the same virus, the squirrel monkeys developed more-severe immunosuppression, higher viral load, and a broader range of clinical signs typical for measles. In contrast, infection with an MeV unable to interact with the epithelial receptor nectin-4, while causing immunosuppression, resulted in only a mild and transient rash and a short-lived elevation of the body temperature. Similar titers of the wild-type and nectin-4-blind MeV were detected in peripheral blood mononuclear cells and lymph node homogenates, but only the wild-type virus was found in tracheal lavage fluids and urine. Thus, our study demonstrates the importance of MeV interactions with nectin-4 for clinical disease in the new and better-performing S. sciureus model of measles pathogenesis. IMPORTANCE The characterization of mechanisms underlying measles virus clinical disease has been hampered by the lack of an animal model that reproduces the course of disease seen in human patients. Here, we report that infection of squirrel monkeys ( Saimiri sciureus ) fulfills these requirements. Comparative infection with wild-type and epithelial cell receptor-blind viruses demonstrated the importance of epithelial cell infection for clinical disease, highlighting the spread to epithelia as an attractive target for therapeutic strategies. Copyright © 2017 American Society for Microbiology.

A constant threat for HIV: Fc-engineering to enhance broadly neutralizing antibody activity for immunotherapy of the acquired immunodeficiency syndrome.

PubMed

Nimmerjahn, Falk

2015-08-01

Passive immunotherapy with polyclonal or hyperimmune serum immunoglobulin G (IgG) preparations provides an efficient means of protecting immunocompromised patients from microbial infections. More recently, the use of passive immunotherapy to prevent or to treat established infections with the human immunodeficiency virus (HIV) has gained much attention, due to promising preclinical data obtained in monkey and humanized mouse in vivo model systems, demonstrating that the transfer of HIV-specific antibodies can not only prevent HIV infection, but also diminish virus load during chronic infection. Furthermore, an array of broadly neutralizing HIV-specific antibodies has become available and the importance of the IgG constant region as a critical modulator of broadly neutralizing activity has been demonstrated. The aim of this review is to summarize the most recent findings with regard to the molecular and cellular mechanisms responsible for antibody-mediated clearance of HIV infection, and to discuss how this may help to improve HIV therapy via optimizing Fcγ-receptor-dependent activities of HIV-specific antibodies. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Patterns of Infection and Patterns of Evolution: How a Malaria Parasite Brought "Monkeys and Man" Closer Together in the 1960s.

PubMed

Mason Dentinger, Rachel

2016-04-01

In 1960, American parasitologist Don Eyles was unexpectedly infected with a malariaparasite isolated from a macaque. He and his supervisor, G. Robert Coatney of the National Institutes of Health, had started this series of experiments with the assumption that humans were not susceptible to "monkey malaria." The revelation that a mosquito carrying a macaque parasite could infect a human raised a whole range of public health and biological questions. This paper follows Coatney's team of parasitologists and their subjects: from the human to the nonhuman; from the American laboratory to the forests of Malaysia; and between the domains of medical research and natural history. In the course of this research, Coatney and his colleagues inverted Koch's postulate, by which animal subjects are used to identify and understand human parasites. In contrast, Coatney's experimental protocol used human subjects to identify and understand monkey parasites. In so doing, the team repeatedly followed malaria parasites across the purported boundary separating monkeys and humans, a practical experience that created a sense of biological symmetry between these separate species. Ultimately, this led Coatney and his colleagues make evolutionary inferences, concluding "that monkeys and man are more closely related than some of us wish to admit." In following monkeys, men, and malaria across biological, geographical, and disciplinary boundaries, this paper offers a new historical narrative, demonstrating that the pursuit of public health agendas can fuel the expansion of evolutionary knowledge.

Outbreak of pasteurellosis in captive Bolivian squirrel monkeys (Saimiri boliviensis)

PubMed Central

YOSHINO, Mizuki; SASAKI, Jun; KURAMOCHI, Konomi; IKEZAWA, Mitsutaka; MUKAIZAWA, Natsuko; GORYO, Masanobu

2017-01-01

In September 2012, five Bolivian squirrel monkeys housed in a zoological park died within sequential several days without obvious clinical signs. In a necrospy, one monkey presented swelling of the kidney with multifocal white nodules in the parenchyma, and other two had pulmonary congestion. Histopathologically, multifocal bacterial colonies of gram-negative coccobacillus were found in the sinusoid of the liver in all monkeys examined (Nos.1−4). Additionally, purulent pyelonephritis, pneumonia and disseminated small bacterial colonies in blood vessels were observed. Immunohistochemically, the bacterial colonies from two monkeys were positive for P. multocida capsular serotype D. Based on these findings, these monkeys were diagnosed as septicemia caused by acute P. multocida infection. PMID:28190821

Outbreak of pasteurellosis in captive Bolivian squirrel monkeys (Saimiri boliviensis).

PubMed

Yoshino, Mizuki; Sasaki, Jun; Kuramochi, Konomi; Ikezawa, Mitsutaka; Mukaizawa, Natsuko; Goryo, Masanobu

2017-03-23

In September 2012, five Bolivian squirrel monkeys housed in a zoological park died within sequential several days without obvious clinical signs. In a necrospy, one monkey presented swelling of the kidney with multifocal white nodules in the parenchyma, and other two had pulmonary congestion. Histopathologically, multifocal bacterial colonies of gram-negative coccobacillus were found in the sinusoid of the liver in all monkeys examined (Nos.1-4). Additionally, purulent pyelonephritis, pneumonia and disseminated small bacterial colonies in blood vessels were observed. Immunohistochemically, the bacterial colonies from two monkeys were positive for P. multocida capsular serotype D. Based on these findings, these monkeys were diagnosed as septicemia caused by acute P. multocida infection.

Effects of logging, hunting, and forest fragment size on physiological stress levels of two sympatric ateline primates in Colombia

PubMed Central

Rimbach, Rebecca; Link, Andrés; Heistermann, Michael; Gómez-Posada, Carolina; Galvis, Nelson; Heymann, Eckhard W.

2013-01-01

Habitat fragmentation and anthropogenic disturbances are of major concern to the conservation of endangered species because of their potentially negative impact on animal populations. Both processes can impose physiological stress (i.e. increased glucocorticoid output) on animals, and chronically elevated stress levels can have detrimental effects on the long-term viability of animal populations. Here, we investigated the effect of fragment size and human impact (logging and hunting pressure) on glucocorticoid levels of two sympatric Neotropical primates, the red howler monkey (Alouatta seniculus) and the critically endangered brown spider monkey (Ateles hybridus). These two species have been reported to contrast strongly in their ability to cope with anthropogenic disturbances. We collected faecal samples from eight spider monkey groups and 31 howler monkey groups, living in seven and 10 different forest fragments in Colombia, respectively. We measured faecal glucocorticoid metabolite (FGCM) levels in both species using previously validated methods. Surprisingly, fragment size did not influence FGCM levels in either species. Spider monkeys showed elevated FGCMs in fragments with the highest level of human impact, whereas we did not find this effect in howler monkeys. This suggests that the two species differ in their physiological responsiveness to anthropogenic changes, further emphasizing why brown spider monkeys are at higher extinction risk than red howler monkeys. If these anthropogenic disturbances persist in the long term, elevated FGCM levels can potentially lead to a state of chronic stress, which might limit the future viability of populations. We propose that FGCM measurements should be used as a tool to monitor populations living in disturbed areas and to assess the success of conservation strategies, such as corridors connecting forest fragments. PMID:27293615

THE INFLUENCE OF IONIZING RADIATION ON THE COURSE OF INFECTION AND THE STATE OF IMMUNITY IN MONKEYS WITH EXPERIMENTALLY INDUCED MEASLES (in Russian)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lapin, B.A.; Stasilevich, Z.K.

1962-07-01

The influence of sublethal doses of x radiation on the course of measles and the formation of immunity was studned. Experiments were staged on 12 monkeys. The results show that during x irradiation in a dose of 300 r and infection of the animals with the measles virus a reciprocal aggravation of the radiation and infectious processes occurs. As a result there is a sharp reduction of the resistance of the monkey's organism with attending complications, which lead to a lethal outcome in nearly haif of the cases. Experiments with irradiation and infection with measles of immune animals disclosed thatmore » the antimeasles immunity evolved earlier proved to be so stable that even irradiation does not weaken it. (auth)« less

Chronic marijuana smoke exposure in the rhesus monkey. IV: Neurochemical effects and comparison to acute and chronic exposure to delta-9-tetrahydrocannabinol (THC) in rats.

PubMed

Ali, S F; Newport, G D; Scallet, A C; Paule, M G; Bailey, J R; Slikker, W

1991-11-01

THC is the major psychoactive constituent of marijuana and is known to produce psychopharmacological effects in humans. These studies were designed to determine whether acute or chronic exposure to marijuana smoke or THC produces in vitro or in vivo neurochemical alterations in rat or monkey brain. For the in vitro study, THC was added (1-100 nM) to membranes prepared from different regions of the rat brain and muscarinic cholinergic (MCh) receptor binding was measured. For the acute in vivo study, rats were injected IP with vehicle, 1, 3, 10, or 30 mg THC/kg and sacrificed 2 h later. For the chronic study, rats were gavaged with vehicle or 10 or 20 mg THC/kg daily, 5 days/week for 90 days and sacrificed either 24 h or 2 months later. Rhesus monkeys were exposed to the smoke of a single 2.6% THC cigarette once a day, 2 or 7 days a week for 1 year. Approximately 7 months after the last exposure, animals were sacrificed by overdose with pentobarbital for neurochemical analyses. In vitro exposure to THC produced a dose-dependent inhibition of MCh receptor binding in several brain areas. This inhibition of MCh receptor binding, however, was also observed with two other nonpsychoactive derivatives of marijuana, cannabidiol and cannabinol. In the rat in vivo study, we found no significant changes in MCh or other neurotransmitter receptor binding in hippocampus, frontal cortex or caudate nucleus after acute or chronic exposure to THC. In the monkey brain, we found no alterations in the concentration of neurotransmitters in caudate nucleus, frontal cortex, hypothalamus or brain stem.(ABSTRACT TRUNCATED AT 250 WORDS)

Cytogenetic damages in peripheral blood of monkey lymphocytes under simulation of cosmonauts irradiation.

NASA Astrophysics Data System (ADS)

Petrov, Vladislav; Ivanov, Alexandr; Barteneva, Svetlana; Snigiryeva, Galina; Shafirkin, Alexandr

Earth modeling of crewmember exposure should be performed for correct estimating radiation hazard during the flight. Such modeling was planned in a monkey experiment for investigating consequences of exposure to a man during an interplanetary flight. It should reflect a chronic impact of galactic cosmic rays and acute and fractional irradiation specified for solar cosmic rays and radiation belts respectively. Due to the difficulty of modeling a chronic impact with the help of a charged particles accelerator it can be used the gamma source. While irradiating big animal groups during a long-term period of time it is preferably to replace chronic irradiation by an equal fractional one. In this case the chosen characteristics of fractional irradiation should ensure the appearances of radiobiological consequences equal to the ones caused by the modeled chronic exposure. So for developing an exposure scheme in the monkey experiment (with Macaca -Rhesus) the model of the acting residual dose, that takes into account repair and recovery processes in the exposed body was used. The total dose value was in the limits from 2.32 Gy up to 3.5 Gy depending on the exposure character. The acting residual dose in all versions of exposure was 2.0 Gy for every monkey. While performing the experiment all the requirements of bioethics for the work with animals were observed. The objects of interest were genomic damages in lymphocytes of monkey's peripheral blood. The data about the CAF during the exposure and at various time moments after exposure particularly directly after the completion of chronicle and fractional irradiation were analyzed. CAF -dose of acute single gamma-irradiation in the range 0 -1.5Gy relationship (calibration curve) was defined in vitro. In addition the rate of the aberrant cells elimination within three months after the irradiation completion was estimated. On the basis of the obtained CAF data we performed verification of applicability of cytogenetic analysis for estimating the monkey gamma -dose exposure in the experiment It was obtained that this method permits to estimate the acting residual dose with accuracy of 30

A Portable Kit for Rapid Diagnosis of Infectious Diseases under Field Conditions

DTIC Science & Technology

1980-08-14

INFECTIONS SHIGELLA TYPHOID FEVER STREPTOCOCCUS An example of a public health application for rapid diagnosis using the COAG test is provided by studies...than in infections in Fig. Principles of gel diffusion (GD) and of counter- monkeys with human parasites (BID%%IAL et al. 1973, immunoelectrophoresis...the cerebrospinal fluid and immunofluorescence tests for detection of malaria te ai preient ith croup inal fuidan antibodies in Aotus monkeys

Impaired performance on a rhesus monkey neuropsychological testing battery following simian immunodeficiency virus infection.

PubMed

Weed, Michael R; Gold, Lisa H; Polis, Ilham; Koob, George F; Fox, Howard S; Taffe, Michael A

2004-01-01

Infection with simian immunodeficiency virus (SIV) in macaques provides an excellent model of AIDS including HIV-induced central nervous system (CNS) pathology and cognitive/behavioral impairment. Recently a behavioral test battery has been developed for macaques based on the CANTAB human neuropsychological testing battery. As with human neuropsychological batteries, different tasks are thought to involve different neural substrates, and therefore performance profiles may assess function in particular brain regions. Ten rhesus monkeys were infected with SIV after being trained on two or more of the battery tasks addressing memory (delayed nonmatching to sample, DNMS), spatial working memory (using a self-ordered spatial search task, SOSS), motivation (progressive-ratio, PR), reaction time (RT), and/or fine motor skills (bimanual motor skill, BMS). Performance was compared to that of 9 uninfected monkeys. Overall, some aspect of performance was impaired in all 10 monkeys following infection. Consistent with results in human AIDS patients, individual performance was impaired most often on battery tasks thought to be sensitive to frontostriatal dopaminergic functioning such as SOSS, RT, and BMS. These results further demonstrate the similarity of behavioral impairment produced by SIV and HIV on homologous behavioral tests, and establish the utility of the testing battery for further investigations into the CNS mechanisms of the reported behavioral changes.

Renal response to seven days of lower body positive pressure in the squirrel monkey

NASA Technical Reports Server (NTRS)

Churchill, Susanne; Pollock, David M.; Natale, Mary Ellen; Moore-Ede, Martin C.

1987-01-01

As a ground-based model for weightlessness, the response of the chair-trained squirrel monkey to lower body positive pressure (LBPP) was evaluated in a length of study similar to a typical Space Shuttle mission (7 days). Results were compared to time control experiments that included chair-sitting without exposure to LBPP. Chronic exposure to LBPP results in an acute diuretic and natriuretic response independent of changes in plasma aldosterone concentrations and produces a chronic reduction in fluid volume lasting the duration in the stimulus.

Identification of a novel simian parvovirus in cynomolgus monkeys with severe anemia. A paradigm of human B19 parvovirus infection.

PubMed Central

O'Sullivan, M G; Anderson, D C; Fikes, J D; Bain, F T; Carlson, C S; Green, S W; Young, N S; Brown, K E

1994-01-01

Although human B19 parvovirus infection has been clearly associated with a number of distinct syndromes (including severe anemia, abortion, and arthritis), detailed knowledge of its pathogenesis has been hindered by the lack of a suitable animal model. We have identified a novel simian parvovirus in cynomolgus monkeys with severe anemia. Sequencing of a 723-bp fragment of cloned viral DNA extracted from serum revealed that the simian parvovirus has 65% homology at the DNA level with the human B19 parvovirus but little homology with other known parvoviruses. Light microscopic examination of bone marrow from infected animals showed intranuclear inclusion bodies, and ultrastructural studies showed viral arrays characteristic of parvoviruses. Another striking feature was the presence of marked dyserythropoiesis in cells of the erythroid lineage, raising the possibility that B19 parvovirus infection may underlie related dyserythropoietic syndromes in human beings. Affected animals had concurrent infection with the immunosuppressive type D simian retrovirus, analogous to HIV patients who develop severe anemia because of infection with B19 parvovirus. The remarkable similarities between the simian and B19 parvoviruses suggest that experimentally infected cynomolgus monkeys may serve as a useful animal model of human B19 infection. Images PMID:8163659

Unrecognized "AIDS" in Monkeys, 1969-1980: Explanations and Implications.

PubMed

Hammett, Theodore M; Bronson, Roderick T

2016-06-01

AIDS was recognized in humans in 1981 and a simian form was described in the years 1983 to 1985. However, beginning in the late 1960s, outbreaks of opportunistic infections of AIDS were seen in monkeys in the United States. This apparent syndrome went unrecognized at the time. We have assembled those early cases in monkeys and offer reasons why they did not result in earlier recognition of simian or human AIDS, including weaknesses in understanding disease mechanisms, absence of evidence of human retroviruses, and a climate of opinion that devalued investigation of infectious disease and immunologic origins of disease. The "epistemological obstacle" explains important elements of this history in that misconceptions blocked understanding of the dependent relationship among viral infection, immunodeficiency, and opportunistic diseases. Had clearer understanding of the evidence from monkeys allowed human AIDS to be recognized earlier, life-saving prevention and treatment interventions might have been implemented sooner.

Unrecognized “AIDS” in Monkeys, 1969–1980: Explanations and Implications

PubMed Central

Bronson, Roderick T.

2016-01-01

AIDS was recognized in humans in 1981 and a simian form was described in the years 1983 to 1985. However, beginning in the late 1960s, outbreaks of opportunistic infections of AIDS were seen in monkeys in the United States. This apparent syndrome went unrecognized at the time. We have assembled those early cases in monkeys and offer reasons why they did not result in earlier recognition of simian or human AIDS, including weaknesses in understanding disease mechanisms, absence of evidence of human retroviruses, and a climate of opinion that devalued investigation of infectious disease and immunologic origins of disease. The “epistemological obstacle” explains important elements of this history in that misconceptions blocked understanding of the dependent relationship among viral infection, immunodeficiency, and opportunistic diseases. Had clearer understanding of the evidence from monkeys allowed human AIDS to be recognized earlier, life-saving prevention and treatment interventions might have been implemented sooner. PMID:27077355

Interspecies radioimmunoassay for the major structural proteins of primate type-D retroviruses

DOE Office of Scientific and Technical Information (OSTI.GOV)

Colcher, D.; Teramoto, Y.A.; Schlom, J.

1977-12-01

A competition radioimmunoassay has been developed in which type-D retroviruses from three primate species compete. The assay utilizes the major structural protein (36,000 daltons) of the endogenous squirrel monkey retrovirus and antisera directed against the major structural protein (27,000 daltons) of the Mason-Pfizer monkey virus isolated from rhesus monkeys. Purified preparations of both viruses grown in heterologous cells, as well as extracts of heterologous cells infected with squirrel monkey retrovirus or Mason-Pfizer monkey virus, compete completely in the assay. Addition of an endogenous virus of the langur monkey also results in complete blocking. No blocking in the assay is observedmore » with type-C baboon viruses, woolly monkey virus, and gibbon virus. Various other type-C and type-B viruses also showed no reactivity. An interspecies assay has thus been developed that recognizes the type-D retroviruses from both Old World monkey (rhesus and langur) and New World monkey (squirrel) species.« less

Monkeys as a source of viral diseases in man

NASA Technical Reports Server (NTRS)

Pille, E. R.

1986-01-01

Under institutional scientific-research conditions, during contact with monkeys or their tissues, there is a danger of infection of the associates by simian viruses which are pathogenic to man. Presented in this paper is information on these stimulants.

Aircraft flight simulation of spacelab experiment using an implanted telemetry system to obtain cardiovascular data from the monkey

NASA Technical Reports Server (NTRS)

Mccutcheon, E. P.; Miranda, R.; Fryer, T. B.; Hodges, G.; Newson, B. D.; Pace, N.

1977-01-01

The utility of a multichannel implantable telemetry system for obtaining cardiovascular data was tested in a monkey with a CV-990 aircraft flight simulation of a space flight experiment. Valuable data were obtained to aid planning and execution of flight experiments using chronically instrumented animals.

Pharmacological evaluation of narcotic antagonist delivery systems in rhesus monkeys.

PubMed

Harrigan, S E; Downs, D A

1981-01-01

Rhesus monkeys were chronically restrained, intravenously catheterized, and allowed to self-administer morphine, methamphetamine, and saline. Various sustained-release systems containing naltrexone were then implanted in the animals and examined for selective morphine blockade. Similarly, continuous intravenous infusions of naltrexone, buprenorphine, and methadone were tested against morphine or heroin self-administration.

Strain-Specific Protective Effect of the Immunity Induced by Live Malarial Sporozoites under Chloroquine Cover

PubMed Central

Wijayalath, Wathsala; Cheesman, Sandra; Tanabe, Kazuyuki; Handunnetti, Shiroma; Carter, Richard; Pathirana, Sisira

2012-01-01

The efficacy of a whole-sporozoite malaria vaccine would partly be determined by the strain-specificity of the protective responses against malarial sporozoites and liver-stage parasites. Evidence from previous reports were inconsistent, where some studies have shown that the protective immunity induced by irradiated or live sporozoites in rodents or humans were cross-protective and in others strain-specific. In the present work, we have studied the strain-specificity of live sporozoite-induced immunity using two genetically and immunologically different strains of Plasmodium cynomolgi, Pc746 and PcCeylon, in toque monkeys. Two groups of monkeys were immunized against live sporozoites of either the Pc746 (n = 5), or the PcCeylon (n = 4) strain, by the bites of 2–4 sporozoite-infected Anopheles tessellates mosquitoes per monkey under concurrent treatments with chloroquine and primaquine to abrogate detectable blood infections. Subsequently, a group of non-immunized monkeys (n = 4), and the two groups of immunized monkeys were challenged with a mixture of sporozoites of the two strains by the bites of 2–5 infective mosquitoes from each strain per monkey. In order to determine the strain-specificity of the protective immunity, the proportions of parasites of the two strains in the challenge infections were quantified using an allele quantification assay, Pyrosequencing™, based on a single nucleotide polymorphism (SNP) in the parasites’ circumsporozoite protein gene. The Pyrosequencing™ data showed that a significant reduction of parasites of the immunizing strain in each group of strain-specifically immunized monkeys had occurred, indicating a stronger killing effect on parasites of the immunizing strain. Thus, the protective immunity developed following a single, live sporozoite/chloroquine immunization, acted specifically against the immunizing strain and was, therefore, strain-specific. As our experiment does not allow us to determine the parasite stage at which the strain-specific protective immunity is directed, it is possible that the target of this immunity could be either the pre-erythrocytic stage, or the blood-stage, or both. PMID:23029282

Resveratrol improves adipose insulin signaling and reduces the inflammatory response in adipose tissue of rhesus monkeys on high-fat, high-sugar diet.

PubMed

Jimenez-Gomez, Yolanda; Mattison, Julie A; Pearson, Kevin J; Martin-Montalvo, Alejandro; Palacios, Hector H; Sossong, Alex M; Ward, Theresa M; Younts, Caitlin M; Lewis, Kaitlyn; Allard, Joanne S; Longo, Dan L; Belman, Jonathan P; Malagon, Maria M; Navas, Placido; Sanghvi, Mitesh; Moaddel, Ruin; Tilmont, Edward M; Herbert, Richard L; Morrell, Christopher H; Egan, Josephine M; Baur, Joseph A; Ferrucci, Luigi; Bogan, Jonathan S; Bernier, Michel; de Cabo, Rafael

2013-10-01

Obesity is associated with a chronic, low-grade, systemic inflammation that may contribute to the development of insulin resistance and type 2 diabetes. Resveratrol, a natural compound with anti-inflammatory properties, is shown to improve glucose tolerance and insulin sensitivity in obese mice and humans. Here, we tested the effect of a 2-year resveratrol administration on proinflammatory profile and insulin resistance caused by a high-fat, high-sugar (HFS) diet in white adipose tissue (WAT) from rhesus monkeys. Resveratrol supplementation (80 and 480 mg/day for the first and second year, respectively) decreased adipocyte size, increased sirtuin 1 expression, decreased NF-κB activation, and improved insulin sensitivity in visceral, but not subcutaneous, WAT from HFS-fed animals. These effects were reproduced in 3T3-L1 adipocytes cultured in media supplemented with serum from monkeys fed HFS ± resveratrol diets. In conclusion, chronic administration of resveratrol exerts beneficial metabolic and inflammatory adaptations in visceral WAT from diet-induced obese monkeys. Copyright © 2013 Elsevier Inc. All rights reserved.

Dyscoria associated with herpesvirus infection in owl monkeys (Aotus nancymae).

PubMed

Gozalo, Alfonso S; Montoya, Enrique J; Weller, Richard E

2008-07-01

"Dyscoria was noted in a female owl monkey and 2 of her offspring. The third offspring was found dead with necrohemorrhagic encephalitis. Two male monkeys paired with the female died, 1 of which showed oral ulcers at necropsy. Histologic examination of the oral ulcers revealed syncytia and eosinophilic intranuclear inclusion bodies in epithelial cells. Ocular examination revealed posterior synechia associated with the dyscoria in all 3 animals. Serum samples from the female and her offspring were positive for Herpesvirus simplex antibodies by ELISA. The clinical history, gross and microscopic lesions, and serology results suggests a herpesviral etiology, possibly H. simplex or H. saimiri 1. This report underscores the risks associated with introducing into breeding or research colonies animals that previously were kept as pets or those from unknown origin that could carry asymptomatic pathogenic Herpesvirus infections. In addition, herpesviral infection should be considered among the differential diagnoses if dyscoria is noted in nonhuman primates."

Dyscoria Associated with Herpesvirus Infection in Owl Monkeys (Aotus nancymae)

PubMed Central

Gozalo, Alfonso S; Montoya, Enrique J; Weller, Richard E

2008-01-01

Dyscoria was noted in a female owl monkey and 2 of her offspring. The third offspring was found dead with necrohemorrhagic encephalitis. Two male monkeys paired with the female died, 1 of which showed oral ulcers at necropsy. Histologic examination of the oral ulcers revealed syncytia and eosinophilic intranuclear inclusion bodies in epithelial cells. Ocular examination revealed posterior synechia associated with the dyscoria in all 3 animals. Serum samples from the female and her offspring were positive for Herpesvirus simplex antibodies by ELISA. The clinical history, gross and microscopic lesions, and serology results suggests a herpesviral etiology, possibly H. simplex or H. saimiri 1. This report underscores the risks associated with introducing into breeding or research colonies animals that previously were kept as pets or those from unknown origin that could carry asymptomatic pathogenic Herpesvirus infections. In addition, herpesviral infection should be considered among the differential diagnoses if dyscoria is noted in nonhuman primates. PMID:18702455

Inflammatory monocytes expressing tissue factor drive SIV and HIV coagulopathy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Schechter, Melissa E.; Andrade, Bruno B.; He, Tianyu

In HIV infection, persistent inflammation despite effective antiretroviral therapy is linked to increased risk of noninfectious chronic complications such as cardiovascular and thromboembolic disease. Thus, a better understanding of inflammatory and coagulation pathways in HIV infection is needed to optimize clinical care. Markers of monocyte activation and coagulation independently predict morbidity and mortality associated with non-AIDS events. We identified a specific subset of monocytes that express tissue factor (TF), persist after virological suppression, and trigger the coagulation cascade by activating factor X. This subset of monocytes expressing TF had a distinct gene signature with up-regulated innate immune markers and evidencemore » of robust production of multiple proinflammatory cytokines, including interleukin-1β (IL-1β), tumor necrosis factor–α (TNF-α), and IL-6, ex vivo and in vitro upon lipopolysaccharide stimulation. We validated our findings in a nonhuman primate model, showing that TF-expressing inflammatory monocytes were associated with simian immunodeficiency virus (SIV)–related coagulopathy in the progressive [pigtail macaques (PTMs)] but not in the nonpathogenic (African green monkeys) SIV infection model. Last, Ixolaris, an anticoagulant that inhibits the TF pathway, was tested and potently blocked functional TF activity in vitro in HIV and SIV infection without affecting monocyte responses to Toll-like receptor stimulation. Strikingly, in vivo treatment of SIV-infected PTMs with Ixolaris was associated with significant decreases in D-dimer and immune activation. These data suggest that TF-expressing monocytes are at the epicenter of inflammation and coagulation in chronic HIV and SIV infection and may represent a potential therapeutic target.« less

Inflammatory monocytes expressing tissue factor drive SIV and HIV coagulopathy

DOE PAGES

Schechter, Melissa E.; Andrade, Bruno B.; He, Tianyu; ...

2017-08-30

In HIV infection, persistent inflammation despite effective antiretroviral therapy is linked to increased risk of noninfectious chronic complications such as cardiovascular and thromboembolic disease. Thus, a better understanding of inflammatory and coagulation pathways in HIV infection is needed to optimize clinical care. Markers of monocyte activation and coagulation independently predict morbidity and mortality associated with non-AIDS events. We identified a specific subset of monocytes that express tissue factor (TF), persist after virological suppression, and trigger the coagulation cascade by activating factor X. This subset of monocytes expressing TF had a distinct gene signature with up-regulated innate immune markers and evidencemore » of robust production of multiple proinflammatory cytokines, including interleukin-1β (IL-1β), tumor necrosis factor–α (TNF-α), and IL-6, ex vivo and in vitro upon lipopolysaccharide stimulation. We validated our findings in a nonhuman primate model, showing that TF-expressing inflammatory monocytes were associated with simian immunodeficiency virus (SIV)–related coagulopathy in the progressive [pigtail macaques (PTMs)] but not in the nonpathogenic (African green monkeys) SIV infection model. Last, Ixolaris, an anticoagulant that inhibits the TF pathway, was tested and potently blocked functional TF activity in vitro in HIV and SIV infection without affecting monocyte responses to Toll-like receptor stimulation. Strikingly, in vivo treatment of SIV-infected PTMs with Ixolaris was associated with significant decreases in D-dimer and immune activation. These data suggest that TF-expressing monocytes are at the epicenter of inflammation and coagulation in chronic HIV and SIV infection and may represent a potential therapeutic target.« less

Parasitology of five primates in Mahale Mountains National Park, Tanzania.

PubMed

Kooriyama, Takanori; Hasegawa, Hideo; Shimozuru, Michito; Tsubota, Toshio; Nishida, Toshisada; Iwaki, Takashi

2012-10-01

Parasitological surveillance in primates has been performed using coprological observation and identification of specimens from chimpanzees (Pan troglodytes schweinfurthii) in Mahale Mountains National Park, Tanzania (Mahale). In this study, we conducted coprological surveillance to identify the fauna of parasite infection in five primate species in Mahale: red colobus (Procolobus badius tephrosceles), red-tailed monkeys (Cercopithecus ascanius schmidti), vervet monkeys (Cercopithecus aethiops pygerythrus), yellow baboons (Papio cynocephalus), and chimpanzees. Fecal samples were examined microscopically, and parasite identification was based on the morphology of cysts, eggs, larvae, and adult worms. Three nematodes (Oesophagostomum spp., Strongyloides sp., and Trichuris sp.), Entamoeba coli, and Entamoeba spp. were found in all five primate species. The following infections were identified: Bertiella studeri was found in chimpanzees and yellow baboons; Balantidium coli was found in yellow baboons; three nematodes (Streptopharagus, Primasubulura, an undetermined genus of Spirurina) and Dicrocoeliidae gen. sp. were found in red-tailed monkeys, vervet monkeys, and yellow baboons; Chitwoodspirura sp. was newly identified in red colobus and red-tailed monkeys; Probstmayria gombensis and Troglocorys cava were newly identified in chimpanzees, together with Troglodytella abrassarti; and Enterobius sp. was newly identified in red colobus. The parasitological data reported for red colobus, vervet monkeys, and yellow baboons in Mahale are the first reports for these species.

[Monkey-pox, a model of emergent then reemergent disease].

PubMed

Georges, A J; Matton, T; Courbot-Georges, M C

2004-01-01

The recent emergence of monkey pox in the United States of America highlights the problem (known for other infectious agents) of dissemination of pathogens outside their endemic area, and of subsequent global threats of variable gravity according to agents. It is a real emergency since monkey pox had been confined to Africa for several decades, where small epidemics occurred from time to time, monkey pox is a "miniature smallpox" which, in Africa, evolves on an endemic (zoonotic) mode with, as reservoirs, several species of wild rodents (mainly squirrels) and some monkey species. It can be accidentally transmitted to man then develops as epidemics, sometimes leading to death. The virus was imported in 2003 in the United States of America, via Gambia rats and wild squirrels (all African species), and infected prairie dogs (which are now in fashion as pets), then crossed the species barrier to man. In the United States of America, screening campaigns, epidemiological investigations, and subsequent treatments led to a rapid control of the epidemic, which is a model of emergent disease for this country. Therapeutic and preventive measures directly applicable to monkey pox are discussed. They can also be applied against other pox virus infections (including smallpox). The risk of criminal introduction of pox viruses is discussed since it is, more than ever, a real worldwide threat.

Causal prophylactic efficacy of primaquine, tafenoquine, and atovaquone-proguanil against Plasmodium cynomolgi in a rhesus monkey model.

PubMed

DiTusa, Charles; Kozar, Michael P; Pybus, Brandon; Sousa, Jason; Berman, Jonathan; Gettayacamin, Montip; Im-erbsin, Rawiwan; Tungtaeng, Anchalee; Ohrt, Colin

2014-10-01

Since the 1940s, the large animal model to assess novel causal prophylactic antimalarial agents has been the Plasmodium cynomolgi sporozoite-infected Indian-origin rhesus monkey. In 2009 the model was reassessed with 3 clinical standards: primaquine (PQ), tafenoquine (TQ), and atovaquone-proguanil. Both control monkeys were parasitemic on day 8 post-sporozoite inoculation on day 0. Primaquine at 1.78 mg base/kg/day on days (-1) to 8 protected 1 monkey and delayed parasitemia patency of the other monkey to day 49. Tafenoquine at 6 mg base/kg/day on days (-1) to 1 protected both monkeys. However, atovaquone-proguanil at 10 mg atovaquone/kg/day on days (-1) to 8 did not protect either monkey and delayed patency only to days 18-19. Primaquine and TQ at the employed regimens are proposed as appropriate doses of positive control drugs for the model at present.

Squirrel Monkey Requirements for Chronic Acceleration

NASA Technical Reports Server (NTRS)

Fuller, Charles A.

1996-01-01

This study examined: (1) the ability of a small non-human primate to tolerate chronic centrifugation on a centrifuge with a radius of 0.9 m, and (2) the influence of centrifuge radius on the response of primates to hyperdynamic fields. Eight adult male squirrel monkeys were exposed to 1.5 g via centrifugation at two different radii (0.9 m and 3.0 m). Body temperature, activity, feeding and drinking were monitored. These primates did tolerate and adapt to 1.5G via centrifugation on either radius centrifuge. The results show, however, that centrifuge radius does have an effect on the responses of the primate to the hyperdynamic environment. Adaptation to the hyperdynamic environment occurred more quickly on the larger centrifuge. This study demonstrates that a small, non-human primate model, such as the squirrel monkey, could be used on a 0.9 m radius centrifuge such as is being considered by the NASA Space Station Program.

Immunogenicity of recombinant measles vaccine expressing fusion protein of respiratory syncytial virus in cynomolgus monkeys.

PubMed

Sawada, Akihito; Yunomae, Kiyokazu; Nakayama, Tetsuo

2018-02-01

Respiratory syncytial virus (RSV) is a common cause of respiratory infections in infants. Effective vaccines are currently being sought, but no vaccine is thus far available. In our previous study, recombinant AIK-C measles vaccine expressing the RSV fusion protein (MVAIK/RSV/F) was developed and protective immunity against RSV demonstrated in cotton rats. In the present study, the immunogenicity and protective effects were investigated in three cynomolgus monkeys immunized with MVAIK/RSV/F. Neutralizing test antibodies against RSV were detected and no infectious virus was recovered from the lungs of monkeys immunized with MVAIK/RSV/F after challenge. MVAIK/RSV/F has the potential to inhibit RSV infection. © 2018 The Societies and John Wiley & Sons Australia, Ltd.

Intracerebral infection of Cebus apella with the XJ-Clone 3 strain of Junín virus.

PubMed

Carballal, G; Oubiña, J R; Molinas, F C; Nagle, C; de la Vega, M T; Videla, C; Elsner, B

1987-03-01

To assess the usefulness of the South American primate Cebus apella as a model for neurovirulence of Junín virus, eight monkeys were inoculated with 10(5) LD50 of the attenuated XJ-Clone 3 Junín virus strain by the intrathalamic route. After the second week, weight loss and polyadenopathies were observed in most animals, one-half of which had a transient leukothrombocytopenia. Moderate clinical central nervous system (CNS) involvement was present in four of eight monkeys, while the rest had only mild neurologic signs. All recovered except one, which developed a deep coma and was killed in a pre-mortem stage at 18 days post-infection (pi). Junín virus was isolated from the throat from five, from the blood from three, and from the brain from two monkeys. In the most severely ill animal, virus titers higher than viremia were detected in both inoculated and contralateral brain hemispheres, as well as in lung, lymph node, and small intestine. Junín antigens and "in vivo" bound immunoglobulins were detected by immunofluorescence (IF) in the brain of four animals at 18, 21, 40, and 155 days pi. Moderate lymphocytic parenchymal and meningeal infiltration were observed in the brain of four animals, and gliosis was also present in the most affected monkey. Although the clinical response to infection was not uniform, all infected monkeys developed high IF antibodies. Cebus apella cannot be used as a highly sensitive model for Argentine hemorrhagic fever (AHF). However, the results obtained show that the XJ-Clone 3 strain can replicate in the primate CNS and to induce lesions and immunoglobulin deposition. In addition, viral persistence is suggested by the late detection of viral antigens in brain at 40 and 155 days pi.

Tetanus antibody titers and duration of immunity to clinical tetanus infections in free-ranging rhesus monkeys (Macaca mulatta).

PubMed

Kessler, Matthew J; Berard, John D; Rawlins, Richard G; Bercovitch, Fred B; Gerald, Melissa S; Laudenslager, Mark L; Gonzalez-Martinez, Janis

2006-07-01

Prior to 1985 tetanus was a major cause of mortality in the free-ranging colony of rhesus monkeys on Cayo Santiago, accounting for almost a quarter of annual deaths. In 1985 and 1986 all animals (except infants) received primary and booster doses, respectively, of tetanus toxoid. In subsequent years primary immunizations were given to all yearlings, and boosters were administered to all 2-year-old animals during the annual capture of the colony. The main objectives of the tetanus immunization program were to reduce the pain and suffering caused by tetanus infections and to decrease mortality in the colony. Other objectives were to evaluate the efficacy of the two-dose tetanus toxoid immunization protocol and to determine whether additional boosters might be required to provide adequate long-term protection against tetanus infections. The immediate effect of the mass immunization program was the elimination of clinical tetanus infections in the population and a 42.2% reduction in the overall mortality rate. Since the immunization program began, no cases of tetanus have been observed in the colony, except in two unimmunized infants, and it has not been necessary to give tertiary injections of tetanus toxoid to maintain protection against infection. A sample collected in 2004 of the original cohort of monkeys immunized in 1985 and 1986 showed that 93.3% (14/15) had protective tetanus antibody titers (>0.01 IU/ml) at the ages of 20-23 years, which is close to the life expectancy of the Cayo Santiago rhesus macaques. Two intramuscular doses of tetanus toxoid provided long-term, if not lifelong, protection against tetanus for rhesus monkeys living in a tropical clime where tetanus is enzootic and the risk of infection is great. (c) 2005 Wiley-Liss, Inc.

Plasmodium knowlesi Skeleton-Binding Protein 1 Localizes to the 'Sinton and Mulligan' Stipplings in the Cytoplasm of Monkey and Human Erythrocytes.

PubMed

Lucky, Amuza Byaruhanga; Sakaguchi, Miako; Katakai, Yuko; Kawai, Satoru; Yahata, Kazuhide; Templeton, Thomas J; Kaneko, Osamu

2016-01-01

The malaria parasite, Plasmodium, exports protein products to the infected erythrocyte to introduce modifications necessary for the establishment of nutrient acquisition and surface display of host interaction ligands. Erythrocyte remodeling impacts parasite virulence and disease pathology and is well documented for the human malaria parasite Plasmodium falciparum, but has been less described for other Plasmodium species. For P. falciparum, the exported protein skeleton-binding protein 1 (PfSBP1) is involved in the trafficking of erythrocyte surface ligands and localized to membranous structures within the infected erythrocyte, termed Maurer's clefts. In this study, we analyzed SBP1 orthologs across the Plasmodium genus by BLAST analysis and conserved gene synteny, which were also recently described by de Niz et al. (2016). To evaluate the localization of an SBP1 ortholog, we utilized the zoonotic malaria parasite, Plasmodium knowlesi. Immunofluorescence assay of transgenic P. knowlesi parasites expressing epitope-tagged recombinant PkSBP1 revealed a punctate staining pattern reminiscent of Maurer's clefts, following infection of either monkey or human erythrocytes. The recombinant PkSBP1-positive puncta co-localized with Giemsa-stained structures, known as 'Sinton and Mulligan' stipplings. Immunoelectron microscopy also showed that recombinant PkSBP1 localizes within or on the membranous structures akin to the Maurer's clefts. The recombinant PkSBP1 expressed in P. falciparum-infected erythrocytes co-localized with PfSBP1 at the Maurer's clefts, indicating an analogous trafficking pattern. A member of the P. knowlesi 2TM protein family was also expressed and localized to membranous structures in infected monkey erythrocytes. These results suggest that the trafficking machinery and induced erythrocyte cellular structures of P. knowlesi are similar following infection of both monkey and human erythrocytes, and are conserved with P. falciparum.

Therapeutic and protective efficacy of a dengue antibody against Zika infection in rhesus monkeys.

PubMed

Abbink, Peter; Larocca, Rafael A; Dejnirattisai, Wanwisa; Peterson, Rebecca; Nkolola, Joseph P; Borducchi, Erica N; Supasa, Piyada; Mongkolsapaya, Juthathip; Screaton, Gavin R; Barouch, Dan H

2018-06-01

Strategies to treat Zika virus (ZIKV) infection in dengue virus (DENV)-endemic areas are urgently needed. Here we show that a DENV-specific antibody against the E-dimer epitope (EDE) potently cross-neutralizes ZIKV and provides robust therapeutic efficacy as well as prophylactic efficacy against ZIKV in rhesus monkeys. Viral escape was not detected, suggesting a relatively high bar to escape. These data demonstrate the potential for antibody-based therapy and prevention of ZIKV.

Chronic suppression of testicular function by constant infusion of gonadotropin-releasing hormone agonist and testosterone supplementation in the bonnet monkey (Macaca radiata).

PubMed

Ravindranath, N; Ramesh, V; Krishnamurthy, H N; Rao, A J; Moudgal, R N

1992-03-01

To study the efficacy of long-term buserelin acetate infusion to desensitize pituitary and block testicular function in adult male monkeys (Macaca radiata). Proven fertile male monkeys exhibiting normal testicular function. Each of the control (n = 5) and experimental monkeys (n = 10) received a fresh miniosmotic pump every 21 days, whereas pumps in controls delivered vehicle of experimentals released 50 micrograms buserelin acetate every 24 hours. On day 170 (renewed every 60 days) a silastic capsule containing crystalline testosterone (T) was implanted in the experimental monkeys. At the end of 3 years, treatment was stopped, and recovery of testicular function and fertility monitored. (1) Treatment resulted in marked reduction of nocturnal but not basal serum T; (2) the pituitary remained desensitized to buserelin acetate throughout the 3-year period; (3) animals were largely azoospermic with occasional oligospermia exhibited by two monkeys; and (4) withdrawal of treatment restored testicular function, with 70% of animals regaining fertility. Long-term infertility (but restorable) can be induced in male monkeys by constant infusion of buserelin acetate and T.

Virulence characteristics of Yersinia pseudotuberculosis isolated from breeding monkeys in Japan.

PubMed

Iwata, Taketoshi; Une, Yumi; Okatani, Alexandre Tomomitsu; Kato, Yukio; Nakadai, Aya; Lee, Ken-Ichi; Watanabe, Maiko; Taniguchi, Takahide; Elhelaly, AbdelAzim Elsayed; Hirota, Yoshikazu; Hayashidani, Hideki

2008-06-22

Between April 2001 and 2007, 18 Yersinia pseudotuberculosis outbreaks occurred in breeding monkeys at 12 zoological gardens in Japan, and 28 monkeys of 8 species died. A total of 18 Y. pseudotuberculosis strains from the dead monkeys, comprising one strain per outbreak, were examined for serotype and the presence of the virulence genes virF, inv, ypm (ypmA, ypmB and ypmC) and irp2. Of the 18 Y. pseudotuberculosis strains, 7 (38.9%) were serotype 4b, 7 (38.9%) were serotype 1b, and there was one each of serotypes 2b, 3, 6 and 7. All the 18 strains examined harbored virF and inv. Sixteen (88.9%) strains, including the strain of serotype 7, harbored ypmA. However, no strain harbored ypmB, ypmC and irp2. This study demonstrated that among other pathogenic factors, almost all the Y. pseudotuberculosis isolated from the outbreaks had the ypm gene encoding the superantigenic toxin, YPM. As most of the monkeys who died in those outbreaks originated from South America and other regions, where the presence of the ypm gene have not been reported, YPM might be the cause, or at least the most important factor for, the high mortality of the breeding monkeys infected by Y. pseudotuberculosis in Japan. This is also the first report of a fatal case due to Y. pseudotuberculosis serotype 7 infection in the world.

Full-length genome sequence of a simian immunodeficiency virus from a wild-captured sun-tailed monkey in Gabon provides evidence for a species-specific monophyletic SIVsun lineage.

PubMed

Liégeois, Florian; Butel, Christelle; Mouinga-Ondéme, Augustin; Verrier, Delphine; Motsch, Peggy; Gonzalez, Jean-Paul; Peeters, Martine; Rouet, François; Onanga, Richard

2011-11-01

Since the first characterization of SIVsun (L14 strain) from a sun-tailed monkey (Cercopithecus solatus) in Gabon in 1999, no further information exists about the evolutionary history and geographic distribution of this lentivirus. Here, we report the full-length molecular characterization of a second SIVsun virus (SIVsunK08) naturally infecting a wild-caught sun-tailed monkey. The SIVsunK08 strain was most closely related to SIVsunL14 and clustered with members of the SIVmnd-1/SIVlhoest group. SIVsunK08 shared identical functional motifs in the LTR, Gag and Env proteins with SIVsunL14. Our data indicate that C. solatus is naturally infected with a monophyletic SIVsun strain.

PCR detection and DNA sequence analysis of the regulatory region of lymphotropic papovavirus in peripheral blood mononuclear cells of an immunocompromised rhesus macaque

NASA Technical Reports Server (NTRS)

Lednicky, John A.; Halvorson, Steven J.; Butel, Janet S.

2002-01-01

A lymphotropic papovavirus (LPV) archetypal regulatory region was amplified from DNA from the blood of an immunocompromised rhesus monkey. We believe this is the first nonserological evidence of LPV infection in rhesus monkeys.

Simian Varicella Virus Infection of Rhesus Macaques Recapitulates Essential Features of Varicella Zoster Virus Infection in Humans

PubMed Central

Messaoudi, Ilhem; Barron, Alexander; Wellish, Mary; Engelmann, Flora; Legasse, Alfred; Planer, Shannon; Gilden, Don; Nikolich-Zugich, Janko; Mahalingam, Ravi

2009-01-01

Simian varicella virus (SVV), the etiologic agent of naturally occurring varicella in primates, is genetically and antigenically closely related to human varicella zoster virus (VZV). Early attempts to develop a model of VZV pathogenesis and latency in nonhuman primates (NHP) resulted in persistent infection. More recent models successfully produced latency; however, only a minority of monkeys became viremic and seroconverted. Thus, previous NHP models were not ideally suited to analyze the immune response to SVV during acute infection and the transition to latency. Here, we show for the first time that intrabronchial inoculation of rhesus macaques with SVV closely mimics naturally occurring varicella (chickenpox) in humans. Infected monkeys developed varicella and viremia that resolved 21 days after infection. Months later, viral DNA was detected only in ganglia and not in non-ganglionic tissues. Like VZV latency in human ganglia, transcripts corresponding to SVV ORFs 21, 62, 63 and 66, but not ORF 40, were detected by RT-PCR. In addition, as described for VZV, SVV ORF 63 protein was detected in the cytoplasm of neurons in latently infected monkey ganglia by immunohistochemistry. We also present the first in depth analysis of the immune response to SVV. Infected animals produced a strong humoral and cell-mediated immune response to SVV, as assessed by immunohistology, serology and flow cytometry. Intrabronchial inoculation of rhesus macaques with SVV provides a novel model to analyze viral and immunological mechanisms of VZV latency and reactivation. PMID:19911054

Simian varicella virus infection of rhesus macaques recapitulates essential features of varicella zoster virus infection in humans.

PubMed

Messaoudi, Ilhem; Barron, Alexander; Wellish, Mary; Engelmann, Flora; Legasse, Alfred; Planer, Shannon; Gilden, Don; Nikolich-Zugich, Janko; Mahalingam, Ravi

2009-11-01

Simian varicella virus (SVV), the etiologic agent of naturally occurring varicella in primates, is genetically and antigenically closely related to human varicella zoster virus (VZV). Early attempts to develop a model of VZV pathogenesis and latency in nonhuman primates (NHP) resulted in persistent infection. More recent models successfully produced latency; however, only a minority of monkeys became viremic and seroconverted. Thus, previous NHP models were not ideally suited to analyze the immune response to SVV during acute infection and the transition to latency. Here, we show for the first time that intrabronchial inoculation of rhesus macaques with SVV closely mimics naturally occurring varicella (chickenpox) in humans. Infected monkeys developed varicella and viremia that resolved 21 days after infection. Months later, viral DNA was detected only in ganglia and not in non-ganglionic tissues. Like VZV latency in human ganglia, transcripts corresponding to SVV ORFs 21, 62, 63 and 66, but not ORF 40, were detected by RT-PCR. In addition, as described for VZV, SVV ORF 63 protein was detected in the cytoplasm of neurons in latently infected monkey ganglia by immunohistochemistry. We also present the first in depth analysis of the immune response to SVV. Infected animals produced a strong humoral and cell-mediated immune response to SVV, as assessed by immunohistology, serology and flow cytometry. Intrabronchial inoculation of rhesus macaques with SVV provides a novel model to analyze viral and immunological mechanisms of VZV latency and reactivation.

Effects of Aroclor 1254 reg sign on hydrocortisone levels in adult Rhesus monkeys (Macaca mulatta)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Loo, J.C.K.; Tryphonas, H.; Jordan, N.

Researchers, using female Sprague Dawley rats, reported the effects of chronic (5-7 months) oral dosing with Aroclor 1254{reg sign} (Polychlorinated biphenyls-PCB) on the serum levels of corticosterone, the principle glucocorticoid in rats. Their findings indicated that corticosterone levels were significantly depressed at dose levels of 479 {mu}g/kg bw/day and above. The objective of the present study was to determine the effects of PCB on the hydrocortisone levels in Rhesus monkey (Macaca mulatta) serum. In the monkey the controlling hormone is hydrocortisone which is identical to that of humans.

FURTHER INVESTIGATIONS OF THE CHEMOTHERAPY OF RADIATION SICKNESS IN EXPERIMENTS ON MONKEYS

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tumanian, M.A.

1958-01-01

>The rational use of chemotherapy in the treatment of radiation siekness prevents the development of postradiational bacteremia and the transformation of a latent chronic dysentery in monkeys into a clinically apparent acute form of the disease. Chemotherapy has a favorable effect on the outcome of radiation sickness in monkeys, preserving the lives of a large proportion of the animals even when exposed to an absolute lethal dose of x rays. Streptomycin in the principal therapeutic program suggested for radiation sickness can be replaced by other antibiotics, albomycin and colimycin, or by the sulfonamide drug phthalylsulfathiazole. (auth)

Modulation of gut-specific mechanisms by chronic δ(9)-tetrahydrocannabinol administration in male rhesus macaques infected with simian immunodeficiency virus: a systems biology analysis.

PubMed

Molina, Patricia E; Amedee, Angela M; LeCapitaine, Nicole J; Zabaleta, Jovanny; Mohan, Mahesh; Winsauer, Peter J; Vande Stouwe, Curtis; McGoey, Robin R; Auten, Matthew W; LaMotte, Lynn; Chandra, Lawrance C; Birke, Leslie L

2014-06-01

Our studies have demonstrated that chronic Δ(9)-tetrahydrocannabinol (THC) administration results in a generalized attenuation of viral load and tissue inflammation in simian immunodeficiency virus (SIV)-infected male rhesus macaques. Gut-associated lymphoid tissue is an important site for HIV replication and inflammation that can impact disease progression. We used a systems approach to examine the duodenal immune environment in 4- to 6-year-old male rhesus monkeys inoculated intravenously with SIVMAC251 after 17 months of chronic THC administration (0.18-0.32 mg/kg, intramuscularly, twice daily). Duodenal tissue samples excised from chronic THC- (N=4) and vehicle (VEH)-treated (N=4) subjects at ∼5 months postinoculation showed lower viral load, increased duodenal integrin beta 7(+)(β7) CD4(+) and CD8(+) central memory T cells, and a significant preferential increase in Th2 cytokine expression. Gene array analysis identified six genes that were differentially expressed in intestinal samples of the THC/SIV animals when compared to those differentially expressed between VEH/SIV and uninfected controls. These genes were identified as having significant participation in (1) apoptosis, (2) cell survival, proliferation, and morphogenesis, and (3) energy and substrate metabolic processes. Additional analysis comparing the duodenal gene expression in THC/SIV vs. VEH/SIV animals identified 93 differentially expressed genes that participate in processes involved in muscle contraction, protein folding, cytoskeleton remodeling, cell adhesion, and cell signaling. Immunohistochemical staining showed attenuated apoptosis in epithelial crypt cells of THC/SIV subjects. Our results indicate that chronic THC administration modulated duodenal T cell populations, favored a pro-Th2 cytokine balance, and decreased intestinal apoptosis. These findings reveal novel mechanisms that may potentially contribute to cannabinoid-mediated disease modulation.

Associations between Parity, Hair Hormone Profiles during Pregnancy and Lactation, and Infant Development in Rhesus Monkeys (Macaca mulatta)

PubMed Central

Dettmer, Amanda M.; Rosenberg, Kendra L.; Suomi, Stephen J.; Meyer, Jerrold S.; Novak, Melinda A.

2015-01-01

Studies examining hormones throughout pregnancy and lactation in women have been limited to single, or a few repeated, short-term measures of endocrine activity. Furthermore, potential differences in chronic hormonal changes across pregnancy/lactation between first-time and experienced mothers are not well understood, especially as they relate to infant development. Hormone concentrations in hair provide long-term assessments of hormone production, and studying these measures in non-human primates allows for repeated sampling under controlled conditions that are difficult to achieve in humans. We studied hormonal profiles in the hair of 26 female rhesus monkeys (Macaca mulatta, n=12 primiparous), to determine the influences of parity on chronic levels of cortisol (hair cortisol concentration, HCC) and progesterone (hair progesterone concentration, HPC) during early- to mid-pregnancy (PREG1), in late pregnancy/early lactation (PREG2/LACT1), and in peak lactation (LACT2). We also assessed infants’ neurobehavioral development across the first month of life. After controlling for age and stage of pregnancy at the first hair sampling period, we found that HCCs overall peaked in PREG2/LACT1 (p=0.02), but only in primiparous monkeys (p<0.001). HPCs declined across pregnancy and lactation for all monkeys (p<0.01), and primiparous monkeys had higher HPCs overall than multiparous monkeys (p=0.02). Infants of primiparous mothers had lower sensorimotor reflex scores (p=0.02) and tended to be more irritable (p=0.05) and less consolable (p=0.08) in the first month of life. Moreover, across all subjects, HCCs in PREG2/LACT1 were positively correlated with irritability (r(s)=0.43, p=0.03) and negatively correlated with sensorimotor scores (r(s)=-0.41, p=0.04). Together, the present results indicate that primiparity influences both chronic maternal hormonal profiles and infant development. These effects may, in part, reflect differential reproductive and maternal effort in mothers with varied caretaking experience. In addition, infant exposure to relatively higher levels of maternal cortisol during the late fetal and early postnatal periods is predictive of poorer developmental outcomes. PMID:26172048

Effect of a chronic treatment with 17β-estradiol on striatal dopamine neurotransmission and the Akt/GSK3 signaling pathway in the brain of ovariectomized monkeys.

PubMed

Sánchez, Maria Gabriela; Morissette, Marc; Di Paolo, Thérèse

2012-02-01

The present experiments sought the effect of chronic treatment with 17β-estradiol on striatal dopaminergic activity and the Akt/GSK3 signaling pathway in the brain of monkeys. Eight female monkeys (Macacca fascicularis) were ovariectomized (OVX) and a month later, half received a month treatment with 17β-estradiol and the other with vehicle. The DA transporter (DAT) was measured by autoradiography with [(125)I]RTI-121 and the vesicular DA transporter (VMAT(2)) with [(3)H]TBZ-OH at three rostro-caudal levels (anterior, middle and posterior) of the caudate nucleus and putamen subdivided in their lateral/medial, ventral/dorsal sub-regions. Specific binding to DAT was increased in all sub-regions of the caudate nucleus and the putamen of 17β-estradiol-treated compared to vehicle-treated monkeys whereas specific binding to VMAT(2) remained unchanged. We measured by Western blot the phosphorylated forms of Akt at serine 473 and threonine 308, GSK3β at serine 9 and tyrosine 216 and GSK3α at serine 21 in anterior, middle and posterior caudate nucleus and putamen. 17β-Estradiol treatment increased in all the caudate nucleus and putamen pAkt (Ser473)/βIII-tubulin, pGSK3β (Ser9)/βIII-tubulin and in putamen Akt/βIII-tubulin compared to vehicle-treated monkeys. In anterior and middle putamen, pAkt (Thr308)/βIII-tubulin was also increased in monkeys treated with 17β-estradiol. pGSK3β (Tyr216)/βIII-tubulin and pGSK3α (Ser21)/βIII-tubulin remained unchanged by the 17β-estradiol treatment. These results suggest that 17β-estradiol activates striatal DA neurotransmission in primates as reflected with increased DAT specific binding and downstream activation of Akt/GSK3 signaling. This supports a beneficial role of a chronic treatment with 17β-estradiol by increasing the activity of signaling pathways implicated in cell survival. Copyright © 2011 Elsevier Ltd. All rights reserved.

Primary simian immunodeficiency virus SIVmnd-2 infection in mandrills (Mandrillus sphinx).

PubMed

Onanga, Richard; Souquière, Sandrine; Makuwa, Maria; Mouinga-Ondeme, Augustin; Simon, François; Apetrei, Cristian; Roques, Pierre

2006-04-01

Mandrills are the only nonhuman primate (NHP) naturally infected by two types of simian immunodeficiency virus (SIV): SIVmnd-1 and SIVmnd-2. We have already reported that the high SIVmnd-1 replication during primary infection contrasts with only transient changes in CD4+ and CD8+ cell counts. Since early virus-host interactions predict viral control and disease progression in human immunodeficiency virus-infected patients, we investigated the dynamics of SIVmnd-2 primary infection in mandrills to examine the impact on immune effectors in blood and lymph nodes (LNs). To avoid in vitro strain selection, all mandrills in this study received plasma from SIVmnd-2-infected mandrills. SIVmnd-2 plasma viremia peaked at 10(7) to 10(8) RNA copies/ml between days 7 and 10. This peak was followed in all four monkeys by a decline in virus replication, with a set point level of 10(5) to 10(6) RNA copies/ml at day 42 postinfection (p.i.). Viral DNA load in PBMC and LNs also peaked between days 7 and 10 (10(5) to 10(6) DNA copies/10(6) cells) and stabilized at 10(3) to 10(4) DNA copies/10(6) cells during the chronic phase. Anti-SIVmnd-2 antibodies were detected starting from days 28 to 32. A transitory decline of CD3+ CD4+ cells in the LNs occurred in animals with high peak VLs. CD4+ and CD8+ T-cell activation in blood and LNs was noted between days 5 and 17 p.i., surrounding the peak of viral replication. This was most significant in the LNs. Activation markers then returned to preinfection values despite continuous and active viral replication during the chronic infection. The dynamics of SIVmnd-2 infection in mandrills showed a pattern similar to that of SIVmnd-1 infection. This might be a general feature of nonpathogenic SIV natural African NHP models.

Virus Diseases: The Global Challenge to Health for All. Asia-Pacific Congress of Medical Virology (2nd) Held in Bangkok, Thailand on November 17-22, 1991. Abstracts

DTIC Science & Technology

1992-07-01

Chicken - pox is often considered a benign disease. However, certain infrequent but severe complications such as encephalitis, Reye’s syndrome and...hepatitis. It has infected people in Asia (including India since 1956 or earlier), Africa, and Mexico . A peculiarity of HEV infections in that levels of... Mexico 󈨚 in cynomolgus and owl monkeys. Disease in cynomolgus monkeys was similar to that which was previously reported; these animals have been our

Comparative Infectivity Determinations of Dengue Virus Vaccine Candidates in Rhesus Monkeys, Mosquitoes, and Cell Cultures

DTIC Science & Technology

1993-01-28

34 are required for the evaluation of these vaccine candidates. RE: DAMDI7-89-C-9175 Page 16 REFERENCES 1. Sabin AB, Sclesinger RW, 1945. Production of...AD-A261 892 CONTRACT NO: DAMD17-89-C-9 175 \\II\\IllI\\I\\I1\\\\~il\\ TITLE: COMPARATIVE INFECTIVITY DETERMINATIONS OF DENGUE VIRUS VACCINE CANDIDATES IN... Vaccine Candidates in Rhesus Monkeys, 63002A Mosquitoes, and Cell Cultures 3M263002D870 AC 6. AUTHOR(S) DA335475 Edmundo Kraiselburd 7. PERFORMING

Simian virus 40 inhibits differentiation and maturation of rhesus macaque DC-SIGN(+) dendritic cells.

PubMed

Changyong, C; Sun, M; Li, H; Brockmeyer, N; Wu, Nan Ping

2010-09-24

Dendritic cells (DC) are the initiators and modulators of the immune responses. Some species of pathogenic microorganisms have developed immune evasion strategies by controlling antigen presentation function of DC. Simian virus 40 (SV40) is a DNA tumor virus of rhesus monkey origin. It can induce cell transformation and tumorigenesis in many vertebrate species, but often causes no visible effects and persists as a latent infection in rhesus monkeys under natural conditions. To investigate the interaction between SV40 and rhesus monkey DC, rhesus monkey peripheral blood monocyte-derived DC were induced using recombinant human Interleukin-4 (rhIL-4) and infective SV40, the phenotype and function of DC-specific intracellular adhesion molecule-3 grabbing nonintegrin (DC-SIGN)(+) DC were analyzed by flow cytometry (FCM) and mixed lymphocyte reaction (MLR). Results showed that SV40 can down-regulate the expression of CD83 and CD86 on DC and impair DC-induced activation of T cell proliferation. These findings suggest that SV40 might also cause immune suppression by influencing differentiation and maturation of DC.

Antimalarial activities of new guanidylimidazole and guanidylimidazoline derivatives.

PubMed

Zhang, Liang; Sathunuru, Ramadas; Caridha, Diana; Pybus, Brandon; O'Neil, Michael T; Kozar, Michael P; Lin, Ai J

2011-10-13

A series of new guanidylimidazole derivatives was prepared and evaluated in mice and Rhesus monkeys infected with malarial sporozoites. The majority of the new compounds showed poor metabolic stability and weak in vitro activities in three clones of Plasmodium falciparum. Compounds 8a, 8h, 9a, 16a, and 16e cured the mice infected with sporozoites of P. berghei at 160 and 320 mg/kg/day × 3 po. Compounds 8a showed better causal prophylactic activity than primaquine, tafenoquine, and Malarone in the Rhesus test. In the radical curative test, 8a cured one monkey and delayed relapse of another for 74 days at 30 mg/kg/day × 7 by im. By oral dosing, 8a delayed relapse 81 days for one and 32 days for other vs 11-12 days for control monkeys treated with 10 mg/kg of chloroquine by po alone. Compound 8h, which showed superior activity to 8a in mouse test, delayed the relapse of treated monkeys for 21-26 days at 30 mg/kg/day × 7 by oral.

Identification of Owl Monkey CD4 Receptors Broadly Compatible with Early-Stage HIV-1 Isolates

PubMed Central

Meyerson, Nicholas R.; Sharma, Amit; Wilkerson, Gregory K.

2015-01-01

ABSTRACT Most HIV-1 variants isolated from early-stage human infections do not use nonhuman primate versions of the CD4 receptor for cellular entry, or they do so poorly. We and others have previously shown that CD4 has experienced strong natural selection over the course of primate speciation, but it is unclear whether this selection has influenced the functional characteristics of CD4 as an HIV-1 receptor. Surprisingly, we find that selection on CD4 has been most intense in the New World monkeys, animals that have never been found to harbor lentiviruses related to HIV-1. Based on this, we sampled CD4 genetic diversity within populations of individuals from seven different species, including five species of New World monkeys. We found that some, but not all, CD4 alleles found in Spix's owl monkeys (Aotus vociferans) encode functional receptors for early-stage human HIV-1 isolates representing all of the major group M clades (A, B, C, and D). However, only some isolates of HIV-1 subtype C can use the CD4 receptor encoded by permissive Spix's owl monkey alleles. We characterized the prevalence of functional CD4 alleles in a colony of captive Spix's owl monkeys and found that 88% of surveyed individuals are homozygous for permissive CD4 alleles, which encode an asparagine at position 39 of the receptor. We found that the CD4 receptors encoded by two other species of owl monkeys (Aotus azarae and Aotus nancymaae) also serve as functional entry receptors for early-stage isolates of HIV-1. IMPORTANCE Nonhuman primates, particularly macaques, are used for preclinical evaluation of HIV-1 vaccine candidates. However, a significant limitation of the macaque model is the fact that most circulating HIV-1 variants cannot use the macaque CD4 receptor to enter cells and have to be adapted to these species. This is particularly true for viral variants from early stages of infection, which represent the most relevant vaccine targets. In this study, we found that some individuals from captive owl monkey populations harbor CD4 alleles that are compatible with a broad collection of HIV-1 isolates, including those isolated from early in infection in highly affected populations and representing diverse subtypes. PMID:26063421

Characterisation of the hepatitis B virus cross-species transmission pattern via Na+/taurocholate co-transporting polypeptides from 11 New World and Old World primate species.

PubMed

Müller, Simon F; König, Alexander; Döring, Barbara; Glebe, Dieter; Geyer, Joachim

2018-01-01

The hepatic Na+/taurocholate co-transporting polypeptide (NTCP in man, Ntcp in animals) is the high-affinity receptor for the hepatitis B (HBV) and hepatitis D (HDV) viruses. Species barriers for human HBV/HDV within the order Primates were previously attributed to Ntcp sequence variations that disable virus-receptor interaction. However, only a limited number of primate Ntcps have been analysed so far. In the present study, a total of 11 Ntcps from apes, Old and New World monkeys were cloned and expressed in vitro to characterise their interaction with HBV and HDV. All Ntcps showed intact bile salt transport. Human NTCP as well as the Ntcps from the great apes chimpanzee and orangutan showed transport-competing binding of HBV derived myr-preS1-peptides. In contrast, all six Ntcps from the group of Old World monkeys were insensitive to HBV myr-preS1-peptide binding and HBV/HDV infection. This is basically predetermined by the amino acid arginine at position 158 of all studied Old World monkey Ntcps. An exchange from arginine to glycine (as present in humans and great apes) at this position (R158G) alone was sufficient to achieve full transport-competing HBV myr-preS1-peptide binding and susceptibility for HBV/HDV infection. New World monkey Ntcps showed higher sequence heterogeneity, but in two cases with 158G showed transport-competing HBV myr-preS1-peptide binding, and in one case (Saimiri sciureus) even susceptibility for HBV/HDV infection. In conclusion, amino acid position 158 of NTCP/Ntcp is sufficient to discriminate between the HBV/HDV susceptible group of humans and great apes (158G) and the non-susceptible group of Old World monkeys (158R). In the case of the phylogenetically more distant New World monkey Ntcps amino acid 158 plays a significant, but not exclusive role.

Persistence and immunogenicity of chemically attenuated blood stage Plasmodium falciparum in Aotus monkeys.

PubMed

De, Sai Lata; Stanisic, Danielle I; van Breda, Karin; Bellete, Bernadette; Harris, Ivor; McCallum, Fiona; Edstein, Michael D; Good, Michael F

2016-08-01

Malaria is a disease caused by a protozoan of the Plasmodium genus and results in 0.5-0.7million deaths per year. Increasing drug resistance of the parasite and insecticide resistance of mosquitoes necessitate alternative control measures. Numerous vaccine candidates have been identified but none have been able to induce robust, long-lived protection when evaluated in malaria endemic regions. Rodent studies have demonstrated that chemically attenuated blood stage parasites can persist at sub-patent levels and induce homologous and heterologous protection against malaria. Parasite-specific cellular responses were detected, with protection dependent on CD4+ T cells. To investigate this vaccine approach for Plasmodium falciparum, we characterised the persistence and immunogenicity of chemically attenuated P. falciparum FVO strain parasites (CAPs) in non-splenectomised Aotus nancymaae monkeys following administration of a single dose. Control monkeys received either normal red blood cells or wild-type parasites followed by drug treatment. Chemical attenuation was performed using tafuramycin A, which irreversibly binds to DNA. CAPs were detected in the peripheral blood for up to 2days following inoculation as determined by thick blood smears, and for up to 8days as determined by quantitative PCR. Parasite-specific IgG was not detected in monkeys that received CAPs; however, in vitro parasite-specific T cell proliferation was observed. Following challenge, the CAP monkeys developed an infection; however, one CAP monkey and the infection and drug-cure monkeys showed partial or complete resistance. These experiments lay the groundwork for further assessment of CAPs as a potential vaccine against malaria. Copyright © 2016 Australian Society for Parasitology. Published by Elsevier Ltd. All rights reserved.

High prevalence of Enterocytozoon bieneusi zoonotic genotype D in captive golden snub-nosed monkey (Rhinopithecus roxellanae) in zoos in China.

PubMed

Yu, Fuchang; Wu, Yayun; Li, Tongyi; Cao, Jianke; Wang, Jiantang; Hu, Suhui; Zhu, Huili; Zhang, Sumei; Wang, Rongjun; Ning, Changshen; Zhang, Longxian

2017-06-05

Enterocytozoon bieneusi is the dominant specie of microsporidia which can infect both anthroponotic and zoonotic species. The golden snub-nosed monkey is an endangered primate which can also infect by E. bieneusi. To date, few genetic data on E. bieneusi from golden snub-nosed monkeys has been published. Therefore, to clarify the prevalence and genotypes of E. bieneusi in captive golden snub-nosed monkeys is necessary to assess the potential for zoonotic transmission. We examined 160 golden snub-nosed monkeys from six zoos in four cities in China, using PCR and comparative sequence analysis of the ribosomal internal transcribed spacer (ITS). The overall prevalence of E. bieneusi was 46.2% (74/160); while the prevalence was 26.7%, 69.1%, 69.4% and 33.3% in Shanghai Zoo, Shanghai Wild Animal Park, Tongling Zoo, and Taiyuan Zoo respectively (P = 0.006). A total of seven E. bieneusi genotypes were found that included four known (D, J, CHG1, and CHG14) and three new (CM19-CM 21) genotypes. The most common genotype was D (54/74, 73.0%), followed by J (14/74, 18.9%); other genotypes were restricted to one or two samples. Phylogenetic analysis revealed that genotype D belonged to the previously-characterized Group 1, with zoonotic potential; whereas genotypes J, CHG1, CHG14 and CM19-CM 21 clustered in the previously-characterized Group 2, the so-called cattle host specificity group. The findings of high prevalence of zoonotic E. bieneusi genotypes D and J in golden snub-nosed monkeys suggest that golden snub-nosed monkeys may be the reservoir hosts for human microsporidiosis, and vice versa.

Effects on body size and composition of chronic exposure to altered gravity. [centrifuging stress in mammals

NASA Technical Reports Server (NTRS)

Pitts, G. C.

1977-01-01

The effects of chronic centrifugation on body composition and growth of rats, mice, monkeys, and man are studied. The benefits of exercise and restraint during acceleration are investigated. Physiological regulation and energy balance are also discussed.

Novel simian foamy virus infections from multiple monkey species in women from the Democratic Republic of Congo

PubMed Central

2012-01-01

Background Zoonotic transmission of simian retroviruses in Central Africa is ongoing and can result in pandemic human infection. While simian foamy virus (SFV) infection was reported in primate hunters in Cameroon and Gabon, little is known about the distribution of SFV in Africa and whether human-to-human transmission and disease occur. We screened 3,334 plasmas from persons living in rural villages in central Democratic Republic of Congo (DRC) using SFV-specific EIA and Western blot (WB) tests. PCR amplification of SFV polymerase sequences from DNA extracted from buffy coats was used to measure proviral loads. Phylogenetic analysis was used to define the NHP species origin of SFV. Participants completed questionnaires to capture NHP exposure information. Results Sixteen (0.5%) samples were WB-positive; 12 of 16 were from women (75%, 95% confidence limits 47.6%, 92.7%). Sequence analysis detected SFV in three women originating from Angolan colobus or red-tailed monkeys; both monkeys are hunted frequently in DRC. NHP exposure varied and infected women lived in distant villages suggesting a wide and potentially diverse distribution of SFV infections across DRC. Plasmas from 22 contacts of 8 WB-positive participants were all WB negative suggesting no secondary viral transmission. Proviral loads in the three women ranged from 14 – 1,755 copies/105 cells. Conclusions Our study documents SFV infection in rural DRC for the first time and identifies infections with novel SFV variants from Colobus and red-tailed monkeys. Unlike previous studies, women were not at lower risk for SFV infection in our population, providing opportunities for spread of SFV both horizontally and vertically. However, limited testing of close contacts of WB-positive persons did not identify human-to-human transmission. Combined with the broad behavioral risk and distribution of NHPs across DRC, our results suggest that SFV infection may have a wider geographic distribution within DRC. These results also reinforce the potential for an increased SFV prevalence throughout the forested regions of Africa where humans and simians co-exist. Our finding of endemic foci of SFV infection in DRC will facilitate longitudinal studies to determine the potential for person-to-person transmissibility and pathogenicity of these zoonotic retroviral infections. PMID:23217108

PrimaTB STAT-PAK Assay, a Novel, Rapid Lateral-Flow Test for Tuberculosis in Nonhuman Primates▿

PubMed Central

Lyashchenko, Konstantin P.; Greenwald, Rena; Esfandiari, Javan; Greenwald, David; Nacy, Carol A.; Gibson, Susan; Didier, Peter J.; Washington, Marc; Szczerba, Peter; Motzel, Sherri; Handt, Larry; Pollock, John M.; McNair, James; Andersen, Peter; Langermans, Jan A. M.; Verreck, Frank; Ervin, Sean; Ervin, Frank; McCombs, Candace

2007-01-01

Tuberculosis (TB) is the most important zoonotic bacterial disease in nonhuman primates (NHP). The current diagnostic method, the intradermal palpebral tuberculin test, has serious shortcomings. We characterized antibody responses in NHP against Mycobacterium tuberculosis to identify immunodominant antigens and develop a rapid serodiagnostic test for TB. A total of 422 NHP were evaluated, including 243 rhesus (Macaca mulatta), 46 cynomolgus (Macaca fascicularis), and 133 African green (Cercopithecus aethiops sabaeus) monkeys at five collaborative centers. Of those, 50 monkeys of the three species were experimentally inoculated with M. tuberculosis. Antibody responses were monitored every 2 to 4 weeks for up to 8 months postinfection by MultiAntigen Print ImmunoAssay with a panel of 12 recombinant antigens. All of the infected monkeys produced antibodies at various levels and with different antigen recognition patterns. ESAT-6 and MPB83 were the most frequently recognized proteins during infection. A combination of selected antigens which detected antibodies in all of the infected monkeys was designed to develop the PrimaTB STAT-PAK assay by lateral-flow technology. Serological evaluation demonstrated high diagnostic sensitivity (90%) and specificity (99%). The highest rate of TB detection was achieved when the skin test was combined with the PrimaTB STAT-PAK kit. This novel immunoassay provides a simple, rapid, and accurate test for TB in NHP. PMID:17652522

Frequency of histopathological changes in Howler monkeys ( Alouatta sp.) naturally infected with yellow fever virus in Brazil.

PubMed

Leal, Silvana Gomes; Romano, Alessandro Pecego Martins; Monteiro, Rafael Veríssimo; Melo, Cristiano Barros de; Vasconcelos, Pedro Fernando da Costa; Castro, Márcio Botelho de

2016-02-01

Due to the importance that Howler monkeys have on the yellow fever (YF) epidemiological sylvatic cycle in Brazil, more accurate morphological diagnostic criteria needs to be established, especially considering the differences that may exist between the genera of Brazilian non-human primates (NHPs) involved in yellow fever virus (YFV) epizootics. Records of YF epizootics in NHPs in Brazil between 2007 and 2009 were obtained from the Brazilian Ministry of Health database to select YF positive (n=98) Howler monkeys (Alouatta sp.) for this study. The changes described in the histopathological reports were categorized by organ and their frequencies calculated. The most frequent lesions observed in the animals with YF were hepatocyte apoptosis (Councilman body formation), midzonal hepatocyte necrosis, steatosis, liver hemorrhage, inflammatory mononuclear cell infiltration of the liver, renal acute tubular necrosis and interstitial nephritis. Midzonal hepatocyte necrosis, steatosis and hemorrhage presented positive correlations with apoptosis of hepatocytes, suggesting strong YFV pathogenic effect association; they were also the main histopathological changes in the Alouatta sp. A pronounced negative correlation between apoptosis of hepatocytes and hepatic mononuclear cell infiltration pointed to significant histopathological differences between YFV infection in Howler monkeys and humans. The results warn that NHPs may exhibit different response patterns following YFV infection and require a more careful diagnosis. Presumptive diagnosis based on primate histopathological lesions may contribute to public health service control.

Production of infectious dromedary camel hepatitis E virus by a reverse genetic system: Potential for zoonotic infection.

PubMed

Li, Tian-Cheng; Zhou, Xianfeng; Yoshizaki, Sayaka; Ami, Yasushi; Suzaki, Yuriko; Nakamura, Tomofumi; Takeda, Naokazu; Wakita, Takaji

2016-12-01

The pathogenicity, epidemiology and replication mechanism of dromedary camel hepatitis E virus (DcHEV), a novel hepatitis E virus (HEV), has been unclear. Here we used a reverse genetic system to produce DcHEV and examined the possibility of zoonotic infection. Capped genomic RNA derived from a synthetic DcHEV cDNA was transfected into human hepatocarcinoma cells PLC/PRF/5. The DcHEV capsid protein and RNA were detected by an enzyme-linked immunosorbent assay (ELISA) or RT-qPCR. A neutralization test for DcHEV was carried out by using antisera against HEV-like particles. DcHEV was used to inoculate two cynomolgus monkeys to examine the potential for cross-species infection. The transfection of PLC/PRF/5 cells with capped DcHEV RNA resulted in the production of infectious DcHEV. The genome sequence analysis demonstrated that both nucleotide and amino acid changes accumulated during the passages in PLC/PRF/5 cells. The cynomolgus monkeys showed serological signs of infection when DcHEV was intravenously inoculated. DcHEV was neutralized by not only anti-DcHEV-LPs antibody, but also anti-genotype 1 (G1), G3 and G4 HEV-LPs antibodies. Moreover, the monkeys immunized with DcHEV escaped the G3 HEV challenge, indicating that the serotype of DcHEV is similar to those of other human HEVs. Infectious DcHEV was produced using a reverse genetic system and propagated in PLC/PRF/5 cells. The antigenicity and immunogenicity of DcHEV are similar to those of G1, G3 and G4 HEV. DcHEV was experimentally transmitted to primates, demonstrating the possibility of a zoonotic infection by DcHEV. Dromedary camel hepatitis E virus (DcHEV) was produced by a reverse genetic system and grows well in PLC/PRF/5 cells. Cynomolgus monkeys experimentally infected with DcHEV indicated serological signs of infection, suggesting that DcHEV has the potential to cause zoonotic HEV infection. Copyright © 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

[Hybrids of human and monkey adenoviruses (adeno-adeno hybrids) that can reproduce in monkey cells: biological and molecular genetic peculiarities].

PubMed

Grinenko, N F; Savitskaia, N V; Pashvykina, G V; Al'tshteĭn, A D

2003-06-01

A highly oncogenic monkey adenovirus SA7(C8) facilitates the reproduction of human adenovirus type 2 (Ad2) in monkey cells. Upon mixed infection of monkey cells with both viruses, these viruses recombine producing defective adeno-adeno hybrids Ad2C8 serologically identical to Ad2 and capable of assisting Ad2 to reproduce in monkey cells. Ad2C8 and Ad2 form an intercomplementary pair inseparable in monkey cells. Unlike oncogenic SA7(C8), Ad2C8 is a nononcogenic virus for hamsters but is able to induce tumor antigens of this virus (T and TSTA). Molecular genetic analysis of 68 clones of adeno-adeno hybrids revealed that the left part of their genome consists of Ad2 DNA, and the right part contains no less than 40% of the viral SA7(C8) genome where E2A, E3, and E4 genes are located. Apparently, the products of these genes contribute to the composition of adenoviral tumor antigens, while the E4 gene is involved in complementation of monkey and human adenoviruses and makes a contribution to host range determination of these viruses.

Plasmodium knowlesi Skeleton-Binding Protein 1 Localizes to the ‘Sinton and Mulligan’ Stipplings in the Cytoplasm of Monkey and Human Erythrocytes

PubMed Central

Lucky, Amuza Byaruhanga; Sakaguchi, Miako; Katakai, Yuko; Kawai, Satoru; Yahata, Kazuhide; Templeton, Thomas J.

2016-01-01

The malaria parasite, Plasmodium, exports protein products to the infected erythrocyte to introduce modifications necessary for the establishment of nutrient acquisition and surface display of host interaction ligands. Erythrocyte remodeling impacts parasite virulence and disease pathology and is well documented for the human malaria parasite Plasmodium falciparum, but has been less described for other Plasmodium species. For P. falciparum, the exported protein skeleton-binding protein 1 (PfSBP1) is involved in the trafficking of erythrocyte surface ligands and localized to membranous structures within the infected erythrocyte, termed Maurer's clefts. In this study, we analyzed SBP1 orthologs across the Plasmodium genus by BLAST analysis and conserved gene synteny, which were also recently described by de Niz et al. (2016). To evaluate the localization of an SBP1 ortholog, we utilized the zoonotic malaria parasite, Plasmodium knowlesi. Immunofluorescence assay of transgenic P. knowlesi parasites expressing epitope-tagged recombinant PkSBP1 revealed a punctate staining pattern reminiscent of Maurer's clefts, following infection of either monkey or human erythrocytes. The recombinant PkSBP1-positive puncta co-localized with Giemsa-stained structures, known as ‘Sinton and Mulligan’ stipplings. Immunoelectron microscopy also showed that recombinant PkSBP1 localizes within or on the membranous structures akin to the Maurer's clefts. The recombinant PkSBP1 expressed in P. falciparum-infected erythrocytes co-localized with PfSBP1 at the Maurer's clefts, indicating an analogous trafficking pattern. A member of the P. knowlesi 2TM protein family was also expressed and localized to membranous structures in infected monkey erythrocytes. These results suggest that the trafficking machinery and induced erythrocyte cellular structures of P. knowlesi are similar following infection of both monkey and human erythrocytes, and are conserved with P. falciparum. PMID:27732628

Shigella sonnei Vaccine Candidates WRSs2 and WRSs3 Are as Immunogenic as WRSS1, a Clinically Tested Vaccine Candidate, in a Primate Model of Infection

DTIC Science & Technology

2011-01-01

Experiments in rabbit ileal loops and in rhesus monkeys have shown that shigellae are initially taken up by antigen sampling microfold (M) cells that are...2011) – Table 1 Shigella antigen-specific immune responses and colonization in rhesus monkeys after nasogastric administration of WRSS1, WRSs2...the respective antigens. 3.3. Mucosal responses in rhesus monkeys The mucosal immune response to Shigella LPS, and Invaplex- 50 antigens are summarized

Prevalence of antibody to adult T-cell leukemia virus-associated antigens (ATLA) in Japanese monkeys and other non-human primates.

PubMed

Hayami, M; Komuro, A; Nozawa, K; Shotake, T; Ishikawa, K; Yamamoto, K; Ishida, T; Honjo, S; Hinuma, Y

1984-02-15

The prevalence of adult T-cell-leukemia virus (ATLV) infection was examined in Japanese monkeys living naturally in various parts of Japan and in other species of non-human primates imported into and kept in Japan. Sera of 2,650 Japanese monkeys from 41 troops throughout Japan were tested. High incidences of anti-ATLV-associated antigen (ATLA)-positive monkeys were found in most troops, not only in the endemic area of human ATL(Southwestern Japan), but also in non-endemic areas. The incidence of sero-positive individuals increased gradually with age, reaching a maximum when the animals became adult, indicating age dependency, like that found by epidemiological studies on humans. Anti-ATLA antibodies were also detected in 90 of 815 sera of imported non-human primates of 33 species other than Japanese monkeys. All the anti-ATLA sero-positive monkeys were Catarrhines (Old World monkeys), mainly macaques of Asian origin. Some sero-positive monkeys were also found among animals of African origin, but no antibody was detected in Prosimians and Platyrrhines (New World monkeys). The clear-cut difference between the geographical distribution of sero-positive simians and that of humans indicates the improbability of direct transmission of ATLV from simians to humans.

Experimental encephalitis in monkeys caused by the Powassan virus.

PubMed

Frolova, M P; Isachkova, L M; Shestopalova, N M; Pogodina, V V

1985-01-01

We have carried out a comparative study of the experimental infection of monkeys with the P-40 strain of the Powassen virus, isolated in the Primor'e Territory of the USSR, and with the Canadian prototype LB strain. The Powassan virus was found to be pathogenic for Macaca rhesus. The clinical and pathomorphological picture of the experimental encephalitis was studied, and the full identity of the infection produced in the monkeys by the P-40 strain and the Canadian LB strain of the Powassan virus was demonstrated. On electron microscopic examination of the central nervous system the virus was detected in the neurons, glial cells, and intercellular spaces. The virions of the strains studied have identical morphological parameters, being 37-45 nm in diameter and of spherical shape. The data obtained indicated a marked neurotropism of the virus. They will contribute to the elucidation of the role of the virus in the infection pathology of humans, i.e., in the differentiation of encephalitis cases not associated etiologically with the virus of the spring-summer tickborne encephalitis.

Fatal Angiostrongylus dujardini infection in callitrichid monkeys and suricates in an Italian zoological garden.

PubMed

Eleni, Claudia; Di Cesare, Angela; Cavicchio, Paolo; Tonnicchia, Maria Cristina; Meoli, Roberta; di Regalbono, Antonio Frangipane; Paoletti, Barbara; Pietrobelli, Mario; De Liberato, Claudio

2016-08-01

This paper reports four fatal cases of metastrongylid nematode Angiostrongylus dujardini infection observed in a Saguinus oedipus and a Callimico goeldii monkey and in two suricates (Suricata suricatta). All animals were kept in captivity in a zoo of central Italy. The two monkeys died with no premonitory signs, while the two-month-old suricates showed malaise, anorexia and tachypnea for a few days prior to death. Cardiomegaly and/or granulomatous pneumonia were the major anatomo-pathological findings. Inflammatory lesions were observed in the liver, heart and kidney of the suricates at histology. A. dujardini diagnosis was confirmed through both morphological identification of adult worms recovered at necropsy and molecular characterization of larvae in tissue samples. Callitrichidae and suricates are active predators and maintain their hunting behaviour in captivity and it is then likely that they were exposed to infection by preying on parasitized gastropods, intermediate hosts of A. dujardini, entering zoo enclosures from the surrounding environment. This is the first report of A. dujardini in Italy and in S. suricatta. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Natural infection of Plasmodium brasilianum in humans: Man and monkey share quartan malaria parasites in the Venezuelan Amazon.

PubMed

Lalremruata, Albert; Magris, Magda; Vivas-Martínez, Sarai; Koehler, Maike; Esen, Meral; Kempaiah, Prakasha; Jeyaraj, Sankarganesh; Perkins, Douglas Jay; Mordmüller, Benjamin; Metzger, Wolfram G

2015-09-01

The quartan malaria parasite Plasmodium malariae is the widest spread and best adapted human malaria parasite. The simian Plasmodium brasilianum causes quartan fever in New World monkeys and resembles P. malariae morphologically. Since the genetics of the two parasites are nearly identical, differing only in a range of mutations expected within a species, it has long been speculated that the two are the same. However, no naturally acquired infection with parasites termed as P. brasilianum has been found in humans until now. We investigated malaria cases from remote Yanomami indigenous communities of the Venezuelan Amazon and analyzed the genes coding for the circumsporozoite protein (CSP) and the small subunit of ribosomes (18S) by species-specific PCR and capillary based-DNA sequencing. Based on 18S rRNA gene sequencing, we identified 12 patients harboring malaria parasites which were 100% identical with P. brasilianum isolated from the monkey, Alouatta seniculus. Translated amino acid sequences of the CS protein gene showed identical immunodominant repeat units between quartan malaria parasites isolated from both humans and monkeys. This study reports, for the first time, naturally acquired infections in humans with parasites termed as P. brasilianum. We conclude that quartan malaria parasites are easily exchanged between humans and monkeys in Latin America. We hypothesize a lack of host specificity in mammalian hosts and consider quartan malaria to be a true anthropozoonosis. Since the name P. brasilianum suggests a malaria species distinct from P. malariae, we propose that P. brasilianum should have a nomenclatorial revision in case further research confirms our findings. The expansive reservoir of mammalian hosts discriminates quartan malaria from other Plasmodium spp. and requires particular research efforts.

Experimental hepatitis A virus (HAV) infection in cynomolgus monkeys (Macaca fascicularis): evidence of active extrahepatic site of HAV replication

PubMed Central

Amado, Luciane A; Marchevsky, Renato S; de Paula, Vanessa S; Hooper, Cleber; Freire, Marcos da S; Gaspar, Ana Maria C; Pinto, Marcelo A

2010-01-01

This work studied the replication sites of hepatitis A virus (HAV) in cynomolgus monkeys (Macaca fascicularis) after intravenous inoculation. The cynomolgus monkeys were inoculated with the Brazilian hepatitis A virus strain (HAF-203). Monkeys were euthanized on days 15, 30, 45 and 60 postinoculation (pi). Liver samples, submandibular salivary gland, mesenteric lymph node and tonsils were removed for virological and pathological evaluation. Immunofluorescence analyses on liver and salivary gland sections using confocal laser scanning microscopy revealed the presence of HAV antigen (HAV Ag). The presence of HAV genome was monitored by real-time PCR. The HAV RNA was detected at 7 days postinoculation (dpi), concomitantly in serum, saliva and faeces. The highest HAV viral load was observed in faeces at 15 dpi (105 copies/ml), followed by serum viral load of 104 copies/ml at 20 dpi and saliva viral load of 103copies/ml at 7 dpi. The animals showed first histological and biochemical signs of hepatitis at 15 dpi. The HAV antigen (Ag) was present from day 7 until day 60 pi in the liver and salivary glands. The HAV replicative intermediate was also detected in the liver (4.5 × 104 copies/mg), salivary glands (1.9 × 103 copies/mg), tonsils (4.2 × 101 copies/mg) and lymph nodes (3.4 × 101 copies/mg). Our data demonstrated that the salivary gland as an extrahepatic site of early HAV replication could create a potential risk of saliva transmitted infection. In addition, the cynomolgus monkey was confirmed as a suitable model to study the pathogenesis of HAV human infection. PMID:20096073

Natural infection of Plasmodium brasilianum in humans: Man and monkey share quartan malaria parasites in the Venezuelan Amazon

PubMed Central

Lalremruata, Albert; Magris, Magda; Vivas-Martínez, Sarai; Koehler, Maike; Esen, Meral; Kempaiah, Prakasha; Jeyaraj, Sankarganesh; Perkins, Douglas Jay; Mordmüller, Benjamin; Metzger, Wolfram G.

2015-01-01

Background The quartan malaria parasite Plasmodium malariae is the widest spread and best adapted human malaria parasite. The simian Plasmodium brasilianum causes quartan fever in New World monkeys and resembles P. malariae morphologically. Since the genetics of the two parasites are nearly identical, differing only in a range of mutations expected within a species, it has long been speculated that the two are the same. However, no naturally acquired infection with parasites termed as P. brasilianum has been found in humans until now. Methods We investigated malaria cases from remote Yanomami indigenous communities of the Venezuelan Amazon and analyzed the genes coding for the circumsporozoite protein (CSP) and the small subunit of ribosomes (18S) by species-specific PCR and capillary based-DNA sequencing. Findings Based on 18S rRNA gene sequencing, we identified 12 patients harboring malaria parasites which were 100% identical with P. brasilianum isolated from the monkey, Alouatta seniculus. Translated amino acid sequences of the CS protein gene showed identical immunodominant repeat units between quartan malaria parasites isolated from both humans and monkeys. Interpretation This study reports, for the first time, naturally acquired infections in humans with parasites termed as P. brasilianum. We conclude that quartan malaria parasites are easily exchanged between humans and monkeys in Latin America. We hypothesize a lack of host specificity in mammalian hosts and consider quartan malaria to be a true anthropozoonosis. Since the name P. brasilianum suggests a malaria species distinct from P. malariae, we propose that P. brasilianum should have a nomenclatorial revision in case further research confirms our findings. The expansive reservoir of mammalian hosts discriminates quartan malaria from other Plasmodium spp. and requires particular research efforts. PMID:26501116

Studies on ’Macaca mulatta’ Infected with Rocky Mountain Spotted Fever

DTIC Science & Technology

1976-09-10

Mountain spotted fever (RMSF) rickettsiae. The LD50 in monkeys of the yolk-sac-grown seed stock was 10 to the 1.35th power plaque-forming units. Blood...acid glycoprotein, haptoglobin and albumin) were measured during a study in 16 male rhesus monkeys to determine the median lethal dose (LD50) of Rocky

Feline Immunodeficiency Virus in South America

PubMed Central

Teixeira, Bruno M.; Hagiwara, Mitika K.; Cruz, Juliano C. M.; Hosie, Margaret J.

2012-01-01

The rapid emergence of AIDS in humans during the period between 1980 and 2000 has led to extensive efforts to understand more fully similar etiologic agents of chronic and progressive acquired immunodeficiency disease in several mammalian species. Lentiviruses that have gene sequence homology with human immunodeficiency virus (HIV) have been found in different species (including sheep, goats, horses, cattle, cats, and several Old World monkey species). Lentiviruses, comprising a genus of the Retroviridae family, cause persistent infection that can lead to varying degrees of morbidity and mortality depending on the virus and the host species involved. Feline immunodeficiency virus (FIV) causes an immune system disease in domestic cats (Felis catus) involving depletion of the CD4+ population of T lymphocytes, increased susceptibility to opportunistic infections, and sometimes death. Viruses related to domestic cat FIV occur also in a variety of nondomestic felids. This is a brief overview of the current state of knowledge of this large and ancient group of viruses (FIVs) in South America. PMID:22590677

Feline immunodeficiency virus in South America.

PubMed

Teixeira, Bruno M; Hagiwara, Mitika K; Cruz, Juliano C M; Hosie, Margaret J

2012-03-01

The rapid emergence of AIDS in humans during the period between 1980 and 2000 has led to extensive efforts to understand more fully similar etiologic agents of chronic and progressive acquired immunodeficiency disease in several mammalian species. Lentiviruses that have gene sequence homology with human immunodeficiency virus (HIV) have been found in different species (including sheep, goats, horses, cattle, cats, and several Old World monkey species). Lentiviruses, comprising a genus of the Retroviridae family, cause persistent infection that can lead to varying degrees of morbidity and mortality depending on the virus and the host species involved. Feline immunodeficiency virus (FIV) causes an immune system disease in domestic cats (Felis catus) involving depletion of the CD4+ population of T lymphocytes, increased susceptibility to opportunistic infections, and sometimes death. Viruses related to domestic cat FIV occur also in a variety of nondomestic felids. This is a brief overview of the current state of knowledge of this large and ancient group of viruses (FIVs) in South America.

Gastrointestinal parasites of the colobus monkeys of Uganda.

PubMed

Gillespie, Thomas R; Greiner, Ellis C; Chapman, Colin A

2005-06-01

From August 1997 to July 2003, we collected 2,103 fecal samples from free-ranging individuals of the 3 colobus monkey species of Uganda-the endangered red colobus (Piliocolobus tephrosceles), the eastern black-and-white colobus (Colobus guereza), and the Angolan black-and-white colobus (C. angolensis)--to identify and determine the prevalence of gastrointestinal parasites. Helminth eggs, larvae, and protozoan cysts were isolated by sodium nitrate flotation and fecal sedimentation. Coprocultures facilitated identification of helminths. Seven nematodes (Strongyloides fulleborni, S. stercoralis, Oesophagostomum sp., an unidentified strongyle, Trichuris sp., Ascaris sp., and Colobenterobius sp.), 1 cestode (Bertiella sp.), 1 trematode (Dicrocoeliidae), and 3 protozoans (Entamoeba coli, E. histolytica, and Giardia lamblia) were detected. Seasonal patterns of infection were not apparent for any parasite species infecting colobus monkeys. Prevalence of S. fulleborni was higher in adult male compared to adult female red colobus, but prevalence did not differ for any other shared parasite species between age and sex classes.

CD4 T Cell Depletion Exacerbates Acute Mycobacterium tuberculosis While Reactivation of Latent Infection Is Dependent on Severity of Tissue Depletion in Cynomolgus Macaques

PubMed Central

Lin, Philana Ling; Rutledge, Tara; Green, Angela M.; Bigbee, Matthew; Fuhrman, Carl; Klein, Edwin

2012-01-01

Abstract CD4 T cells are believed to be important in protection against Mycobacterium tuberculosis, but the relative contribution to control of initial or latent infection is not known. Antibody-mediated depletion of CD4 T cells in M. tuberculosis-infected cynomolgus macaques was used to study the role of CD4 T cells during acute and latent infection. Anti-CD4 antibody severely reduced levels of CD4 T cells in blood, airways, and lymph nodes. Increased pathology and bacterial burden were observed in CD4-depleted monkeys during the first 8 weeks of infection compared to controls. CD4-depleted monkeys had greater interferon (IFN)-γ expression and altered expression of CD8 T cell activation markers. During latent infection, CD4 depletion resulted in clinical reactivation in only three of six monkeys. Reactivation was associated with lower CD4 T cells in the hilar lymph nodes. During both acute and latent infection, CD4 depletion was associated with reduced percentages of CXCR3+ expressing CD8 T cells, reported to be involved in T cell recruitment, regulatory function, and effector and memory T cell maturation. CXCR3+ CD8 T cells from hilar lymph nodes had more mycobacteria-specific cytokine expression and greater coexpression of multiple cytokines compared to CXCR3− CD8 T cells. CD4 T cells are required for protection against acute infection but reactivation from latent infection is dependent on the severity of depletion in the draining lymph nodes. CD4 depletion influences CD8 T cell function. This study has important implications for human HIV–M. tuberculosis coinfection. PMID:22480184

Partial protection of SIV-infected rhesus monkeys against superinfection with a heterologous SIV isolate

DOE Office of Scientific and Technical Information (OSTI.GOV)

Korber, Bette

2009-01-01

Although there is increasing evidence that individuals already infected with human immunodeficiency virus type 1 (HIV-1) can be infected with a heterologous strain of the virus, the extent of protection against superinfection conferred by the first infection and the biologic consequences of superinfection are not well understood. We explored these questions in the simian immunodeficiency virus (SIV)/rhesus monkey model of HIV-1/AIDS. We infected cohorts of rhesus monkeys with either SIVmac251 or SIVsmE660 and then exposed animals to the reciprocal virus through intrarectal inoculations. Employing a quantitative real-time PCR assay, we determined the replication kinetics of the two strains of virusmore » for 20 weeks. We found that primary infection with a replication-competent virus did not protect against acquisition of infection by a heterologous virus but did confer relative control of the superinfecting virus. In animals that became superinfected, there was a reduction in peak replication and rapid control of the second virus. The relative susceptibility to superinfection was not correlated with CD4(+) T-cell count, CD4(+) memory T-cell subsets, cytokine production by virus-specific CD8(+) or CD4(+) cells, or neutralizing antibodies at the time of exposure to the second virus. Although there were transient increases in viral loads of the primary virus and a modest decline in CD4(+) T-cell counts after superinfection, there was no evidence of disease acceleration. These findings indicate that an immunodeficiency virus infection confers partial protection against a second immunodeficiency virus infection, but this protection may be mediated by mechanisms other than classical adaptive immune responses.« less

Monkey Viperin Restricts Porcine Reproductive and Respiratory Syndrome Virus Replication.

PubMed

Fang, Jianyu; Wang, Haiyan; Bai, Juan; Zhang, Qiaoya; Li, Yufeng; Liu, Fei; Jiang, Ping

2016-01-01

Porcine reproductive and respiratory syndrome virus (PRRSV) is an important pathogen which causes huge economic damage globally in the swine industry. Current vaccination strategies provide only limited protection against PRRSV infection. Viperin is an interferon (IFN) stimulated protein that inhibits some virus infections via IFN-dependent or IFN-independent pathways. However, the role of viperin in PRRSV infection is not well understood. In this study, we cloned the full-length monkey viperin (mViperin) complementary DNA (cDNA) from IFN-α-treated African green monkey Marc-145 cells. It was found that the mViperin is up-regulated following PRRSV infection in Marc-145 cells along with elevated IRF-1 gene levels. IFN-α induced mViperin expression in a dose- and time-dependent manner and strongly inhibits PRRSV replication in Marc-145 cells. Overexpression of mViperin suppresses PRRSV replication by blocking the early steps of PRRSV entry and genome replication and translation but not inhibiting assembly and release. And mViperin co-localized with PRRSV GP5 and N protein, but only interacted with N protein in distinct cytoplasmic loci. Furthermore, it was found that the 13-16 amino acids of mViperin were essential for inhibiting PRRSV replication, by disrupting the distribution of mViperin protein from the granular distribution to a homogeneous distribution in the cytoplasm. These results could be helpful in the future development of novel antiviral therapies against PRRSV infection.

Discovery of Herpes B Virus-Encoded MicroRNAs▿

PubMed Central

Besecker, Michael I.; Harden, Mallory E.; Li, Guanglin; Wang, Xiu-Jie; Griffiths, Anthony

2009-01-01

Herpes B virus (BV) naturally infects macaque monkeys and is a close relative of herpes simplex virus. BV can zoonotically infect humans to cause a rapidly ascending encephalitis with ∼80% mortality. Therefore, BV is a serious danger to those who come into contact with these monkeys or their tissues and cells. MicroRNAs are regulators of gene expression, and there have been reports of virus-encoded microRNAs. We hypothesize that BV-encoded microRNAs are important for the regulation of viral and cellular genes. Herein, we report the discovery of three herpes B virus-encoded microRNAs. PMID:19144716

Cercopithecine herpesvirus 1 risk in a child bitten by a Bonnet Macaque monkey.

PubMed

Tregle, Rodney William; Loe, Catherine Lindsay; Earhart, Robert Hailes; d'Autremont, Sarah Baillio

2011-10-01

Exotic animal importation and trade has the potential to expose the public to a variety of injuries and diseases not endemic to the United States. Bonnet Macaque monkeys are a fairly common primate illegally held in captivity. These monkeys become aggressive as they age past 2 years and are known to carry asymptomatic Cercopithecine herpesvirus 1 infection. This case is presented to illustrate the point that simple wound management alone may not only be insufficient but could be fatal in certain exotic animal bites and that the emergency physician should consult with authorities familiar with exotic animals when treating a patient with an exotic animal bite. We present the case of a 2-year-old child that was bitten by his neighbor's pet Bonnet Macaque monkey. This species of Old World monkey carries the Cercopithecine herpesvirus 1 (simian B virus) 73-100% of the time. This infection in humans can lead to an encephalitis that has a 70% mortality rate. Consultation with animal authorities led to the proper treatment, which included routine wound care, rabies prophylaxis, irrigation with sodium hypochlorite solution, and treatment with antiviral medication. Simple wound management alone may not be enough in patients bitten by exotic animals. Consultation with local zoo officials, veterinary medical schools, or the Centers for Disease Control and Prevention is recommended in these cases. Copyright © 2011 Elsevier Inc. All rights reserved.

Susceptibility and lack of evidence for a viremic state of rabies in the night owl monkey, Aotus nancymaae

PubMed Central

2012-01-01

Background Rabies causes an acute fatal encephalomyelitis in most mammals following infection with rhabdovirus of the genus Lyssavirus. Little is known about rabies virus infection in species of New World non-human Primates (NHP). To investigate the suitability of the owl monkey Aotus nancymaae asissue sections examined were unremarkable for inflammation or other histologic signs of rabies a viable animal model for rabies virus candidate vaccine testing, we used clinical presentation, serology, viral isolation, and PCR to evaluate the incubation period, immunity, and pathogenesis of infected animals. We tested the hypothesis that no viremic state exists for rabies virus. Methods Eight monkeys divided into two equal groups were inoculated intramuscularly either in the neck or footpad with 105 pfu of rabies virus (Pasteur/V-13R) and observed for >130 days. Oral and blood samples were collected and analyzed. Results Two monkeys inoculated in the neck displayed classic paralytic rabies. The mean incubation period was 11.5 days. The average maximum IgG response (antibody titer >0.200 O.D.) was achieved at day 10.0 and 62.3 in the clinical rabies and non-clinical rabies cases, respectively (p = 0.0429). No difference in IgM or IgG time to seroconversion or average maximum IgM level was observed between neck versus footpad inoculation groups. No viremia or viral shedding was detected by PCR or viral isolation during the observation period, including within the two symptomatic animals three days after disease onset. Tissue sections examined were unremarkable for inflammation or other histologic signs of rabies within the asymptomatic animal. Similarly none of the brain sections exhibited immunoreactivity for rabies virus antibody. Discussion This study demonstrates there is no difference in time to immune response between inoculation sites and distance to the brain; however, immune response tends to be more rapid in cases of clinically apparent disease and prolonged in cases infected at sites further from the brain. Conclusions Our findings support the hypothesis that a viremic state for rabies does not exist in the New World Monkey, Aotus nancymaae, and it appears that this species may be refractory to infection. The species does provide a suitable model to assess post infection immune responses. Additional studies that address the limitations of sample size, length of observation, and lack of measurable infection should be conducted. PMID:22612895

Complex of simian virus 40 large-T antigen and host 53,000-molecular-weight protein in monkey cells.

PubMed Central

Harlow, E; Pim, D C; Crawford, L V

1981-01-01

Mouse cells transformed by simian virus 40 (SV40) have been shown to contain a complex of the virus-coded large-T antigen with a host 53,000-molecular-weight (53K) protein. Initial attempts to detect a similar complex in lytically infected cells were unsuccessful, and it therefore seemed that the complex might be peculiar to transformed or abortively transformed nonpermissive cells. Immunoprecipitation of [32P]phosphate-labeled extracts of SV40-infected CV-1 African green monkey kidney cells with antibodies specific for large-T or the 53K protein revealed that the large-T-53K protein complex was formed during lytic infections. Only a minor fraction of the large-T present was associated with 53K protein, and large-T and the 53K host protein cosedimented during centrifugation through sucrose gradients. We used monospecific sera and monoclonal antibodies to study the rate of synthesis and phosphorylation of the 53K protein during lytic infections. Infection of CV-1 cells with SV40 increased the rate of synthesis of the 53K protein fivefold over that in mock-infected cells. At the same time, the rate of phosphorylation of the 53K protein increased more than 30-fold compared with control cultures. Monkey cells transformed by UV-irradiated SV40 (Gluzman et al., J. Virol. 22:256-266, 1977) also contained the large-T-53K protein complex. The formation of the complex is therefore not a peculiarity of SV40-transformed rodent cells but is a common feature of SV40 infections. Images PMID:6163871

Experimental Oral Candidiasis in Animal Models

PubMed Central

Samaranayake, Yuthika H.; Samaranayake, Lakshman P.

2001-01-01

Oral candidiasis is as much the final outcome of the vulnerability of the host as of the virulence of the invading organism. We review here the extensive literature on animal experiments mainly appertaining to the host predisposing factors that initiate and perpetuate these infections. The monkey, rat, and mouse are the choice models for investigating oral candidiasis, but comparisons between the same or different models appear difficult, because of variables such as the study design, the number of animals used, their diet, the differences in Candida strains, and the duration of the studies. These variables notwithstanding, the following could be concluded. (i) The primate model is ideal for investigating Candida-associated denture stomatitis since both erythematous and pseudomembranous lesions have been produced in monkeys with prosthetic plates; they are, however, expensive and difficult to obtain and maintain. (ii) The rat model (both Sprague-Dawley and Wistar) is well proven for observing chronic oral candidal colonization and infection, due to the ease of breeding and handling and their ready availability. (iii) Mice are similar, but in addition there are well characterized variants simulating immunologic and genetic abnormalities (e.g., athymic, euthymic, murine-acquired immune deficiency syndrome, and severe combined immunodeficient models) and hence are used for short-term studies relating the host immune response and oral candidiasis. Nonetheless, an ideal, relatively inexpensive model representative of the human oral environment in ecological and microbiological terms is yet to be described. Until such a model is developed, researchers should pay attention to standardization of the experimental protocols described here to obtain broadly comparable and meaningful data. PMID:11292645

Monkey Malaria in a European Traveler Returning from Malaysia

PubMed Central

Marti, Hanspeter; Felger, Ingrid; Müller, Dania; Jokiranta, T. Sakari

2008-01-01

In 2007, a Finnish traveler was infected in Peninsular Malaysia with Plasmodium knowlesi, a parasite that usually causes malaria in monkeys. P. knowlesi has established itself as the fifth Plasmodium species that can cause human malaria. The disease is potentially life-threatening in humans; clinicians and laboratory personnel should become more aware of this pathogen in travelers. PMID:18760013

Novel Vaccine Approach Achieves “Functional Cure” of AIDS Virus in Monkeys | Poster

Cancer.gov

By Frank Blanchard, Staff Writer, and Jeff Lifson, Guest Writer Scientists at the Oregon Health & Science University and the AIDS and Cancer Virus Program of the Frederick National Laboratory for Cancer Research have used a novel vaccine approach to achieve a “functional cure” and apparent eradication of infection with a monkey version of the AIDS virus.

Monkey-based research on human disease: the implications of genetic differences.

PubMed

Bailey, Jarrod

2014-11-01

Assertions that the use of monkeys to investigate human diseases is valid scientifically are frequently based on a reported 90-93% genetic similarity between the species. Critical analyses of the relevance of monkey studies to human biology, however, indicate that this genetic similarity does not result in sufficient physiological similarity for monkeys to constitute good models for research, and that monkey data do not translate well to progress in clinical practice for humans. Salient examples include the failure of new drugs in clinical trials, the highly different infectivity and pathology of SIV/HIV, and poor extrapolation of research on Alzheimer's disease, Parkinson's disease and stroke. The major molecular differences underlying these inter-species phenotypic disparities have been revealed by comparative genomics and molecular biology - there are key differences in all aspects of gene expression and protein function, from chromosome and chromatin structure to post-translational modification. The collective effects of these differences are striking, extensive and widespread, and they show that the superficial similarity between human and monkey genetic sequences is of little benefit for biomedical research. The extrapolation of biomedical data from monkeys to humans is therefore highly unreliable, and the use of monkeys must be considered of questionable value, particularly given the breadth and potential of alternative methods of enquiry that are currently available to scientists. 2014 FRAME.

Longitudinal analysis of behavioral, neurophysiological, viral and immunological effects of SIV infection in rhesus monkeys.

PubMed

Gold, L H; Fox, H S; Henriksen, S J; Buchmeier, M J; Weed, M R; Taffe, M A; Huitrón-Resendiz, S; Horn, T F; Bloom, F E

1998-01-01

A model is proposed in which a neurovirulent, microglial-passaged, simian immunodeficiency virus (SIV) is used to produce central nervous system (CNS) pathology and behavioral deficits in rhesus monkeys reminiscent of those seen in humans infected with human immunodeficiency virus (HIV). The time course of disease progression was characterized by using functional measures of cognition and motor skill, as well as neurophysiologic monitoring. Concomitant assessment of immunological and virological parameters illustrated correspondence between impaired behavioral performance and viral pathogenesis. Convergent results were obtained from neuropathological findings indicative of significant CNS disease. In ongoing studies, this SIV model is being used to explore the behavioral sequelae of immunodeficiency virus infection, the viral and host factors leading to neurologic dysfunction, and to begin testing potential therapeutic agents.

Simian hepatitis A virus derived from a captive rhesus monkey in India is similar to the strain isolated from wild African green monkeys in Kenya.

PubMed

Arankalle, V A; Ramakrishnan, J

2009-03-01

A simian hepatitis A virus (HAV) was identified retrospectively in a faecal sample from a rhesus monkey in India, inoculated in 1995 with a faecal suspension from a suspected patient of non-A to E hepatitis. The monkey was in captivity for 2 years in one of the experimental primate facilities in western India before being moved to the National Institute of Virology, Pune for experimentation. Phylogenetic analysis based on a partial sequence of the 5' noncoding region placed this virus in genotype V, the only other member being the AGM-27 strain recovered in 1986 from African green monkeys in Kenya. The source of infection of the monkey remains unclear. The full genome was amplified in nine fragments and sequenced. The genome of the Indian simian HAV (IND-SHAV) is 7425 nucleotides long including the poly-A tail of 14 nucleotides at the 3' end. At the nucleotide and amino acid levels, IND-SHAV was 99.8 and 100% identical with AGM27, respectively.

Phenobarbital increases monkey in vivo nicotine disposition and induces liver and brain CYP2B6 protein

PubMed Central

Lee, Anna M; Miksys, Sharon; Tyndale, Rachel F

2006-01-01

CYP2B6 is a drug-metabolizing enzyme expressed in the liver and brain that can metabolize bupropion (Zyban®, a smoking cessation drug), activate tobacco-smoke nitrosamines, and inactivate nicotine. Hepatic CYP2B6 is induced by phenobarbital and induction may affect in vivo nicotine disposition, while brain CYP2B6 induction may affect local levels of centrally acting substrates. We investigated the effect of chronic phenobarbital treatment on induction of in vivo nicotine disposition and CYP2B6 expression in the liver and brain of African Green (Vervet) monkeys. Monkeys were split into two groups (n=6 each) and given oral saccharin daily for 22 days; one group was supplemented with 20 mg kg−1 phenobarbital. Monkeys were given a 0.1 mg kg−1 nicotine dose subcutaneously before and after treatment. Phenobarbital treatment resulted in a significant, 56%, decrease (P=0.04) in the maximum nicotine plasma concentration and a 46% decrease (P=0.003) in the area under the concentration–time curve. Phenobarbital also increased hepatic CYP2B6 protein expression. In monkey brain, significant induction (P<0.05) of CYP2B6 protein levels was observed in all regions tested (caudate, putamen, hippocampus, cerebellum, brain stem and frontal cortex) ranging from 2-fold to 150-fold. CYP2B6 expression was induced in specific cells, such as frontal cortical pyramidal cells and thalamic neurons. In conclusion, chronic phenobarbital treatment in monkeys resulted in increased in vivo nicotine disposition, and induced hepatic and brain CYP2B6 protein levels and cellular expression. This induction may alter the metabolism of CYP2B6 substrates including peripherally acting drugs such as cyclophosphamide and centrally acting drugs such as bupropion, ecstasy and phencyclidine. PMID:16751792

Reduced noradrenergic innervation of ventral midbrain dopaminergic cell groups and the subthalamic nucleus in MPTP-treated parkinsonian monkeys.

PubMed

Masilamoni, Gunasingh Jeyaraj; Groover, Olivia; Smith, Yoland

2017-04-01

There is anatomical and functional evidence that ventral midbrain dopaminergic (DA) cell groups and the subthalamic nucleus (STN) receive noradrenergic innervation in rodents, but much less is known about these interactions in primates. Degeneration of NE neurons in the locus coeruleus (LC) and related brainstem NE cell groups is a well-established pathological feature of Parkinson's disease (PD), but the development of such pathology in animal models of PD has been inconsistent across species and laboratories. We recently demonstrated 30-40% neuronal loss in the LC, A5 and A6 NE cell groups of rhesus monkeys rendered parkinsonian by chronic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In this study, we used dopamine-beta-hydroxylase (DβH) immunocytochemistry to assess the impact of this neuronal loss on the number of NE terminal-like varicosities in the substantia nigra pars compacta (SNC), ventral tegmental area (VTA), retrorubral field (RRF) and STN of MPTP-treated parkinsonian monkeys. Our findings reveal that the NE innervation of the ventral midbrain and STN of normal monkeys is heterogeneously distributed being far more extensive in the VTA, RRF and dorsal tier of the SNC than in the ventral SNC and STN. In parkinsonian monkeys, all regions underwent a significant (~50-70%) decrease in NE innervation. At the electron microscopic level, some DβH-positive terminals formed asymmetric axo-dendritic synapses in VTA and STN. These findings demonstrate that the VTA, RRF and SNCd are the main ventral midbrain targets of ascending NE inputs, and that these connections undergo a major break-down in chronically MPTP-treated parkinsonian monkeys. This severe degeneration of the ascending NE system may contribute to the pathophysiology of ventral midbrain and STN neurons in PD. Copyright © 2017 Elsevier Inc. All rights reserved.

Circulation of Campylobacter spp. in rhesus monkeys (Macaca mulatta) held in captivity: a longitudinal study.

PubMed

Andrade, Márcia Cristina Ribeiro; Gabeira, Sanny Cerqueira de Oliveira; Abreu-Lopes, Danielle; Esteves, Wagner Thadeu Cardoso; Vilardo, Mônica de Castro Britto; Thomé, Jacqueline D'arc da Silva; Cabello, Pedro Hernan; Lauria-Filgueiras, Ana Luzia

2007-02-01

Campylobacteriosis is an extremely important zoonosis, circulating freely in the environment. In nonhuman primates kept in open facilities and bred for experimental purposes, the presence of Campylobacter spp. could cause severe damage to the production and interfere with the results of scientific research. In this paper, we assessed the circulation of Campylobacter spp. in a colony of clinically healthy rhesus monkeys (Macaca mulatta) destined to research. The analysis was carried out during seven non-consecutive years. Data showed that despite several changes made in animal management along the studied years in order to control this zoonosis, reduction of bacterial charge did not occur. Significant differences among the age groups and sex were observed. Infants showed higher susceptibility than adult animals. In general males were more infected than females. Modifications adopted in the handling techniques need to be reviewed with the intent of improving the production, reducing bacterial infection of the stock and avoiding undesirable cross reactions in the research carried out with these animals. Therefore, this paper alerts professionals that work directly with captive rhesus monkeys about the risks of Campylobacter spp. infection and possible interference on the experimental procedures.

Evaluation in Rhesus Monkeys of a Bivalent Live Attenuated Dengue Vaccine Containing Types 2 and 4 Viruses.

DTIC Science & Technology

1984-06-01

previous reports,(1) antibody levels of most of the vaccinated animals declined markedly on or before post vacination day 150. PR13s showed that the EM-4...V.H., Gould, D.J., Chapple, F.E., and Russell, P.K.: Dengue 2 vacine , viremia and Inmune response in rhesus monkeys. Infect. Immun. 27, 181-186, 1980. 2

IMMUNITY TO YELLOW FEVER ENCEPHALITIS OF MONKEYS AND MICE IMMUNIZED BY NEURAL AND EXTRANEURAL ROUTES

PubMed Central

Fox, John P.

1943-01-01

Monkeys and mice surviving cerebral infection with yellow fever virus of relatively avirulent strains have been found to resist maximal intracerebral doses of yellow fever virus of a highly neurotropic strain. Such animals, however, do not resist more than very small doses of intracerebrally inoculated virus of Eastern equine encephalomyelitis. Animals immunized by extraneural routes, on the other hand, are not uniformly resistant to neural infection with neurotropic yellow fever virus. Monkeys which have undergone systemic infection with virus of the avirulent 17D strain or of several jungle strains resist only small intracerebral doses of neurotropic virus; while mice, even when possessed of very high serum-antibody levels as the result of intraperitoneal hyperimmunization, manifest only an irregular resistance to intracerebral challenge inocula. The difference in the resistance of neurally and extraneurally immunized animals is not related to similar differences in the levels of protective antibody in the sera. Indeed, the average of the serum-antibody titers of the hyperimmune mice is several times that of the intracerebral immunes. A possibly significant relation does exist, however, between the resistance of mice to neural infection and the content of protective antibody in the brain. The protective activity of suspensions of brains from mice surviving cerebral infection was found to be several times that of brain suspensions from the hyperimmunized animals. It is concluded that the superior resistance to neural infection of animals whose immunity results from a previous non-fatal infection of the nervous system is effected by a specific local mechanism which is based at least in part upon an increased concentration of antibody in the cerebral tissue. PMID:19871299

Hierarchical Cluster Analysis of Three-Dimensional Reconstructions of Unbiased Sampled Microglia Shows not Continuous Morphological Changes from Stage 1 to 2 after Multiple Dengue Infections in Callithrix penicillata

PubMed Central

Diniz, Daniel G.; Silva, Geane O.; Naves, Thaís B.; Fernandes, Taiany N.; Araújo, Sanderson C.; Diniz, José A. P.; de Farias, Luis H. S.; Sosthenes, Marcia C. K.; Diniz, Cristovam G.; Anthony, Daniel C.; da Costa Vasconcelos, Pedro F.; Picanço Diniz, Cristovam W.

2016-01-01

It is known that microglial morphology and function are related, but few studies have explored the subtleties of microglial morphological changes in response to specific pathogens. In the present report we quantitated microglia morphological changes in a monkey model of dengue disease with virus CNS invasion. To mimic multiple infections that usually occur in endemic areas, where higher dengue infection incidence and abundant mosquito vectors carrying different serotypes coexist, subjects received once a week subcutaneous injections of DENV3 (genotype III)-infected culture supernatant followed 24 h later by an injection of anti-DENV2 antibody. Control animals received either weekly anti-DENV2 antibodies, or no injections. Brain sections were immunolabeled for DENV3 antigens and IBA-1. Random and systematic microglial samples were taken from the polymorphic layer of dentate gyrus for 3-D reconstructions, where we found intense immunostaining for TNFα and DENV3 virus antigens. We submitted all bi- or multimodal morphological parameters of microglia to hierarchical cluster analysis and found two major morphological phenotypes designated types I and II. Compared to type I (stage 1), type II microglia were more complex; displaying higher number of nodes, processes and trees and larger surface area and volumes (stage 2). Type II microglia were found only in infected monkeys, whereas type I microglia was found in both control and infected subjects. Hierarchical cluster analysis of morphological parameters of 3-D reconstructions of random and systematic selected samples in control and ADE dengue infected monkeys suggests that microglia morphological changes from stage 1 to stage 2 may not be continuous. PMID:27047345

Hierarchical Cluster Analysis of Three-Dimensional Reconstructions of Unbiased Sampled Microglia Shows not Continuous Morphological Changes from Stage 1 to 2 after Multiple Dengue Infections in Callithrix penicillata.

PubMed

Diniz, Daniel G; Silva, Geane O; Naves, Thaís B; Fernandes, Taiany N; Araújo, Sanderson C; Diniz, José A P; de Farias, Luis H S; Sosthenes, Marcia C K; Diniz, Cristovam G; Anthony, Daniel C; da Costa Vasconcelos, Pedro F; Picanço Diniz, Cristovam W

2016-01-01

It is known that microglial morphology and function are related, but few studies have explored the subtleties of microglial morphological changes in response to specific pathogens. In the present report we quantitated microglia morphological changes in a monkey model of dengue disease with virus CNS invasion. To mimic multiple infections that usually occur in endemic areas, where higher dengue infection incidence and abundant mosquito vectors carrying different serotypes coexist, subjects received once a week subcutaneous injections of DENV3 (genotype III)-infected culture supernatant followed 24 h later by an injection of anti-DENV2 antibody. Control animals received either weekly anti-DENV2 antibodies, or no injections. Brain sections were immunolabeled for DENV3 antigens and IBA-1. Random and systematic microglial samples were taken from the polymorphic layer of dentate gyrus for 3-D reconstructions, where we found intense immunostaining for TNFα and DENV3 virus antigens. We submitted all bi- or multimodal morphological parameters of microglia to hierarchical cluster analysis and found two major morphological phenotypes designated types I and II. Compared to type I (stage 1), type II microglia were more complex; displaying higher number of nodes, processes and trees and larger surface area and volumes (stage 2). Type II microglia were found only in infected monkeys, whereas type I microglia was found in both control and infected subjects. Hierarchical cluster analysis of morphological parameters of 3-D reconstructions of random and systematic selected samples in control and ADE dengue infected monkeys suggests that microglia morphological changes from stage 1 to stage 2 may not be continuous.

Antibody Responses to a Novel Plasmodium falciparum Merozoite Surface Protein Vaccine Correlate with Protection against Experimental Malaria Infection in Aotus Monkeys

PubMed Central

Cavanagh, David R.; Kocken, Clemens H. M.; White, John H.; Cowan, Graeme J. M.; Samuel, Kay; Dubbeld, Martin A.; der Wel, Annemarie Voorberg-van; Thomas, Alan W.; McBride, Jana S.; Arnot, David E.

2014-01-01

The Block 2 region of the merozoite surface protein-1 (MSP-1) of Plasmodium falciparum has been identified as a target of protective immunity by a combination of seroepidemiology and parasite population genetics. Immunogenicity studies in small animals and Aotus monkeys were used to determine the efficacy of recombinant antigens derived from this region of MSP-1 as a potential vaccine antigen. Aotus lemurinus griseimembra monkeys were immunized three times with a recombinant antigen derived from the Block 2 region of MSP-1 of the monkey-adapted challenge strain, FVO of Plasmodium falciparum, using an adjuvant suitable for use in humans. Immunofluorescent antibody assays (IFA) against erythrocytes infected with P. falciparum using sera from the immunized monkeys showed that the MSP-1 Block 2 antigen induced significant antibody responses to whole malaria parasites. MSP-1 Block 2 antigen-specific enzyme-linked immunosorbent assays (ELISA) showed no significant differences in antibody titers between immunized animals. Immunized animals were challenged with the virulent P. falciparum FVO isolate and monitored for 21 days. Two out of four immunized animals were able to control their parasitaemia during the follow-up period, whereas two out of two controls developed fulminating parasitemia. Parasite-specific serum antibody titers measured by IFA were four-fold higher in protected animals than in unprotected animals. In addition, peptide-based epitope mapping of serum antibodies from immunized Aotus showed distinct differences in epitope specificities between protected and unprotected animals. PMID:24421900

Effect of daily morphine administration and its discontinuation on delay discounting of food in rhesus monkeys

PubMed Central

Maguire, David R; Gerak, Lisa R; France, Charles P

2015-01-01

Opioid abusers discount delayed reinforcers more rapidly than non-users; however, it is unclear whether chronic drug administration or its discontinuation impact discounting. This study examined daily morphine administration and its discontinuation on delay discounting of food in rhesus monkeys. Responding on one lever delivered 1 food pellet immediately; responding on another lever delivered 2 food pellets either immediately or after a delay (30–120 sec) that increased within the session. Monkeys (n=3) responded for the large reinforcer when both reinforcers were delivered immediately and more for the smaller, immediately available reinforcer as delay to delivery of the large reinforcer increased. When administered acutely, morphine (0.032–5.6 mg/kg) increased trial omissions and had variable effects on choice, with small doses decreasing and large doses increasing choice of the large delayed reinforcer. Chronic morphine administration (0.1 mg/kg/day to 3.2 mg/kg twice daily) reduced choice of the large delayed reinforcer in two monkeys while increasing choice in a third monkey. Despite the development of tolerance to some effects (i.e., rightward shifts in dose-effect curves for the number of trials omitted) and evidence of mild opioid dependence (e.g., decrease in the number of trials completed as well as body weight), discontinuation of treatment did not appear to systematically impact discounting. Overall, these results suggest that repeated opioid administration causes persistent effects on choice under a delay discounting procedure; however, differences in the direction of effect among individuals suggest factors other than, or in addition to, changes in discounting might play a role. PMID:26397762

Establishment of a rhesus monkey model of chronic temporal lobe epilepsy using repetitive unilateral intra-amygdala kainic acid injections.

PubMed

Chi, Yajie; Wu, Bolin; Guan, Jianwei; Xiao, Kuntai; Lu, Ziming; Li, Xiao; Xu, Yuting; Xue, Shan; Xu, Qiang; Rao, Junhua; Guo, Yanwu

2017-09-01

Temporal lobe epilepsy (TLE) is a common type of acquired epilepsy refractory to medical treatment. As such, establishing animal models of this disease is critical to developing new and effective treatment modalities. Because of their small head size, rodents are not suitable for comprehensive electroencephalography (EEG) evaluation via scalp or subdural electrodes. Therefore, a larger primate model that closely recapitulates signs of TLE is needed; here we describe a rhesus monkey model resembling chronic TLE. Eight monkeys were divided into two groups: kainic acid (KA) group (n=6) and saline control group (n=2). Intra-amygdala KA injections were performed biweekly via an Ommaya device until obvious epileptiform discharges were recorded. Video-EEG recording was conducted intermittently throughout the experiment using both scalp and subdural electrodes. Brains were then analyzed for Nissl and glial fibrillary acid protein (GFAP) immunostaining. After 2-4 injections of KA (approximately 1.2-2.4mg, 0.12-0.24mg/kg), interictal epileptiform discharges (IEDs) were recorded in all KA-treated animals. Spontaneous recurrent seizures (SRSs) accompanied by symptoms mimicking temporal lobe absence (undetectable without EEG recording), but few mild motor signs, were recorded in 66.7% (four of six) KA-treated animals. Both IEDs and seizures indicated a primary epileptic zone in the right temporal region and contralateral discharges were later detected. Segmental pyramidal cell loss and gliosis were detected in the brain of a KA-treated monkey. Through a modified protocol of unilateral repetitive intra-amygdala KA injections, a rhesus monkey model with similar behavioral and brain electrical features as TLE was developed. Copyright © 2017 Elsevier Inc. All rights reserved.

Seven Years of Recording from Monkey Cortex with a Chronically Implanted Multiple Microelectrode

PubMed Central

Krüger, Jürgen; Caruana, Fausto; Volta, Riccardo Dalla; Rizzolatti, Giacomo

2010-01-01

A brush of 64 microwires was chronically implanted in the ventral premotor cortex of a macaque monkey. Contrary to common approaches, the wires were inserted from the white matter side. This approach, by avoiding mechanical pressure on the dura and pia mater during penetration, disturbed only minimally the cortical recording site. With this approach isolated potentials and multiunit activity were recorded for more than 7 years in about one-third of electrodes. The indirect insertion method also provided an excellent stability within each recording session, and in some cases even allowed recording from the same neurons for several years. Histological examination of the implanted brain region shows only a very marginal damage to the recording area. Advantages and problems related to long-term recording are discussed. PMID:20577628

[Experimental monkey encephalitis caused by Powassan virus].

PubMed

Frolova, M P; Isachkova, L M; Shestopalova, N M; Pogodina, V V

1981-01-01

A comparative study of the experimental infection of monkeys caused by brain P-40 of Powassan virus isolated in the Primorye Territory of the USSR and by the prototype Canadian strain LB was carried out. Powassan virus was found to be pathogenic for Macaca rhesus. Clinical and pathomorphological picture of the experimental encephalitis was studied. Full identity of the infection caused in the monkeys by the strain P-40 and the Canadian strain LB of Powassan virus has been proved. On electronmicroscopic examination of the central nervous system the virus was detected in the neurons, glial cells and intercellular spaces. The virions of the strains studied have identical morphological parameters, being 37 to 45 nm in diameter and having spherical shape. The data obtained point to a marked neurotropism of the virus. They will contribute to elucidation of the virus role in the infectious pathology of man, and namely, in verification of encephalitis cases not associated etiologically with the virus of the spring-summer tick-borne encephalitis.

Studies on heterologous immunity in schistosomiasis*

PubMed Central

Amin, M. A.; Nelson, G. S.; Saoud, M. F. A.

1968-01-01

Previous studies on heterologous immunity in mice have indicated that Schistosoma bovis and S. mattheei could be used to limit the severity of infection resulting from subsequent challenge by S. mansoni. These observations have now been extended to study the immunizing effect in rhesus monkeys of both S. mattheei and S. bovis. The bovine schistosomes were shown to be relatively non-pathogenic in rhesus monkeys. Immunization with 1000-2000 cercariae resulted in a marked reduction in the pathogenic effect of subsequent challenge with S. mansoni. This effect was demonstrated by a decrease in the worm load and tissue egg densities in 10 immunized monkeys as compared with 5 control animals. There was no correlation between fluorescent antibody titres and the intensity of infection or the degree of acquired immunity. There was a cross-reaction between S. mansoni and the bovine schistosomes. It is suggested that natural heterologous immunity (zooprophylaxis) may be of considerable epidemiological importance in determining the severity of schistosomiasis in man. PMID:4970323

Metabolic alkalosis during immobilization in monkeys (M. nemestrina)

NASA Technical Reports Server (NTRS)

Young, D. R.; Yeh, I.; Swenson, R. S.

1983-01-01

The systemic and renal acid-base response of monkeys during ten weeks of immobilization was studied. By three weeks of immobilization, arterial pH and bicarbonate concentrations were elevated (chronic metabolic alkalosis). Net urinary acid excretion increased in immobilized animals. Urinary bicarbonate excretion decreased during the first three weeks of immobilization, and then returned to control levels. Sustained increases in urinary ammonium excretion were seen throughout the time duration of immobilization. Neither potassium depletion nor hypokalemia was observed. Most parameters returned promptly to the normal range during the first week of recovery. Factors tentatively associated with changes in acid-base status of monkeys include contraction of extracellular fluid volume, retention of bicarbonate, increased acid excretion, and possible participation of extrarenal buffers.

Recursion-based depletion of human immunodeficiency virus-specific naive CD4(+) T cells may facilitate persistent viral replication and chronic viraemia leading to acquired immunodeficiency syndrome.

PubMed

Tsukamoto, Tetsuo; Yamamoto, Hiroyuki; Okada, Seiji; Matano, Tetsuro

2016-09-01

Although antiretroviral therapy has made human immunodeficiency virus (HIV) infection a controllable disease, it is still unclear how viral replication persists in untreated patients and causes CD4(+) T-cell depletion leading to acquired immunodeficiency syndrome (AIDS) in several years. Theorists tried to explain it with the diversity threshold theory in which accumulated mutations in the HIV genome make the virus so diverse that the immune system will no longer be able to recognize all the variants and fail to control the viraemia. Although the theory could apply to a number of cases, macaque AIDS models using simian immunodeficiency virus (SIV) have shown that failed viral control at the set point is not always associated with T-cell escape mutations. Moreover, even monkeys without a protective major histocompatibility complex (MHC) allele can contain replication of a super infected SIV following immunization with a live-attenuated SIV vaccine, while those animals are not capable of fighting primary SIV infection. Here we propose a recursion-based virus-specific naive CD4(+) T-cell depletion hypothesis through thinking on what may happen in individuals experiencing primary immunodeficiency virus infection. This could explain the mechanism for impairment of virus-specific immune response in the course of HIV infection. Copyright © 2016 Elsevier Ltd. All rights reserved.

THE SUSCEPTIBILITY OF MARMOSETS TO YELLOW FEVER VIRUS

PubMed Central

Davis, Nelson C.

1930-01-01

1. It has been possible to introduce yellow fever virus into the small Brazilian monkeys, Callithrix albicollis and Leontocebus ursulus, by the bites of infected mosquitoes and to carry the virus through a series of four passages in each species and back to rhesus monkeys by the bites of Stegomyia mosquitoes fed on the last marmoset of each series. 2. Five specimens of L. ursulus were used. Four developed fever, and all died during the experiments. At least two showed liver necroses comparable to those found in human beings and rhesus monkeys that died of yellow fever. 3. Twenty specimens of C. albicollis were used. Very few showed a temperature reaction following the introduction of virus. Of those that died, none had lesions typical of yellow fever as seen in certain other species of monkeys and in humans. 4. The convalescent serum from each of five C. albicollis protected a rhesus monkey against yellow fever virus, but the serum from a normal marmoset of the same species was found to be non-protective. PMID:19869773

Ancestry of a human endogenous retrovirus family.

PubMed Central

Mariani-Costantini, R; Horn, T M; Callahan, R

1989-01-01

The human endogenous retrovirus type II (HERVII) family of HERV genomes has been found by Southern blot analysis to be characteristic of humans, apes, and Old World monkeys. New World monkeys and prosimians lack HERVII proviral genomes. Cellular DNAs of humans, common chimpanzees, gorillas, and orangutans, but not lesser ape lar gibbons, appear to contain the HERVII-related HLM-2 proviral genome integrated at the same site (HLM-2 maps to human chromosome 1). This suggests that the ancestral HERVII retrovirus(es) entered the genomes of Old World anthropoids by infection after the divergence of New World monkeys (platyrrhines) but before the evolutionary radiation of large hominoids. Images PMID:2507793

Spaceflight and immune responses of Rhesus monkeys

NASA Technical Reports Server (NTRS)

Sonnenfeld, Gerald

1994-01-01

Evidence from both human and rodent studies indicates that alterations in immunological parameters occur after space flight. The objective of this project is to determine the effects of space flight on immune responses of Rhesus monkeys. The expected significance of the work is a determination of the range of immunological functions of the Rhesus monkey, a primate similar in many ways to man, affected by space flight. Changes in immune responses that could yield alterations in resistance to infection may be determined as well as the duration of alterations in immune responses. Additional information on the nature of cellular interactions for the generation of immune responses may also be obtained.

Plasma omega 3 polyunsaturated fatty acid status and monounsaturated fatty acids are altered by chronic social stress and predict endocrine responses to acute stress in titi monkeys

USDA-ARS?s Scientific Manuscript database

Disturbances in fatty acid (FA) metabolism may link chronic psychological stress, endocrine responsiveness, and psychopathology. Therefore, lipid metabolome-wide responses and their relationships with endocrine (cortisol; insulin; adiponectin) responsiveness to acute stress (AS) were assessed in a ...

Induction of Encephalitis in Rhesus Monkeys Infused with Lymphocryptovirus-Infected B-Cells Presenting MOG34–56 Peptide

PubMed Central

Haanstra, Krista G.; Wubben, Jacqueline A. M.; Jonker, Margreet; Hart, Bert A. ‘t.

2013-01-01

The overlapping epidemiology of multiple sclerosis (MS) and Epstein-Barr virus (EBV), the increased risk to develop MS after infectious mononucleosis (IM) and the localization of EBV-infected B-cells within the MS brain suggest a causal link between EBV and MS. However, the underlying mechanism is unknown. We hypothesize that EBV-infected B-cells are capable of eliciting a central nervous system (CNS) targeting autoimmune reaction. To test this hypothesis we have developed a novel experimental model in rhesus monkeys of IM-like disease induced by infusing autologous B-lymphoblastoid cells (B-LCL). Herpesvirus papio (HVP) is a lymphocryptovirus related to EBV and was used to generate rhesus monkey B-LCL. Three groups of five animals were included; each group received three intravenous infusions of B-LCL that were either pulsed with the encephalitogenic self peptide MOG34–56 (group A), a mimicry peptide (981–1003) of the major capsid protein of cytomegalovirus (CMVmcp981–1003; group B) or the citrullinated MOG34–56 (cMOG34–56; group C). Groups A and B received on day 98 a single immunization with MOG34–56 in incomplete Freund’s adjuvant (IFA). Group C monkeys were euthanized just prior to day 98 without booster immunization. We observed self-peptide-specific proliferation of T-cells, superimposed on similar strong proliferation of CD3+CD8+ T-cells against the B-LCL as observed in IM. The brains of several monkeys contained perivascular inflammatory lesions of variable size, comprising CD3+ and CD68+ cells. Moreover, clusters of CD3+ and CD20+ cells were detected in the meninges. The only evident clinical sign was substantial loss of bodyweight (>15%), a symptom observed both in early autoimmune encephalitis and IM. In conclusion, this model suggests that EBV-induced B-LCL can elicit a CNS targeting inflammatory (auto)immune reaction. PMID:23977076

Lassa Virus Infection of Rhesus Monkeys: Pathogenesis and Treatment with Ribavirin

DTIC Science & Technology

1980-05-01

virus is a severe, gen- data have suggested that mild or subclinical infec- eralized disease described as Lassa fever [1-31. tions may occur [2...Liberia and Sierra Management of Lassa fever would be facilitated if Leone; serologic data also suggest the presence of an effective antiviral drug...of Laboratory monkey model for human Lassa fever . The results Animal Resources, National Research Council. The facilities are encouraging, suggesting

Africa and the AIDS myth.

PubMed

Versi, A

1990-04-01

The recently released television documentary, "Monkey Business, AIDS: The African Story," has created controversy in Europe with its premise that AIDS did not originate in Africa. Although AIDS 1st appeared in New York in 1981 and was not recorded in Africa until 1983, researchers and the media have promoted the theory that AIDS came from Africa through human contact with the green monkey. Subsequent research forced the original champions of this "green monkey connection" theory to acknowledge that the AIDS virus and the green monkey virus are so dissimilar that they could not be historically linked. Then, the focus turned to the theory that a remote pygmy tribe had been endemically infected with the AIDS virus and carried the disease, by airplane, out of the country. This theory, too, was refuted by the failure to locate any HIV-positive pygmies in the Central African Republic. Still determined to prove that AIDS did not have an American or European origin, researchers reported that blood testing conducted in 1984 revealed 50-90% of Africans to be HIV-infected. Retesting with a more accurate procedure revealed the rate of infectivity to be only 0.02%; yet the media have continued to portray Africa as the source of the AIDS scourge. Moreover, it appears that AIDS cases are actually overreported from Africa--not underreported--due to confusion with conditions such as malnutrition and tropical diseases. To some, this relentless drive to vilify Africa reflects racism. Others believe that it represents an effort to cover up the possibility that the AIDS virus is man-made--a result of an accident in gene technology or microbiology.

Global gene expression analysis of peripheral blood mononuclear cells in rhesus monkey infants with CA16 infection-induced HFMD.

PubMed

Song, Jie; Hu, Yajie; Hu, Yunguang; Wang, Jingjing; Zhang, Xiaolong; Wang, Lichun; Guo, Lei; Wang, Yancui; Ning, Ruotong; Liao, Yun; Zhang, Ying; Zheng, Huiwen; Shi, Haijing; He, Zhanlong; Li, Qihan; Liu, Longding

2016-03-02

Coxsackievirus A16 (CA16) is a dominant pathogen that results in hand, foot, and mouth disease and causes outbreaks worldwide, particularly in the Asia-Pacific region. However, the underlying molecular mechanisms remain unclear. Our previous study has demonstrated that the basic CA16 pathogenic process was successfully mimicked in rhesus monkey infant. The present study focused on the global gene expression changes in peripheral blood mononuclear cells of rhesus monkey infants with hand, foot, and mouth disease induced by CA16 infection at different time points. Genome-wide expression analysis was performed with Agilent whole-genome microarrays and established bioinformatics tools. Nine hundred and forty-eight significant differentially expressed genes that were associated with 5 gene ontology categories, including cell communication, cell cycle, immune system process, regulation of transcription and metabolic process were identified. Subsequently, the mapping of genes related to the immune system process by PANTHER pathway analysis revealed the predominance of inflammation mediated by chemokine and cytokine signaling pathways and the interleukin signaling pathway. Ultimately, co-expressed genes and their networks were analyzed. The results revealed the gene expression profile of the immune system in response to CA16 in rhesus monkey infants and suggested that such an immune response was generated as a result of the positive mobilization of the immune system. This initial microarray study will provide insights into the molecular mechanism of CA16 infection and will facilitate the identification of biomarkers for the evaluation of vaccines against this virus. Copyright © 2016 Elsevier B.V. All rights reserved.

Antiviral treatment normalizes neurophysiological but not movement abnormalities in simian immunodeficiency virus–infected monkeys

PubMed Central

Fox, Howard S.; Weed, Michael R.; Huitron-Resendiz, Salvador; Baig, Jamal; Horn, Thomas F.W.; Dailey, Peter J.; Bischofberger, Norbert; Henriksen, Steven J.

2000-01-01

Simian immunodeficiency virus (SIV) infection of rhesus monkeys provides an excellent model of the central nervous system (CNS) consequences of HIV infection. To discern the relationship between viral load and abnormalities induced in the CNS by the virus, we infected animals with SIV and later instituted antiviral treatment to lower peripheral viral load. Measurement of sensory-evoked potentials, assessing CNS neuronal circuitry, revealed delayed latencies after infection that could be reversed by lowering viral load. Cessation of treatment led to the reappearance of these abnormalities. In contrast, the decline in general motor activity induced by SIV infection was unaffected by antiviral treatment. An acute increase in the level of the chemokine monocyte chemoattractant protein-1 (MCP-1) was found in the cerebrospinal fluid (CSF) relative to plasma in the infected animals at the peak of acute viremia, likely contributing to an early influx of immune cells into the CNS. Examination of the brains of the infected animals after return of the electrophysiological abnormalities revealed diverse viral and inflammatory findings. Although some of the physiological abnormalities resulting from SIV infection can be at least temporarily reversed by lowering viral load, the viral-host interactions initiated by infection may result in long-lasting changes in CNS-mediated functions. PMID:10880046

Antiviral treatment normalizes neurophysiological but not movement abnormalities in simian immunodeficiency virus-infected monkeys.

PubMed

Fox, H S; Weed, M R; Huitron-Resendiz, S; Baig, J; Horn, T F; Dailey, P J; Bischofberger, N; Henriksen, S J

2000-07-01

Simian immunodeficiency virus (SIV) infection of rhesus monkeys provides an excellent model of the central nervous system (CNS) consequences of HIV infection. To discern the relationship between viral load and abnormalities induced in the CNS by the virus, we infected animals with SIV and later instituted antiviral treatment to lower peripheral viral load. Measurement of sensory-evoked potentials, assessing CNS neuronal circuitry, revealed delayed latencies after infection that could be reversed by lowering viral load. Cessation of treatment led to the reappearance of these abnormalities. In contrast, the decline in general motor activity induced by SIV infection was unaffected by antiviral treatment. An acute increase in the level of the chemokine monocyte chemoattractant protein-1 (MCP-1) was found in the cerebrospinal fluid (CSF) relative to plasma in the infected animals at the peak of acute viremia, likely contributing to an early influx of immune cells into the CNS. Examination of the brains of the infected animals after return of the electrophysiological abnormalities revealed diverse viral and inflammatory findings. Although some of the physiological abnormalities resulting from SIV infection can be at least temporarily reversed by lowering viral load, the viral-host interactions initiated by infection may result in long-lasting changes in CNS-mediated functions.

Peripheral Blood Biomarkers of Disease Outcome in a Monkey Model of Rift Valley Fever Encephalitis.

PubMed

Wonderlich, Elizabeth R; Caroline, Amy L; McMillen, Cynthia M; Walters, Aaron W; Reed, Douglas S; Barratt-Boyes, Simon M; Hartman, Amy L

2018-02-01

Rift Valley Fever (RVF) is an emerging arboviral disease of livestock and humans. Although the disease is caused by a mosquito-borne virus, humans are infected through contact with, or inhalation of, virus-laden particles from contaminated animal carcasses. Some individuals infected with RVF virus (RVFV) develop meningoencephalitis, resulting in morbidity and mortality. Little is known about the pathogenic mechanisms that lead to neurologic sequelae, and thus, animal models that represent human disease are needed. African green monkeys (AGM) exposed to aerosols containing RVFV develop a reproducibly lethal neurological disease that resembles human illness. To understand the disease process and identify biomarkers of lethality, two groups of 5 AGM were infected by inhalation with either a lethal or a sublethal dose of RVFV. Divergence between lethal and sublethal infections occurred as early as 2 days postinfection (dpi), at which point CD8 + T cells from lethally infected AGM expressed activated caspase-3 and simultaneously failed to increase levels of major histocompatibility complex (MHC) class II molecules, in contrast to surviving animals. At 4 dpi, lethally infected animals failed to demonstrate proliferation of total CD4 + and CD8 + T cells, in contrast to survivors. These marked changes in peripheral blood cells occur much earlier than more-established indicators of severe RVF disease, such as granulocytosis and fever. In addition, an early proinflammatory (gamma interferon [IFN-γ], interleukin 6 [IL-6], IL-8, monocyte chemoattractant protein 1 [MCP-1]) and antiviral (IFN-α) response was seen in survivors, while very late cytokine expression was found in animals with lethal infections. By characterizing immunological markers of lethal disease, this study furthers our understanding of RVF pathogenesis and will allow the testing of therapeutics and vaccines in the AGM model. IMPORTANCE Rift Valley Fever (RVF) is an important emerging viral disease for which we lack both an effective human vaccine and treatment. Encephalitis and neurological disease resulting from RVF lead to death or significant long-term disability for infected people. African green monkeys (AGM) develop lethal neurological disease when infected with RVF virus by inhalation. Here we report the similarities in disease course between infected AGM and humans. For the first time, we examine the peripheral immune response during the course of infection in AGM and show that there are very early differences in the immune response between animals that survive infection and those that succumb. We conclude that AGM are a novel and suitable monkey model for studying the neuropathogenesis of RVF and for testing vaccines and therapeutics against this emerging viral pathogen. Copyright © 2018 American Society for Microbiology.

Intrapericardial denervation: Responses to water immersion in rhesus monkeys

NASA Technical Reports Server (NTRS)

McKeever, Kenneth H.; Keil, Lanny C.; Sandler, Harold

1995-01-01

Eleven anesthetized rhesus monkeys were used to study cardiovascular, renal, and endocrine alterations associated with 120 min of head-out water immersion. Five animals underwent complete intrapericardial denervation using the Randall technique, while the remaining six monkeys served as intact controls. Each animal was chronically instrumented with an electromagnetic flow probe on the ascending aorta, a strain gauge pressure transducer implanted in the apex of the left ventricle (LV), and electrocardiogram leads anchored to the chest wall and LV. During immersion, LV end-diastolic pressure, urine flow, glomerular filtration rate, sodium excretion, and circulating atrial natriuretic peptide (ANP) each increased (P less than 0.05) for intact and denervated monkeys. There were no alterations in free water clearance in either group during immersion, yet fractional excretion of free water increased (P less than 0.05) in the intact monkeys. Plasma renin activity (PRA) decreased (P less than 0.05) during immersion in intact monkeys but not the denervated animals. Plasma vasopressin (PVP) concentration decreased (P less than 0.05) during the first 30 min of immersion in both groups but was not distinguishable from control by 60 min of immersion in denervated monkeys. These data demonstrate that complete cardiac denervation does not block the rise in plasma ANP or prevent the natriuresis associated with head-out water immersion. The suppression of PVP during the first minutes of immersion after complete cardiac denervation suggests that extracardiac sensing mechanisms associated with the induced fluid shifts may be responsible for the findings. water immersion; natriuresis; vasopressin; eardiae denervation; monkey

Effect of chronic antipsychotic exposure on astrocyte and oligodendrocyte numbers in macaque monkeys

PubMed Central

Konopaske, Glenn T.; Dorph-Petersen, Karl-Anton; Sweet, Robert A.; Pierri, Joseph N.; Zhang, Wei; Sampson, Allan R.; Lewis, David A.

2008-01-01

Background Both in vivo and post-mortem studies suggest that oligodendrocyte and myelination alterations are present in individuals with schizophrenia. However, it is unclear whether prolonged treatment with antipsychotic medications contributes to these disturbances. We recently reported that chronic exposure of macaque monkeys to haloperidol or olanzapine was associated with a 10−18% lower glial cell number in the parietal grey matter. Consequently, in this study we sought to determine whether the lower glial cell number was due to fewer oligodendrocytes as opposed to lower numbers of astrocytes. Methods Using fluorescent immunocytochemical techniques, we optimized the visualization of each cell type throughout the entire thickness of tissue sections, while minimizing final tissue shrinkage. As a result, we were able to obtain robust stereological estimates of total oligodendrocyte and astrocyte numbers in the parietal grey matter using the optical fractionator method. Results We found a significant 20.5% lower astrocyte number with a non-significant 12.9% lower oligodendrocyte number in the antipsychotic-exposed monkeys. Similar effects were seen in both the haloperidol and olanzapine groups. Conclusion These findings suggest that studies investigating glial cell alterations in schizophrenia must take into account the effect of antipsychotic treatment. PMID:17945195

Monkey motor stimulation and altered social behavior during chronic methadone administration.

PubMed

Crowley, T J; Hydinger, M; Stynes, A J; Feiger, A

1975-08-21

To assess the effects of chronic methadone administration on locomotor, social, and eating behavior od drug-native individuals under circumstances approximating those of methadone "maintenance" clinics, we gave single, daily oral doses of methadone to 5 Macaca radiata monkeys living in a social group. We obtained motor activity counts automatically during 6 weeks of baseline, 10 weeks of drug administration, and 3 weeks of post-drug abstinence. Social behaviors of association, dominance, submission, and sexuality were counted 5 days per week, and animal weights, food eaten and food-reinforced work were recorded. Plasma methadone levels were near those achieved in mechadone clincs. Methadone produced mixed stimulation and sedation in the daytime, with stimulation predominating for 4 hrs following administration. At night the subjects moved less while taking the drug. Associative behaviors were reduced by methadone, but dominance, submission, and sexual behaviors were not altered. The monkeys ate less while taking the drug, losing weight and working less for food. In these primates methadone had significant stimulant properties, impaired important social behaviors, and reduced the potency of food as a reinforcer of work. The results are compared with methadone's effects upon humans.

Ecology of malaria parasites infecting Southeast Asian macaques: evidence from cytochrome b sequences

PubMed Central

Putaporntip, Chaturong; Jongwutiwes, Somchai; Thongaree, Siriporn; Seethamchai, Sunee; Grynberg, Priscila; Hughes, Austin L.

2010-01-01

Although malaria parasites infecting non-human primates are important models for human malaria, little is known of the ecology of infection by these parasites in the wild. We extensively sequenced cytochrome b (cytb) of malaria parasites (Apicomplexa: Haemosporida) from free-living Southeast Asian monkeys Macaca nemestrina and M. fascicularis. The two most commonly observed taxa were P. inui and Hepatocystis sp., but certain other sequences did not cluster closely with any previously sequenced species. Most of the major clades of parasites were found in both Macaca species; and the two most commonly occurring parasite infected the two Macaca species at approximately equal levels. However, P. inui showed evidence of genetic differentiation between the populations infecting the two Macaca species, suggesting limited movement of this parasite among hosts. Moreover, coinfection with Plasmodium and Hepatocystis species occurred significantly less frequently than expected on the basis of the rates of infection with either taxon alone, suggesting the possibility of competitive exclusion. The results revealed unexpectedly complex communities of Plasmodium and Hepatocystis taxa infecting wild Southeast Asian monkeys. Parasite taxa differed with respect to both the frequency of between-host movement and their frequency of coinfection. PMID:20646216

American Trypanosomiasis

DTIC Science & Technology

2011-06-01

the flagellate protozoon Trypanosoma cruzi (previously Schizo- trypanum cruzi). In humans, T. cruzi can infect parenchy- mal cells of many different...Hemiptera, suborder Het- eroptera, family Reduviidae, subfamily Triatominae), the arthropod vector, in Brazil in 1909.1,2 Chagas used infected reduviid...bugs to experimentally infect a monkey, from which he subsequently isolated blood-stage parasites. Cha- gas later identified the same parasites in the

The PapG-adhesin at the tip of P-fimbriae provides Escherichia coli with a competitive edge in experimental bladder infections of cynomolgus monkeys

PubMed Central

1995-01-01

Human urinary tract infection is an infectious disease that depends on a series of host-microbial interactions. The bacteria first colonize the colon and then the periurethral/vaginal areas; they ascend to and infect first the bladder and then the kidneys. Expression of Escherichia coli P-fimbriae constitutes the strongest correlation to renal pathogenicity, but is also related to first-time cystitis in children. The role of P-fimbriae in the preceding steps in the infectious process is unknown. To examine this, we constructed, from a P-fimbriated E. coli strain with a class II G-adhesin preferentially binding to globoside, one isogenic mutant lacking the G-adhesin and another isogenic mutant in which we replaced the papG class II allele with a class III adhesin preferentially binding to the Forssman antigen. We report here the comparison of the adhesin knockout mutant (DS17-8) and the class-switch mutant (DS17-1) with the wild-type (DS17) for in vivo colonization of the gut, vagina, and bladder of cynomolgus monkeys. It was recently shown that the class II tip G-adhesin is a prerequisite for acute pyelonephritis to occur in the monkey model in the absence of other kidney-specific adhesins or obstruction of the urinary flow. Here we show that it is not required for bladder infection but gives a competitive advantage in mixed infections. In the vagina and colon, the G-adhesin gives no competitive advantage. PMID:7500014

Hemopoiesis in the pig-tailed monkey Macaca nemestrina during chronic altitude exposure.

NASA Technical Reports Server (NTRS)

Buderer, M. C.; Pace, N.

1972-01-01

Study of monkeys for 180 days at 3800 m altitude to examine their hemopoietic response. Plasma volume was found to be reduced while red cell volume increased steadily for four to five months. Reduction in mean corpuscular hemoglobin content was observed from day 30 to day 120 at altitude. Total plasma protein concentration was unchanged at altitude, but marked reduction in the albumin/globulin ratio occurred. Total circulating plasma protein and albumin were reduced in amount, whereas nonalbumin protein was unchanged. These results imply loss of albumin coupled with a corresponding loss of water from the blood and maintenance of normal plasma osmotic pressure. The body/venous hematocrit ratio was found to be reduced at altitude, possibly as a consequence of the expanded capillary volume of the body. The hemopoietic responses of the pig-tailed monkey at altitude require at least several months for completion, and closely resemble those seen in man; thus, the monkey can serve well for long-term studies of high-altitude acclimatization.

Telemetric recordings of single neuron activity and visual scenes in monkeys walking in an open field.

PubMed

Lei, Yanlin; Sun, Ninglei; Wilson, Fraser A W; Wang, Xiusong; Chen, Nanhui; Yang, Jianzhen; Peng, Yanping; Wang, Jianhong; Tian, Shaohua; Wang, Maohua; Miao, Yingda; Zhu, Weina; Qi, Hua; Ma, Yuanye

2004-05-30

This paper describes a portable recording system and methods for obtaining chronic recordings of single units and tracking rhesus monkey behavior in an open field. The integrated system consists of four major components: (1) microelectrode assembly; (2) head-stage; (3) recording station; and (4) data storage station, the first three of which are carried by the monkey and weigh 800 g. Our system provides synchronized video and electrophysiological signals, which are transmitted by a wireless system to a distance of 50 m. Its major advantages are that neuronal recordings are made in freely moving monkeys, and well-separated action potentials with amplitude five times higher than the background noise are usually recorded and readily kept for many hours. Using this system, we were able to study "place cells" in non-human primate brains. The described methods provide a new way to examine correlations between single neuron activity and primate behaviors, and can also be used to study the cellular basis of social behaviors in non-human primates.

Cynomolgus monkeys (Macaca fascicularis) experimentally infected with B19V and hepatitis A virus: no evidence of the co-infection as a cause of acute liver failure.

PubMed

Leon, Luciane Almeida Amado; Marchevsky, Renato Sergio; Gaspar, Ana Maria Coimbra; Garcia, Rita de Cassia Nasser Cubel; Almeida, Adilson José de; Pelajo-Machado, Marcelo; Castro, Tatiana Xavier de; Nascimento, Jussara Pereira do; Brown, Kevin E; Pinto, Marcelo Alves

2016-04-01

This study was conducted to analyse the course and the outcome of the liver disease in the co-infected animals in order to evaluate a possible synergic effect of human parvovirus B19 (B19V) and hepatitis A virus (HAV) co-infection. Nine adult cynomolgus monkeys were inoculated with serum obtained from a fatal case of B19V infection and/or a faecal suspension of acute HAV. The presence of specific antibodies to HAV and B19V, liver enzyme levels, viraemia, haematological changes, and necroinflammatory liver lesions were used for monitoring the infections. Seroconversion was confirmed in all infected groups. A similar pattern of B19V infection to human disease was observed, which was characterised by high and persistent viraemia in association with reticulocytopenia and mild to moderate anaemia during the period of investigation (59 days). Additionally, the intranuclear inclusion bodies were observed in pro-erythroblast cell from an infected cynomolgus and B19V Ag in hepatocytes. The erythroid hypoplasia and decrease in lymphocyte counts were more evident in the co-infected group. The present results demonstrated, for the first time, the susceptibility of cynomolgus to B19V infection, but it did not show a worsening of liver histopathology in the co-infected group.

Cynomolgus monkeys (Macaca fascicularis) experimentally infected with B19V and hepatitis A virus: no evidence of the co-infection as a cause of acute liver failure

PubMed Central

Leon, Luciane Almeida Amado; Marchevsky, Renato Sergio; Gaspar, Ana Maria Coimbra; Garcia, Rita de Cassia Nasser Cubel; de Almeida, Adilson José; Pelajo-Machado, Marcelo; de Castro, Tatiana Xavier; do Nascimento, Jussara Pereira; Brown, Kevin E; Pinto, Marcelo Alves

2016-01-01

This study was conducted to analyse the course and the outcome of the liver disease in the co-infected animals in order to evaluate a possible synergic effect of human parvovirus B19 (B19V) and hepatitis A virus (HAV) co-infection. Nine adult cynomolgus monkeys were inoculated with serum obtained from a fatal case of B19V infection and/or a faecal suspension of acute HAV. The presence of specific antibodies to HAV and B19V, liver enzyme levels, viraemia, haematological changes, and necroinflammatory liver lesions were used for monitoring the infections. Seroconversion was confirmed in all infected groups. A similar pattern of B19V infection to human disease was observed, which was characterised by high and persistent viraemia in association with reticulocytopenia and mild to moderate anaemia during the period of investigation (59 days). Additionally, the intranuclear inclusion bodies were observed in pro-erythroblast cell from an infected cynomolgus and B19V Ag in hepatocytes. The erythroid hypoplasia and decrease in lymphocyte counts were more evident in the co-infected group. The present results demonstrated, for the first time, the susceptibility of cynomolgus to B19V infection, but it did not show a worsening of liver histopathology in the co-infected group. PMID:27074255

Intrapericardial Denervation: Responses to Water Immersion in Rhesus Monkeys

NASA Technical Reports Server (NTRS)

McKeever, Kenneth H.; Keil, Lanny C.; Sandler, Harold

1995-01-01

Eleven anesthetized rhesus monkeys were used to study cardiovascular, renal, and endocrine alterations associated with 120 min of head-out water immersion. Five animals underwent complete intrapericardial denervation using the Randall technique, while the remaining six monkeys served as intact controls. Each animal was chronically instrumented with an electromagnetic flow probe on the ascending aorta, a strain gauge pressure transducer implanted in the apex of the left ventricle (LV), and electrocardiogram leads anchored to the chest wall and LV. During immersion, LV end-diastolic pressure, urine flow, glomerular filtration rate, sodium excretion, and circulating atrial natriuretic peptide (ANP) each increased (P less than 0.05) for intact and denervated monkeys. There were no alterations in free water clearance in either group during immersion, yet fractional excretion of free water increased (P less than 0.05) in the intact monkeys. Plasma renin activity (PRA) decreased (P less than 0.05) during immersion in intact monkeys but not the denervated animals. Plasma vasopressin (PVP) concentration decreased (P less than 0.05) during the first 30 min of immersion in both groups but was not distinguishable from control by 60 min of immersion in denervated monkeys. These data demonstrate that complete cardiac denervation does not block the rise in plasma ANP or prevent the natriuresis associated with head-out water immersion. The suppression of PVP during the first minutes of immersion after complete cardiac denervation suggests that extracardiac sensing mechanisms associated with the induced fluid shifts may be responsible for the findings.

Detection of viral agents in fecal specimens of monkeys with diarrhea.

PubMed

Wang, Yuhuan; Tu, Xinming; Humphrey, Charles; McClure, Harold; Jiang, Xi; Qin, Chuan; Glass, Roger I; Jiang, Baoming

2007-04-01

Diarrheal disease is a major cause of morbidity and mortality in humans and animals, including non human primates. While the diagnostics for gastrointestinal bacterial and parasitic pathogens and their etiological role in disease are well established, little is known about the epidemiology, prevalence and role of viral agents in diarrheal illness among monkeys. We collected fecal specimens from monkeys with diarrhea that were housed in two primate colonies, the Institute of Laboratory Animal Sciences, Beijing, China and the Yerkes National Primate Research Center, Georgia, USA. We screened these fecal specimens for rotaviruses and enteric adenoviruses 40/41 by using commercial EIA kits (Rotaclone and Adenoclone), enteroviruses by RT-PCR and Southern blot hybridization, and picobirnaviruses by polyacrylamide gel electrophoresis and silver staining. Some of the specimens were examined by EM for coronaviruses and noroviruses. Of the 92 specimens from China, we found 63 (68%) positive for viruses, including enteroviruses (52%), enteric adenoviruses (21%), rotaviruses (20%), and picobirnaviruses (2%). Coronaviruses were detected in some specimens. Mixed infection of two or more viral agents was seen in 23 (25%) specimens. In the US collection, we detected enteroviruses and enteric adenoviruses in 76% (45/59) and 14% (7/50) of the specimens, respectively. Electron microscopy showed norovirus-like particles in some specimens from both colonies. Our findings indicate endemic infections with enteric viruses in monkeys of both colonies. The availability of new simian rotaviruses, enteric adenoviruses, enteroviruses, and coronaviruses and the discovery of noroviruses and picobirnaviruses may allow us to develop better diagnostics for these agents and determine which of these agents are clearly associated with gastroenteritis in monkeys.

Simian T-Cell Leukemia Virus (STLV) Infection in Wild Primate Populations in Cameroon: Evidence for Dual STLV Type 1 and Type 3 Infection in Agile Mangabeys (Cercocebus agilis)

PubMed Central

Courgnaud, Valerie; Van Dooren, Sonia; Liegeois, Florian; Pourrut, Xavier; Abela, Bernadette; Loul, Severin; Mpoudi-Ngole, Eitel; Vandamme, Annemieke; Delaporte, Eric; Peeters, Martine

2004-01-01

Three types of human T-cell leukemia virus (HTLV)-simian T-cell leukemia virus (STLV) (collectively called primate T-cell leukemia viruses [PTLVs]) have been characterized, with evidence for zoonotic origin from primates for HTLV type 1 (HTLV-1) and HTLV-2 in Africa. To assess human exposure to STLVs in western Central Africa, we screened for STLV infection in primates hunted in the rain forests of Cameroon. Blood was obtained from 524 animals representing 18 different species. All the animals were wild caught between 1999 and 2002; 328 animals were sampled as bush meat and 196 were pets. Overall, 59 (11.2%) of the primates had antibodies cross-reacting with HTLV-1 and/or HTLV-2 antigens; HTLV-1 infection was confirmed in 37 animals, HTLV-2 infection was confirmed in 9, dual HTLV-1 and HTLV-2 infection was confirmed in 10, and results for 3 animals were indeterminate. Prevalences of infection were significantly lower in pets than in bush meat, 1.5 versus 17.0%, respectively. Discriminatory PCRs identified STLV-1, STLV-3, and STLV-1 and STLV-3 in HTLV-1-, HTLV-2-, and HTLV-1- and HTLV-2-cross-reactive samples, respectively. We identified for the first time STLV-1 sequences in mustached monkeys (Cercopithecus cephus), talapoins (Miopithecus ogouensis), and gorillas (Gorilla gorilla) and confirmed STLV-1 infection in mandrills, African green monkeys, agile mangabeys, and crested mona and greater spot-nosed monkeys. STLV-1 long terminal repeat (LTR) and env sequences revealed that the strains belonged to different PTLV-1 subtypes. A high prevalence of PTLV infection was observed among agile mangabeys (Cercocebus agilis); 89% of bush meat was infected with STLV. Cocirculation of STLV-1 and STLV-3 and STLV-1-STLV-3 coinfections were identified among the agile mangabeys. Phylogenetic analyses of partial LTR sequences indicated that the agile mangabey STLV-3 strains were more related to the STLV-3 CTO604 strain isolated from a red-capped mangabey (Cercocebus torquatus) from Cameroon than to the STLV-3 PH969 strain from an Eritrean baboon or the PPA-F3 strain from a baboon in Senegal. Our study documents for the first time that (i) a substantial proportion of wild-living monkeys in Cameroon is STLV infected, (ii) STLV-1 and STLV-3 cocirculate in the same primate species, (iii) coinfection with STLV-1 and STLV-3 occurs in agile mangabeys, and (iv) humans are exposed to different STLV-1 and STLV-3 subtypes through handling primates as bush meat. PMID:15078952

Paucity of CD4+CCR5+ T cells is a typical feature of natural SIV hosts

PubMed Central

Pandrea, Ivona; Apetrei, Cristian; Gordon, Shari; Barbercheck, Joseph; Dufour, Jason; Bohm, Rudolf; Sumpter, Beth; Roques, Pierre; Marx, Preston A.; Hirsch, Vanessa M.; Kaur, Amitinder; Lackner, Andrew A.; Veazey, Ronald S.; Silvestri, Guido

2007-01-01

In contrast to lentiviral infections of humans and macaques, simian immunodeficiency virus (SIV) infection of natural hosts is nonpathogenic despite high levels of viral replication. However, the mechanisms underlying this absence of disease are unknown. Here we report that natural hosts for SIV infection express remarkably low levels of CCR5 on CD4+ T cells isolated from blood, lymph nodes, and mucosal tissues. Given that this immunologic feature is found in 5 different species of natural SIV hosts (sooty mangabeys, African green monkeys, mandrills, sun-tailed monkeys, and chimpanzees) but is absent in 5 nonnatural/recent hosts (humans, rhesus, pigtail, cynomolgus macaques, and baboons), it may represent a key feature of the coevolution between the virus and its natural hosts that led to a nonpathogenic infection. Beneficial effects of low CCR5 expression on CD4+ T cells may include the reduction of target cells for viral replication and a decreased homing of activated CD4+ T cells to inflamed tissue. PMID:17003371

An Anti-HIV-1 V3 Loop Antibody Fully Protects Cross-Clade and Elicits T-Cell Immunity in Macaques Mucosally Challenged with an R5 Clade C SHIV

PubMed Central

Lakhashe, Samir K.; Humbert, Michael; Sholukh, Anton; Hemashettar, Girish; Wong, Yin Ling; Yoon, John K.; Wang, Wendy; Novembre, Francis J.; Villinger, Francois; Ibegbu, Chris; Patel, Kalpana; Corti, Davide; Agatic, Gloria; Vanzetta, Fabrizia; Bianchi, Siro; Heeney, Jonathan L.; Sallusto, Federica; Lanzavecchia, Antonio; Ruprecht, Ruth M.

2011-01-01

Neutralizing antibodies have been shown to protect macaques against SHIV challenge. However, genetically diverse HIV-1 clades have evolved, and a key question left unanswered is whether neutralizing antibodies can confer cross-clade protection in vivo. The novel human monoclonal antibody HGN194 was isolated from an individual infected with an HIV-1 clade AG recombinant circulating recombinant form (CRF). HGN194 targets an epitope in the third hypervariable loop (V3) of HIV-1 gp120 and neutralizes a range of relatively neutralization-sensitive and resistant viruses. We evaluated the potential of HGN194 to protect infant rhesus monkeys against a SHIV encoding a primary CCR5-tropic HIV-1 clade C envelope. After high-dose mucosal challenge, all untreated controls became highly viremic while all HGN194-treated animals (50 mg/kg) were completely protected. When HGN194 was given at 1 mg/kg, one out of two monkeys remained aviremic, whereas the other had delayed, lower peak viremia. Interestingly, all protected monkeys given high-dose HGN194 developed Gag-specific proliferative responses of both CD4+ and CD8+ T cells. To test whether generation of the latter involved cryptic infection, we ablated CD8+ cells after HGN194 clearance. No viremia was detected in any protected monkeys, thus ruling out virus reservoirs. Thus, induction of CD8 T-cell immunity may have resulted from transient “Hit and Run” infection or cross priming via Ag-Ab-mediated cross-presentation. Together, our data identified the HGN194 epitope as protective and provide proof-of-concept that this anti-V3 loop mAb can prevent infection with sterilizing immunity after challenge with virus of a different clade, implying that V3 is a potential vaccine target. PMID:21483815

Health Risk Assessment of Embedded Depleted Uranium: Behavior, Physiology, Histology and Biokenetic Modeling

DTIC Science & Technology

1997-10-01

mg/in) (or in dogs or monkeys exposed for 5 years). Yet uranium concentrations in the kidney were as high as 1.1 tg U/g kidney wet weight in the rat...8.3 in the dog and 17.0 in the monkey), levels reported to cause acute renal toxicity (e.g., 2). Thus the chronic effects of uranium exposure remain...Anesthesia is induced with ketamine hydrochloride (80 mg/kg) in combination with xylazine hydrochloride (4 mg/kg), given i.p. Fragments are implanted within

DOE Office of Scientific and Technical Information (OSTI.GOV)

McAllister, R.S.

Contents: Visual Acquisition Functions in Operational Environments; Investigation of Causes of Military Aircraft Accidents Involving Pilot Vertigo/Disorientation; Long Term Pulmonary Effects of Repeated Use of 100% Oxygen; Effects of Microwave Radiation on Naval Personnel; Effects of Extremely Low Frequency Radiation on Man; Behavioral Characteristics of Monkeys and Rats Irradiated with Microwaves; Evaluation of the Squirrel Monkey (Saimiri sciureus) as an Experimental Animal Model for Dysbaric Osteonecrosis; Oculovestibular Effects on Visual Performance in Moving Military Systems; Chronic Exposure of Mammals to Non-ionizing Electric and Magnetic Fields--Physiological and Psychophysiological Effects; and Open Literature Publications by Staff Members.

Pathology of experimental Ebola virus infection in African green monkeys. Involvement of fibroblastic reticular cells.

PubMed

Davis, K J; Anderson, A O; Geisbert, T W; Steele, K E; Geisbert, J B; Vogel, P; Connolly, B M; Huggins, J W; Jahrling, P B; Jaax, N K

1997-08-01

Ebola virus has been responsible for explosive lethal outbreaks of hemorrhagic fever in both humans and nonhuman primates. Previous studies showed a predilection of Ebola virus for cells of the mononuclear phagocyte system and endothelial cells. To examine the distribution of lesions and Ebola virus antigen in the tissues of six adult male African green monkeys (Cercopithecus aethiops) that died 6 to 7 days after intraperitoneal inoculation of Ebola-Zaire (Mayinga) virus. Tissues were examined histologically, immunohistochemically, and ultrastructurally. A major novel finding of this study was that fibroblastic reticular cells were immunohistochemically and ultrastructurally identified as targets of Ebola virus infection. The role of Ebola virus-infected fibroblastic reticular cells in the pathogenesis of Ebola hemorrhagic fever warrants further investigation. This is especially important because of recent observations indicating that fibroblastic reticular cells, along with the reticular fibers they produce, maximize the efficiency of the immune response.

Risk factors associated with Toxoplasma gondii infection in captive Sapajus spp

USDA-ARS?s Scientific Manuscript database

The aim of this study was to identify risk factors associated with prevalence of Toxoplasma gondii infection in captive capuchin monkeys at a facility in the northeastern Brazil. Serum samples from 116 bearded capuchin (Sapajus libidinosus), nine blonde capuchin (Sapajus flavius), five black-capped ...

A Single-Dose Recombinant Parainfluenza Virus 5-Vectored Vaccine Expressing Respiratory Syncytial Virus (RSV) F or G Protein Protected Cotton Rats and African Green Monkeys from RSV Challenge.

PubMed

Wang, Dai; Phan, Shannon; DiStefano, Daniel J; Citron, Michael P; Callahan, Cheryl L; Indrawati, Lani; Dubey, Sheri A; Heidecker, Gwendolyn J; Govindarajan, Dhanasekaran; Liang, Xiaoping; He, Biao; Espeseth, Amy S

2017-06-01

Human respiratory syncytial virus (RSV) is a common cause of severe respiratory disease among infants, immunocompromised individuals, and the elderly. No licensed vaccine is currently available. In this study, we evaluated two parainfluenza virus 5 (PIV5)-vectored vaccines expressing RSV F (PIV5/F) or G (PIV5/G) protein in the cotton rat and African green monkey models for their replication, immunogenicity, and efficacy of protection against RSV challenge. Following a single intranasal inoculation, both animal species shed the vaccine viruses for a limited time but without noticeable clinical symptoms. In cotton rats, the vaccines elicited RSV F- or G-specific serum antibodies and conferred complete lung protection against RSV challenge at doses as low as 10 3 PFU. Neither vaccine produced the enhanced lung pathology observed in animals immunized with formalin-inactivated RSV. In African green monkeys, vaccine-induced serum and mucosal antibody responses were readily detected, as well. PIV5/F provided nearly complete protection against RSV infection in the upper and lower respiratory tract at a dose of 10 6 PFU of vaccine. At the same dose levels, PIV5/G was less efficacious. Both PIV5/F and PIV5/G were also able to boost neutralization titers in RSV-preexposed African green monkeys. Overall, our data indicated that PIV5/F is a promising RSV vaccine candidate. IMPORTANCE A safe and efficacious respiratory syncytial virus (RSV) vaccine remains elusive. We tested the recombinant parainfluenza virus 5 (PIV5) vectors expressing RSV glycoproteins for their immunogenicity and protective efficacy in cotton rats and African green monkeys, which are among the best available animal models to study RSV infection. In both species, a single dose of intranasal immunization with PIV5-vectored vaccines was able to produce systemic and local immunity and to protect animals from RSV challenge. The vaccines could also boost RSV neutralization antibody titers in African green monkeys that had been infected previously. Our data suggest that PIV5-vectored vaccines could potentially protect both the pediatric and elderly populations and support continued development of the vector platform. Copyright © 2017 American Society for Microbiology.

Wide distribution and ancient evolutionary history of simian foamy viruses in New World primates.

PubMed

Ghersi, Bruno M; Jia, Hongwei; Aiewsakun, Pakorn; Katzourakis, Aris; Mendoza, Patricia; Bausch, Daniel G; Kasper, Matthew R; Montgomery, Joel M; Switzer, William M

2015-10-29

Although simian foamy viruses (SFV) are the only exogenous retroviruses to infect New World monkeys (NWMs), little is known about their evolutionary history and epidemiology. Previous reports show distinct SFVs among NWMs but were limited to small numbers of captive or wild monkeys from five (Cebus, Saimiri, Ateles, Alouatta, and Callithrix) of the 15 NWM genera. Other studies also used only PCR testing or serological assays with limited validation and may have missed infection in some species. We developed and validated new serological and PCR assays to determine the prevalence of SFV in blood specimens from a large number of captive NWMs in the US (n = 274) and in captive and wild-caught NWMs (n = 236) in Peruvian zoos, rescue centers, and illegal trade markets. Phylogenetic and co-speciation reconciliation analyses of new SFV polymerase (pol) and host mitochondrial cytochrome B sequences, were performed to infer SFV and host co-evolutionary histories. 124/274 (45.2 %) of NWMs captive in the US and 59/157 (37.5 %) of captive and wild-caught NWMs in Peru were SFV WB-positive representing 11 different genera (Alouatta, Aotus, Ateles, Cacajao, Callithrix, Cebus, Lagothrix, Leontopithecus, Pithecia, Saguinus and Saimiri). Seroprevalences were lower at rescue centers (10/53, 18.9 %) compared to zoos (46/97, 47.4 %) and illegal trade markets (3/7, 8/19, 42.9 %) in Peru. Analyses showed that the trees of NWM hosts and SFVs have remarkably similar topologies at the level of species and sub-populations suggestive of co-speciation. Phylogenetic reconciliation confirmed 12 co-speciation events (p < 0.002) which was further supported by obtaining highly similar divergence dates for SFV and host genera and correlated SFV-host branch times. However, four ancient cross-genus transmission events were also inferred for Pitheciinae to Atelidae, Cacajao to ancestral Callithrix or Cebus monkeys, between Callithrix and Cebus monkeys, and Lagothrix to Alouatta. We demonstrate a broad distribution and stable co-speciation history of SFV in NWMs at the species level. Additional studies are necessary to further explore the epidemiology and natural history of SFV infection of NWMs and to determine the zoonotic potential for persons exposed to infected monkeys in captivity and in the wild.

VP1 amino acid residue 145 of enterovirus 71 is a key residue for its receptor attachment and resistance to neutralizing antibody during cynomolgus monkey infection.

PubMed

Fujii, Ken; Sudaka, Yui; Takashino, Ayako; Kobayashi, Kyousuke; Kataoka, Chikako; Suzuki, Tadaki; Iwata-Yoshikawa, Naoko; Kotani, Osamu; Ami, Yasushi; Shimizu, Hiroyuki; Nagata, Noriyo; Mizuta, Katsumi; Matsuzaki, Yoko; Koike, Satoshi

2018-05-30

Enterovirus 71 (EV71) is a causative agent of hand, foot, and mouth disease and sometimes causes severe or fatal neurological complications. The amino acid at VP1-145 determines virological characteristics of EV71. Viruses with glutamic acid (E) at VP1-145 (VP1-145E) are virulent in neonatal mice and transgenic mice expressing human scavenger receptor B2, whereas those with glutamine (Q) or glycine (G) are not. However, the contribution of this variation to pathogenesis in humans is not fully understood. We compared the virulence of VP1-145E and VP1-145G viruses of Isehara and C7/Osaka backgrounds in cynomolgus monkeys. VP1-145E, but not VP1-145G, viruses induced neurological symptoms. VP1-145E viruses were frequently detected in the tissues of infected monkeys. VP1-145G viruses were detected less frequently and disappeared quickly. Instead, mutants that had a G to E mutation at VP1-145 emerged, suggesting that VP1-145E viruses have a replication advantage in the monkeys. This is consistent with our hypothesis proposed in the accompanying paper that the VP1-145G virus is attenuated due to its adsorption by heparan sulfate. Monkeys infected with both viruses produced neutralizing antibodies before the onset of the disease. Interestingly, VP1-145E viruses were more resistant to neutralizing antibodies than VP1-145G viruses in vitro A small amount of neutralizing antibody raised in the early phase of infection may not be sufficient to block the dissemination of VP1-145E viruses. The different resistance of the VP1-145 variants to neutralizing antibodies may be one of the reasons for the difference in virulence. IMPORTANCE The contribution of VP1-145 variants in humans is not fully understood. In some reports, VP1-145G/Q viruses were more frequently isolated from severely affected than from mildly affected patients, suggesting that VP1-145G/Q viruses are more virulent. In the accompanying paper, we showed that VP1-145E viruses are more virulent than VP1-145G viruses in human SCARB2 transgenic mice. Heparan sulfate acts as a decoy to specifically trap the VP1-145G viruses and leads to abortive infection. Here, we demonstrated that VP1-145G was attenuated in cynomolgus monkeys, suggesting that this hypothesis is also true in a non-human primate model. VP1-145E viruses, but not VP1-145G viruses, were highly resistant to neutralizing antibodies. We propose the difference in resistance against neutralizing antibodies as another mechanism of EV71 virulence. In summary, VP1-145 contributes to virulence determination by controlling attachment receptor usage and antibody sensitivity. Copyright © 2018 American Society for Microbiology.

Effect of space flight on cytokine production and other immunologic parameters of rhesus monkeys

NASA Technical Reports Server (NTRS)

Sonnenfeld, G.; Davis, S.; Taylor, G. R.; Mandel, A. D.; Konstantinova, I. V.; Lesnyak, A.; Fuchs, B. B.; Peres, C.; Tkackzuk, J.; Schmitt, D. A.

1996-01-01

During a recent flight of a Russian satellite (Cosmos #2229), initial experiments examining the effects of space flight on immunologic responses of rhesus monkeys were performed to gain insight into the effect of space flight on resistance to infection. Experiments were performed on tissue samples taken from the monkeys before and immediately after flight. Additional samples were obtained approximately 1 month after flight for a postflight restraint study. Two types of experiments were carried out throughout this study. The first experiment determined the ability of leukocytes to produce interleukin-1 and to express interleukin-2 receptors. The second experiment examined the responsiveness of rhesus bone marrow cells to recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF). Human reagents that cross-reacted with monkey tissue were utilized for the bulk of the studies. Results from both studies indicated that there were changes in immunologic function attributable to space flight. Interleukin-1 production and the expression of interleukin-2 receptors was decreased after space flight. Bone marrow cells from flight monkeys showed a significant decrease in their response to GM-CSF compared with the response of bone marrow cells from nonflight control monkeys. These results suggest that the rhesus monkey may be a useful surrogate for humans in future studies that examine the effect of space flight on immune response, particularly when conditions do not readily permit human study.

Decoding Lower Limb Muscle Activity and Kinematics from Cortical Neural Spike Trains during Monkey Performing Stand and Squat Movements

PubMed Central

Ma, Xuan; Ma, Chaolin; Huang, Jian; Zhang, Peng; Xu, Jiang; He, Jiping

2017-01-01

Extensive literatures have shown approaches for decoding upper limb kinematics or muscle activity using multichannel cortical spike recordings toward brain machine interface (BMI) applications. However, similar topics regarding lower limb remain relatively scarce. We previously reported a system for training monkeys to perform visually guided stand and squat tasks. The current study, as a follow-up extension, investigates whether lower limb kinematics and muscle activity characterized by electromyography (EMG) signals during monkey performing stand/squat movements can be accurately decoded from neural spike trains in primary motor cortex (M1). Two monkeys were used in this study. Subdermal intramuscular EMG electrodes were implanted to 8 right leg/thigh muscles. With ample data collected from neurons from a large brain area, we performed a spike triggered average (SpTA) analysis and got a series of density contours which revealed the spatial distributions of different muscle-innervating neurons corresponding to each given muscle. Based on the guidance of these results, we identified the locations optimal for chronic electrode implantation and subsequently carried on chronic neural data recordings. A recursive Bayesian estimation framework was proposed for decoding EMG signals together with kinematics from M1 spike trains. Two specific algorithms were implemented: a standard Kalman filter and an unscented Kalman filter. For the latter one, an artificial neural network was incorporated to deal with the nonlinearity in neural tuning. High correlation coefficient and signal to noise ratio between the predicted and the actual data were achieved for both EMG signals and kinematics on both monkeys. Higher decoding accuracy and faster convergence rate could be achieved with the unscented Kalman filter. These results demonstrate that lower limb EMG signals and kinematics during monkey stand/squat can be accurately decoded from a group of M1 neurons with the proposed algorithms. Our findings provide new insights for extending current BMI design concepts and techniques on upper limbs to lower limb circumstances. Brain controlled exoskeleton, prostheses or neuromuscular electrical stimulators for lower limbs are expected to be developed, which enables the subject to manipulate complex biomechatronic devices with mind in more harmonized manner. PMID:28223914

The Role of VP1 Amino Acid Residue 145 of Enterovirus 71 in Viral Fitness and Pathogenesis in a Cynomolgus Monkey Model

PubMed Central

Kataoka, Chikako; Suzuki, Tadaki; Kotani, Osamu; Iwata-Yoshikawa, Naoko; Nagata, Noriyo; Ami, Yasushi; Wakita, Takaji; Nishimura, Yorihiro; Shimizu, Hiroyuki

2015-01-01

Enterovirus 71 (EV71), a major causative agent of hand, foot, and mouth disease, occasionally causes severe neurological symptoms. We identified P-selectin glycoprotein ligand-1 (PSGL-1) as an EV71 receptor and found that an amino acid residue 145 in the capsid protein VP1 (VP1-145) defined PSGL-1-binding (PB) and PSGL-1-nonbinding (non-PB) phenotypes of EV71. However, the role of PSGL-1-dependent EV71 replication in neuropathogenesis remains poorly understood. In this study, we investigated viral replication, genetic stability, and the pathogenicity of PB and non-PB strains of EV71 in a cynomolgus monkey model. Monkeys were intravenously inoculated with cDNA-derived PB and non-PB strains of EV71, EV71-02363-EG and EV71-02363-KE strains, respectively, with two amino acid differences at VP1-98 and VP1-145. Mild neurological symptoms, transient lymphocytopenia, and inflammatory cytokine responses, were found predominantly in the 02363-KE-inoculated monkeys. During the early stage of infection, viruses were frequently detected in clinical samples from 02363-KE-inoculated monkeys but rarely in samples from 02363-EG-inoculated monkeys. Histopathological analysis of central nervous system (CNS) tissues at 10 days postinfection revealed that 02363-KE induced neuropathogenesis more efficiently than that induced by 02363-EG. After inoculation with 02363-EG, almost all EV71 variants detected in clinical samples, CNS, and non-CNS tissues, possessed a G to E amino acid substitution at VP1-145, suggesting a strong in vivo selection of VP1-145E variants and CNS spread presumably in a PSGL-1-independent manner. EV71 variants with VP1-145G were identified only in peripheral blood mononuclear cells in two out of four 02363-EG-inoculated monkeys. Thus, VP1-145E variants are mainly responsible for the development of viremia and neuropathogenesis in a non-human primate model, further suggesting the in vivo involvement of amino acid polymorphism at VP1-145 in cell-specific viral replication, in vivo fitness, and pathogenesis in EV71-infected individuals. PMID:26181772

Studies on Typhus and Spotted Fever.

DTIC Science & Technology

1980-02-01

prowazekii-infected human somatic (fibroblast, endothelia)), but not chick, mouse or monkey , cells in culture: (a) intracellular antirickettsial action...that of the controls. No such effect on growth was apparent in CE cells, Nu E % o0 M Ŕ ZOO - .0 E 00 (1 CI - 4D W = .) C ~ o r- -!NBI Go !N 21501,,o o...human origin transformed or malignant cells, monkey primary or diploid and primary mouse embryo fibroblasts will permit expression of these effects to

Drinking typography established by scheduled induction predicts chronic heavy drinking in a monkey model of ethanol self-administration.

PubMed

Grant, Kathleen A; Leng, Xiaoyan; Green, Heather L; Szeliga, Kendall T; Rogers, Laura S M; Gonzales, Steven W

2008-10-01

We have developed an animal model of alcohol self-administration that initially employs schedule-induced polydipsia (SIP) to establish reliable ethanol consumption under open access (22 h/d) conditions with food and water concurrently available. SIP is an adjunctive behavior that is generated by constraining access to an important commodity (e.g., flavored food). The induction schedule and ethanol polydipsia generated under these conditions affords the opportunity to investigate the development of drinking typologies that lead to chronic, excessive alcohol consumption. Adult male cynomolgus monkeys (Macaca fascicularis) were induced to drink water and 4% (w/v in water) ethanol by a Fixed-Time 300 seconds (FT-300 seconds) schedule of banana-flavored pellet delivery. The FT-300 seconds schedule was in effect for 120 consecutive sessions, with daily induction doses increasing from 0.0 to 0.5 g/kg to 1.0 g/kg to 1.5 g/kg every 30 days. Following induction, the monkeys were allowed concurrent access to 4% (w/v) ethanol and water for 22 h/day for 12 months. Drinking typographies during the induction of drinking 1.5 g/kg ethanol emerged that were highly predictive of the daily ethanol intake over the next 12 months. Specifically, the frequency in which monkeys ingested 1.5 g/kg ethanol without a 5-minute lapse in drinking (defined as a bout of drinking) during induction strongly predicted (correlation 0.91) subsequent ethanol intake over the next 12 months of open access to ethanol. Blood ethanol during induction were highly correlated with intake and with drinking typography and ranged from 100 to 160 mg% when the monkeys drank their 1.5 g/kg dose in a single bout. Forty percent of the population became heavy drinkers (mean daily intakes >3.0 g/kg for 12 months) characterized by frequent "spree" drinking (intakes >4.0 g/kg/d). This model of ethanol self-administration identifies early alcohol drinking typographies (gulping the equivalent of 6 drinks) that evolve into chronic heavy alcohol consumption in primates (drinking the equivalent of 16 to 20 drinks per day). The model may aid in identifying biological risks for establishing harmful alcohol drinking.

Drinking Typography Established by Scheduled Induction Predicts Chronic Heavy Drinking in a Monkey Model of Ethanol Self-Administration

PubMed Central

Grant, Kathleen A.; Leng, Xiaoyan; Green, Heather L.; Szeliga, Kendall T.; Rogers, Laura S. M.; Gonzales, Steven W.

2010-01-01

Background We have developed an animal model of alcohol self-administration that initially employs schedule-induced polydipsia (SIP) to establish reliable ethanol consumption under open access (22 h/d) conditions with food and water concurrently available. SIP is an adjunctive behavior that is generated by constraining access to an important commodity (e.g., flavored food). The induction schedule and ethanol polydipsia generated under these conditions affords the opportunity to investigate the development of drinking typologies that lead to chronic, excessive alcohol consumption. Methods Adult male cynomolgus monkeys (Macaca fascicularis) were induced to drink water and 4% (w/v in water) ethanol by a Fixed-Time 300 seconds (FT-300 seconds) schedule of banana-flavored pellet delivery. The FT-300 seconds schedule was in effect for 120 consecutive sessions, with daily induction doses increasing from 0.0 to 0.5 g/kg to 1.0 g/kg to 1.5 g/kg every 30 days. Following induction, the monkeys were allowed concurrent access to 4% (w/v) ethanol and water for 22 h/day for 12 months. Results Drinking typographies during the induction of drinking 1.5 g/kg ethanol emerged that were highly predictive of the daily ethanol intake over the next 12 months. Specifically, the frequency in which monkeys ingested 1.5 g/kg ethanol without a 5-minute lapse in drinking (defined as a bout of drinking) during induction strongly predicted (correlation 0.91) subsequent ethanol intake over the next 12 months of open access to ethanol. Blood ethanol during induction were highly correlated with intake and with drinking typography and ranged from 100 to 160 mg% when the monkeys drank their 1.5 g/kg dose in a single bout. Forty percent of the population became heavy drinkers (mean daily intakes >3.0 g/kg for 12 months) characterized by frequent “spree” drinking (intakes >4.0 g/kg/d). Conclusion This model of ethanol self-administration identifies early alcohol drinking typographies (gulping the equivalent of 6 drinks) that evolve into chronic heavy alcohol consumption in primates (drinking the equivalent of 16 to 20 drinks per day). The model may aid in identifying biological risks for establishing harmful alcohol drinking. PMID:18702645

STUDIES ON EXPERIMENTAL PNEUMONIA : IX. PRODUCTION IN MONKEYS OF AN ACUTE RESPIRATORY DISEASE RESEMBLING INFLUENZA BY INOCULATION WITH BACILLUS INFLUENZAE.

PubMed

Blake, F G; Cecil, R L

1920-11-30

Twelve normal monkeys inoculated on the mucous membranes of the nose or nose and mouth with a strain of Bacillus influenzae; originally isolated in pure culture from the pleural exudate of a case of empyema following influenzal pneumonia in man and subsequently raised in virulence by animal passage, developed an acute self-limited respiratory disease of from 3 to 5 days duration, characterized by sudden onset with profound prostration, the development of rhinitis and tracheobronchitis, with sneezing, cough, and the outpouring of a scanty mucoid, or mucopurulent exudate, a variable febrile reaction, and either a leucopenia or no significant change in the leucocyte count. This disease was complicated in five instances by purulent sinusitis of one or both antra, in three by bronchopneumonia. Bacillus influenzae was recovered at autopsy from the lesions of the disease either in pure culture or in association with organisms that are normal inhabitants of the upper respiratory tract of monkeys. Of ten normal monkeys injected intratracheally with the same strain of Bacillus influenzae, seven developed bronchopneumonia, two developed tracheobronchitis without pneumonia, and one resisted infection. The general symptoms and duration of the disease were similar to those of the preceding group. There were a severe cough and accelerated respirations. Bacillus influenzae was recovered in pure culture from the lungs, bronchi, or trachea in the animals killed during the active stage of the disease. It disappeared promptly from the respiratory tract with recovery. The significance of the first series of experiments in which monkeys were inoculated in the upper respiratory tract is twofold. First, they establish the fact that Bacillus influenzae can initiate in monkeys an acute infection of the normal mucous membranes of the upper respiratory tract; that is, it can act as a primary incitant of respiratory infection without the assistance of a preceding or concomitant contributing cause. In this respect it differs radically from the pneumococcus and Streptococcus haemolyticus, since experiments previously reported(2, 4) have shown that neither of these organisms possesses the property of initiating an infection of the normal mucous membranes of the upper respiratory tract of monkeys, even though the strains used were incalculably more virulent for monkeys than the strain of Bacillus influenzae used in the foregoing experiments. Secondly, the experiments show that Bacillus influenzae infection of the mucous membranes of the upper respiratory tract may spread by continuity to the paranasal sinuses, setting up an acute sinusitis, that it spreads readily to the lower respiratory tract, producing a tracheobronchitis and permitting the ready invasion of secondary bacteria, and that it may penetrate as far as the terminal bronchioles, alveolar ducts, atria, and alveoli, there setting up a bronchiolitis and true bronchopneumonia. In these respects it likewise differs radically from the pneumococcus and Streptococcus haemolyticus which do not possess these pathogenic properties as previous experiments have shown.(2, 4) The bearing of these facts on the possible etiologic relation of Bacillus influenzae to influenza is important, since they show that Bacillus influenzae possesses certain definite primary pathogenic properties which distinguish it and therefore separate it from the group of recognized secondary organisms in influenzal complications, of which the pneumococcus and the streptococcus are the most frequent. The possible etiologic relation of Bacillus influenzae to influenza is further supported by the character of the respiratory disease that occurred in the monkeys. The sudden onset with profound prostration, the absence of leucocytosis or often a leucopenia, the congestion of the mucous membranes of the respiratory tract, the development on the 2nd or 3rd day of an irritative cough due to an inflammatory tracheitis or tracheobronchitis, the brief self-limited course of the infection, and the irregular febrile reactions are all characteristic of influenza. Many of these symptoms were in striking contrast with the symptoms and course of pneumococcus or streptococcus infections in monkeys in which there were no prostration at onset, invariable leucocytosis, and infrequent cough developing only late in the disease. While all the above features of the disease produced in monkeys are characteristic of influenza in man, none are pathognomonic and, in fact, it is doubtful whether uncomplicated influenza possesses any pathognomonic features by which it may be diagnosed certainly in the absence of an epidemic. Even during epidemic times many respiratory infections arise which, though presumably influenza, it is impossible to diagnose as such with certainty. Nor does pathology help in this respect, since there would appear to be no established distinctive lesions of uncomplicated influenza in man, nor for that matter of the complications of influenza, apart from the complications which have been ascribed by Pfeiffer,(5) MacCallum,(6) Wolbach,(7) and others to infection with Bacillus influenzae because of the association of Bacillus influenzae in pure culture with these complications. For these reasons, although the disease produced in monkeys appears to be essentially identical with influenza in man with respect to its clinical course and complications, it is impossible to determine certainly whether it is actually so. The experiments are advanced, therefore, as evidence in favor of the etiologic relation of Bacillus influenzae to influenza, though they do not permit of a definite conclusion in this respect. Their bearing upon the relation of Bacillus influenzae to certain of the complications of influenza would appear to be reasonably conclusive. The recovery of Bacillus influenzae in pure culture at autopsy from the antra, from the trachea and bronchi, and from the lungs in some of the animals developing sinusitis, bronchiolitis, and a characteristic type of bronchopneumonia confirms by animal experiment the etiologic relation of Bacillus influenzae to these complications of influenza, which hitherto has rested solely upon the frequent association of the influenza bacillus with these lesions in man. The production of tracheobronchitis and the same type of bronchopneumonia by the intratracheal injection of Bacillus influenzae in the second series of experiments serves as additional confirmation of this, but has no direct bearing on the etiologic relation of Bacillus influenzae to uncomplicated influenzae.

Central nervous system correlates of behavioral deficits following simian immunodeficiency virus infection.

PubMed

Weed, Michael R; Hienz, Robert D; Brady, Joseph V; Adams, Robert J; Mankowski, Joseph L; Clements, Janice E; Zink, M Christine

2003-08-01

Despite the high incidence of cognitive and motor impairment in acquired immunodeficiency syndrome (AIDS) patients, the mechanisms of AIDS-related central nervous system (CNS) pathology are not completely understood. Infection with simian immunodeficiency virus (SIV) in macaques provides an excellent model of AIDS, including human immunodeficiency virus (HIV)-induced CNS pathology and cognitive/behavioral impairment. Co-inoculation with two SIV strains, SIV/17E-Fr and SIV/DeltaB670, accelerates SIV CNS disease, producing SIV encephalitis in over 90% of pig-tailed macaques within 3 months. In the present study, this SIV model was employed to identify cellular and viral correlates of behavioral impairment following SIV infection. Measures of psychomotor speed (simple reaction time), fine motor control (bimanual motor task), and general motor activity (home cage movement) were all adversely affected by SIV disease. Prior to euthanasia, performance was significantly impaired in both a simple reaction time task in 6 of 12 monkeys and a bimanual motor task in 5 of 6 monkeys. All monkeys evaluated (11 of 11) showed significant reductions in spontaneous motor activity. Significant correlations were found between impaired performance on the bimanual motor test and axonal damage (accumulation of beta-amyloid precursor protein in the corpus callosum) as well as increased microglial activation and macrophage infiltration (levels of CD68 and Ham56 immunostaining). These results suggest that axonal damage is related to the behavioral impairment induced by infection with SIV. The axonal damage may result from neuroimmune responses, including microglial and macrophage activation. Therefore, axonal damage may be a morphologic manifestation of neuronal dysfunction that underlies development of behavioral impairment in HIV/SIV CNS infection.

Short- and Long-Term Clinical Outcomes in Rhesus Monkeys Inoculated with a Highly Pathogenic Chimeric Simian/Human Immunodeficiency Virus

PubMed Central

Endo, Yasuyuki; Igarashi, Tatsuhiko; Nishimura, Yoshiaki; Buckler, Charles; Buckler-White, Alicia; Plishka, Ronald; Dimitrov, Dimiter S.; Martin, Malcolm A.

2000-01-01

A highly pathogenic simian/human immunodeficiency virus (SHIV), SHIVDH12R, isolated from a rhesus macaque that had been treated with anti-human CD8 monoclonal antibody at the time of primary infection with the nonpathogenic, molecularly cloned SHIVDH12, induced marked and rapid CD4+ T cell loss in all rhesus macaques intravenously inoculated with 1.0 50% tissue culture infective dose (TCID50) to 4.1 × 105 TCID50s of virus. Animals inoculated with 650 TCID50s of SHIVDH12R or more experienced irreversible CD4+ T lymphocyte depletion and developed clinical disease requiring euthanasia between weeks 12 and 23 postinfection. In contrast, the CD4+ T-cell numbers in four of five monkeys receiving 25 TCID50s of SHIVDH12R or less stabilized at low levels, and these surviving animals produced antibodies capable of neutralizing SHIVDH12R. In the fifth monkey, no recovery from the CD4+ T cell decline occurred, and the animal had to be euthanized. Viral RNA levels, subsequent to the initial peak of infection but not at peak viremia, correlated with the virus inoculum size and the eventual clinical course. Both initial infection rate constants, k, and decay constants, d, were determined, but only the latter were statistically correlated to clinical outcome. The attenuating effects of reduced inoculum size were also observed when virus was inoculated by the mucosal route. Because the uncloned SHIVDH12R stock possessed the genetic properties of a lentivirus quasispecies, we were able to assess the evolution of the input virus swarm in animals surviving the acute infection by monitoring the emergence of neutralization escape viral variants. PMID:10888632

Points to consider in the development of a surrogate for efficacy of novel Japanese encephalitis virus vaccines.

PubMed

Markoff, L

2000-05-26

Although an effective killed virus vaccine to prevent illness due to Japanese encephalitis virus (JEV) infection exists, many authorities recognize that a safe, effective live JEV vaccine is desirable in order to reduce the cost and the number of doses of vaccine required per immunization. A large-scale clinical efficacy trail for such a vaccine would be both unethical and impractical. Therefore, a surrogate for the efficacy of JE vaccines should be established. Detection of virus-neutralizing antibodies in sera of vaccinees could constitute such a surrogate for efficacy. Field studies of vaccinees in endemic areas and studies done in mice already exist to support this concept. Also, titers of virus-neutralizing antibodies are already accepted as a surrogate for the efficacy of yellow fever virus vaccines and for the efficacy of other viral vaccines as well. In developing a correlation between N antibody titers and protection from JEV infection, standard procedures must be validated and adopted for both measuring N antibodies and for testing in animals. A novel live virus vaccine could be tested in the mouse and/or the monkey model of JEV infection to establish a correlation between virus-neutralizing antibodies elicited by the vaccines and protection from encephalitis. In addition, sera of subjects receiving the novel live JEV vaccine in early clinical trials could be passively transferred to mice or monkeys in order to establish the protective immunogenicity of the vaccine in humans. A monkey model for JEV infection was recently established by scientists at WRAIR in the US. From this group, pools of JEV of known infectivity for Rhesus macaques may be obtained for testing of immunity elicited by live JE vaccine virus.

Atlas-Guided Segmentation of Vervet Monkey Brain MRI

PubMed Central

Fedorov, Andriy; Li, Xiaoxing; Pohl, Kilian M; Bouix, Sylvain; Styner, Martin; Addicott, Merideth; Wyatt, Chris; Daunais, James B; Wells, William M; Kikinis, Ron

2011-01-01

The vervet monkey is an important nonhuman primate model that allows the study of isolated environmental factors in a controlled environment. Analysis of monkey MRI often suffers from lower quality images compared with human MRI because clinical equipment is typically used to image the smaller monkey brain and higher spatial resolution is required. This, together with the anatomical differences of the monkey brains, complicates the use of neuroimage analysis pipelines tuned for human MRI analysis. In this paper we developed an open source image analysis framework based on the tools available within the 3D Slicer software to support a biological study that investigates the effect of chronic ethanol exposure on brain morphometry in a longitudinally followed population of male vervets. We first developed a computerized atlas of vervet monkey brain MRI, which was used to encode the typical appearance of the individual brain structures in MRI and their spatial distribution. The atlas was then used as a spatial prior during automatic segmentation to process two longitudinal scans per subject. Our evaluation confirms the consistency and reliability of the automatic segmentation. The comparison of atlas construction strategies reveals that the use of a population-specific atlas leads to improved accuracy of the segmentation for subcortical brain structures. The contribution of this work is twofold. First, we describe an image processing workflow specifically tuned towards the analysis of vervet MRI that consists solely of the open source software tools. Second, we develop a digital atlas of vervet monkey brain MRIs to enable similar studies that rely on the vervet model. PMID:22253661

Spontaneous Cholelithiasis in a Squirrel Monkey (Saimiri sciureus)

PubMed Central

Lieberman, Mia T.; Wachtman, Lynn M.; Marini, Robert P.; Bakthavatchalu, Vasu; Fox, James G.

2016-01-01

A mature female squirrel monkey was noted during routine semiannual examinations to have moderate progressive weight loss. Serum chemistry panels revealed marked increases in hepatic enzyme, bilirubin, and bile salt concentrations and hypoalbuminemia. Abdominal ultrasonography revealed echogenic, shadowing debris in the gallbladder, consistent with cholelithiasis. At necropsy, marked thickening and distension of the gallbladder, cystic duct, and common bile duct was noted, and more than 50 irregularly shaped, black gallstones were removed from the biliary tract. Gallbladder tissue, bile, and gallstones cultured positive for Escherichia coli and Proteus spp., suggesting a brown-pigment gallstone type secondary to a bacterial nidus. Histopathology revealed severe chronic–active diffuse cholecystitis and severe chronic-active hepatic degeneration and necrosis with severe cholestasis. To our knowledge, this report is the first description of spontaneous choleilthiasis in a squirrel monkey. PMID:26884412

Monkey alcohol tissue research resource: banking tissues for alcohol research.

PubMed

Daunais, James B; Davenport, April T; Helms, Christa M; Gonzales, Steven W; Hemby, Scott E; Friedman, David P; Farro, Jonathan P; Baker, Erich J; Grant, Kathleen A

2014-07-01

An estimated 18 million adults in the United States meet the clinical criteria for diagnosis of alcohol abuse or alcoholism, a disorder ranked as the third leading cause of preventable death. In addition to brain pathology, heavy alcohol consumption is comorbid with damage to major organs including heart, lungs, liver, pancreas, and kidneys. Much of what is known about risk for and consequences of heavy consumption derive from rodent or retrospective human studies. The neurobiological effects of chronic intake in rodent studies may not easily translate to humans due to key differences in brain structure and organization between species, including a lack of higher-order cognitive functions, and differences in underlying prefrontal cortical neural structures that characterize the primate brain. Further, rodents do not voluntarily consume large quantities of ethanol (EtOH) and they metabolize it more rapidly than primates. The basis of the Monkey Alcohol Tissue Research Resource (MATRR) is that nonhuman primates, specifically monkeys, show a range of drinking excessive amounts of alcohol (>3.0 g/kg or a 12 drink equivalent per day) over long periods of time (12 to 30 months) with concomitant pathological changes in endocrine, hepatic, and central nervous system (CNS) processes. The patterns and range of alcohol intake that monkeys voluntarily consume parallel what is observed in humans with alcohol use disorders and the longitudinal experimental design spans stages of drinking from the EtOH-naïve state to early exposure through chronic abuse. Age- and sex-matched control animals self-administer an isocaloric solution under identical operant procedures. The MATRR is a unique postmortem tissue bank that provides CNS and peripheral tissues, and associated bioinformatics from monkeys that self-administer EtOH using a standardized experimental paradigm to the broader alcohol research community. This resource provides a translational platform from which we can better understand the disease processes associated with alcoholism. Copyright © 2014 by the Research Society on Alcoholism.

Activities of Various 4-Aminoquinolines Against Infections with Chloroquine-Resistant Strains of Plasmodium falciparum1

PubMed Central

Schmidt, L. H.; Vaughan, Dennis; Mueller, Donna; Crosby, Ruth; Hamilton, Rebecca

1977-01-01

The studies reported here stemmed from a personal report by Geiman on the capacity of the 4-aminoquinoline amodiaquin to inhibit in vitro maturation of ring stages of the chloroquine-resistant Monterey strain of Plasmodium falciparum. This observation, confirmed in owl monkeys infected with this strain, led to a comparison of the activities of chloroquine, amodiaquin, amopyroquin, and dichlorquinazine (12,278 RP) against infections with various chloroquine-susceptible and chloroquine-resistant strains. The results showed that: (i) these 4-aminoquinolines were essentially equally active against infections with chloroquine-susceptible strains and (ii) the activities of amodiaquin, amopyroquin, and dichlorquinazine were reduced significantly in the face of chloroquine resistance, but (iii) well-tolerated doses of these compounds would cure infections with strains that fully resisted treatment with maximally tolerated doses of chloroquine. Two other 4-aminoquinolines, SN-8137 and SN-9584, which also exhibited activity against chloroquine-resistant parasites in vitro, displayed curative activity in monkeys infected with a chloroquine-resistant strain. These observations show that there is cross-resistance among the 4-aminoquinolines, confirming earlier findings, but indicate that the dimensions of this phenomenon are sufficiently limited so that some derivatives are therapeutically effective against infections refractory to maximally tolerated doses of chloroquine. PMID:406829

Anti-α4 antibody treatment blocks virus traffic to the brain and gut early, and stabilizes CNS injury late in infection.

PubMed

Campbell, Jennifer H; Ratai, Eva-Maria; Autissier, Patrick; Nolan, David J; Tse, Samantha; Miller, Andrew D; González, R Gilberto; Salemi, Marco; Burdo, Tricia H; Williams, Kenneth C

2014-12-01

Four SIV-infected monkeys with high plasma virus and CNS injury were treated with an anti-α4 blocking antibody (natalizumab) once a week for three weeks beginning on 28 days post-infection (late). Infection in the brain and gut were quantified, and neuronal injury in the CNS was assessed by MR spectroscopy, and compared to controls with AIDS and SIV encephalitis. Treatment resulted in stabilization of ongoing neuronal injury (NAA/Cr by 1H MRS), and decreased numbers of monocytes/macrophages and productive infection (SIV p28+, RNA+) in brain and gut. Antibody treatment of six SIV infected monkeys at the time of infection (early) for 3 weeks blocked monocyte/macrophage traffic and infection in the CNS, and significantly decreased leukocyte traffic and infection in the gut. SIV - RNA and p28 was absent in the CNS and the gut. SIV DNA was undetectable in brains of five of six early treated macaques, but proviral DNA in guts of treated and control animals was equivalent. Early treated animals had low-to-no plasma LPS and sCD163. These results support the notion that monocyte/macrophage traffic late in infection drives neuronal injury and maintains CNS viral reservoirs and lesions. Leukocyte traffic early in infection seeds the CNS with virus and contributes to productive infection in the gut. Leukocyte traffic early contributes to gut pathology, bacterial translocation, and activation of innate immunity.

Virulence of invasive Salmonella Typhimurium ST313 in animal models of infection.

PubMed

Ramachandran, Girish; Panda, Aruna; Higginson, Ellen E; Ateh, Eugene; Lipsky, Michael M; Sen, Sunil; Matson, Courtney A; Permala-Booth, Jasnehta; DeTolla, Louis J; Tennant, Sharon M

2017-08-01

Salmonella Typhimurium sequence type (ST) 313 produces septicemia in infants in sub-Saharan Africa. Although there are known genetic and phenotypic differences between ST313 strains and gastroenteritis-associated ST19 strains, conflicting data about the in vivo virulence of ST313 strains have been reported. To resolve these differences, we tested clinical Salmonella Typhimurium ST313 and ST19 strains in murine and rhesus macaque infection models. The 50% lethal dose (LD50) was determined for three Salmonella Typhimurium ST19 and ST313 strains in mice. For dissemination studies, bacterial burden in organs was determined at various time-points post-challenge. Indian rhesus macaques were infected with one ST19 and one ST313 strain. Animals were monitored for clinical signs and bacterial burden and pathology were determined. The LD50 values for ST19 and ST313 infected mice were not significantly different. However, ST313-infected BALB/c mice had significantly higher bacterial numbers in blood at 24 h than ST19-infected mice. ST19-infected rhesus macaques exhibited moderate-to-severe diarrhea while ST313-infected monkeys showed no-to-mild diarrhea. ST19-infected monkeys had higher bacterial burden and increased inflammation in tissues. Our data suggest that Salmonella Typhimurium ST313 invasiveness may be investigated using mice. The non-human primate results are consistent with clinical data, suggesting that ST313 strains do not cause diarrhea.

Serological reactions in Rhesus monkeys inoculated with the 17D strain of yellow fever virus.

PubMed

GROOT, H

1962-01-01

Haemagglutination-inhibition tests, which depend on the appearance of haemagglutination-inhibiting antibodies in the serum in virus infections, are in common use in the study of arthropod-borne diseases. This paper contains the results of an investigation into the appearance and pattern of haemagglutination-inhibiting antibodies in the serum of rhesus monkeys inoculated intracerebrally with the 17D strain of yellow fever virus during the testing of seed lots of yellow fever vaccine. These antibodies appeared on the tenth day after inoculation, and were still demonstrable four years later. In all of the eight monkeys tested complement-fixing and neutralizing antibodies against yellow fever antigens also developed, and in six out of the eight heterologous antigens developed.

Preclinical Characterization and Human Microdose Pharmacokinetics of ITMN-8187, a Nonmacrocyclic Inhibitor of the Hepatitis C Virus NS3 Protease

PubMed Central

Pan, Lin; Schaefer, Caralee; Nicholas, John; Lim, Sharlene; Misialek, Shawn; Stevens, Sarah; Hooi, Lisa; Aleskovski, Natalia; Ruhrmund, Donald; Kossen, Karl; Huang, Lea; Yap, Sophia; Beigelman, Leonid; Serebryany, Vladimir; Liu, Jyanwei; Sastry, Srikonda; Seiwert, Scott; Buckman, Brad

2016-01-01

Abstract The current paradigm for the treatment of chronic hepatitis C virus (HCV) infection involves combinations of agents that act directly on steps of the HCV life cycle. Here we report the preclinical characteristics of ITMN-8187, a nonmacrocyclic inhibitor of the NS3/4A HCV protease. X-ray crystallographic studies of ITMN-8187 and simeprevir binding to NS3/4A protease demonstrated good agreement between structures. Low nanomolar biochemical potency was maintained against NS3/4A derived from HCV genotypes 1, 2b, 4, 5, and 6. In cell-based potency assays, half-maximal reduction of genotype 1a and 1b HCV replicon RNA was afforded by 11 and 4 nM doses of ITMN-8187, respectively. Combinations of ITMN-8187 with other directly acting antiviral agents in vitro displayed additive antiviral efficacy. A 30-mg/kg of body weight dose of ITMN-8187 administered for 4 days yielded significant viral load reductions through day 5 in a chimeric mouse model of HCV. A 3-mg/kg oral dose administered to rats, dogs, or monkeys yielded concentrations in plasma 16 h after dosing that exceeded the half-maximal effective concentration of ITMN-8187. Human microdose pharmacokinetics showed low intersubject variability and prolonged oral absorption with first-order elimination kinetics compatible with once-daily dosing. These preclinical characteristics compare favorably with those of other NS3/4A inhibitors approved for the treatment of chronic HCV infection. PMID:27795376

Development and Evaluation of Adeno-HTLV-III Hybrid Virus and Non-Cytopathic HTLV-III Mutant for Vaccine Use.

DTIC Science & Technology

1987-10-28

34" HIV will be tested. The recombinant Adeno-HIV virus is being developed as part of this proposal. The vaccines will be tested in two species of monkeys...vaccinia-HIV viruses was investigated (Table 4). All the vaccinated monkeys developed antibodies to HIV envelope antigen. However, no neutralizing antibody...Table 5). Epstein Barr virus transformed autologous B cells infected with recon- binant vaccinia-HIV virus may be used as targets. 30 chimpanzees from

Visual Acuity and Its Dependence Upon Receptor Density and Retinal Ganglion Cell Receptive Field Overlap.

DTIC Science & Technology

1981-11-01

organization of retinal receptive fields in monkeys and cats has been used to model the information flow to the retina in relation to the psychophysical...EXPERIMENTAL PROCEDURE Types of Animals Used Three types of monkeys were used in the present study, rhesus (Macaca mulatta), the Himalayan Macaque (Macaca...during the course of the program, although one died of Shigella infection. Attempts were made to trade the animals with local users in order to obtain

Development of In Vitro Correlate Assays of Immunity to Infection with Yersinia Pestis

DTIC Science & Technology

2007-05-01

cynomolgus macaques (CM) and African green (Chlorocebus aethiops) monkeys (AGM) vaccinated s.c. three times at 4-week intervals with the F1-V fusion...Yersinia pestis in African green monkeys . Arch. Pathol. Lab. Med. 120:156–163. 15. Faure, K., J. Fujimoto, D. W. Shimabukuro, T. Ajayi, N. Shime, K...A. Kuwae, C. Sasakawa, and S. Imajoh-Ohmi. 1999. Shigella flexneri YSH6000 induces two types of cell death, apoptosis and oncosis, in the

Nosocomial Infection of Serratia marcescens May Induce a Protective Effect of Monkeys Exposed to Bacillus anthracis

DTIC Science & Technology

2008-01-01

B. anthracis or a detectable level of protective antigen in the bloodstream. It appears that the presence of S . marcescens may have induced a "Coley’s...Available online 6 June 2008KEYWORDS Inhalation anthrax; Innate immunity; B. anthracis; S . marcescens ; African green monkey* Corresponding author. Tel.: þ1 30...had S . marcescens contam- ination in the catheter; indicated by pure colonies grown from the blood. None of these AGMs showed clinical signs of illness

A new type of recording chamber with an easy-to-exchange microdrive array for chronic recordings in macaque monkeys.

PubMed

Galashan, F Orlando; Rempel, Hanna C; Meyer, Anneke; Gruber-Dujardin, Eva; Kreiter, Andreas K; Wegener, Detlef

2011-06-01

In monkeys, long-term recordings with chronically implanted microelectrodes frequently suffer from a continuously decreasing probability to record single units or even small multiunit clusters. This problem is associated with two technical limitations of the available devices: first, restrictions for electrode movement, and second, absent possibility to exchange electrodes easily on a regular basis. Permitting to adjust the recording site and to use new recording tracks with proper electrodes may avoid these problems and make chronic more similar to acute recordings. Here, we describe a novel type of implant tackling this issue. It consists of a new type of recording chamber combined with an exchangeable multielectrode array that precisely fits into it. The multielectrode array is reversibly fixed to the chamber, and within a minute it can be exchanged against another array equipped with new electrodes at the awake animal. The array allows for bidirectional movement of six electrodes for a distance of up to 12 mm. The recording chamber enables hermetical isolation of the intracranial space, resulting in long-lasting aseptic conditions and reducing dural thickening to a minimum, as confirmed by microbiological and histopathological analysis. The device has a simple design and is both easy to produce and low in cost. Functionality has been tested in primary and secondary visual cortex of three macaque monkeys over a period of up to 15 mo. The results show that even after more than a year, single and multiunit responses can be obtained with high incidence.

Successful passive and active immunization of cynomolgus monkeys against hepatitis E.

PubMed Central

Tsarev, S A; Tsareva, T S; Emerson, S U; Govindarajan, S; Shapiro, M; Gerin, J L; Purcell, R H

1994-01-01

Virtually full protection against hepatitis E and partial or complete protection against infection with hepatitis E virus (HEV) were achieved in passively or actively immunized cynomolgus monkeys. Hepatitis, viremia, and shedding of the virus in feces were detected in all nonimmunized animals that were challenged with HEV. HEV titers detected by reverse transcriptase PCR were higher in feces than in serum of nonimmunized animals. Anti-HEV antibody titers at the time of challenge ranged between 1:40 and 1:200 in animals passively immunized with convalescent plasma from a cynomolgus monkey previously infected with HEV and between 1:100 and 1:10,000 in animals actively immunized with a recombinant 55-kDa open reading frame 2 protein. The estimated 50% protective titer of passively acquired anti-HEV antibodies was 1:40. Although only one of four passively immunized animals showed histopathologic evidence of hepatitis, all four were infected after challenge; however, the titers of HEV in serum and feces were lower in the passively immunized animals than in the nonimmunized group. The actively immunized animals developed neither hepatitis nor viremia when challenged with HEV and virus was either not detected or was present in low titer in feces. The protective response was a function of the ELISA anti-HEV antibody titer at the time of challenge and the immunization schedule. PMID:7937861

Gastrointestinal Parasites of Ecuadorian Mantled Howler Monkeys (Alouatta palliata aequatorialis) Based on Fecal Analysis.

PubMed

Helenbrook, William D; Wade, Susan E; Shields, William M; Stehman, Stephen V; Whipps, Christopher M

2015-06-01

An analysis of gastrointestinal parasites of Ecuadorian mantled howler monkeys, Alouatta palliata aequatorialis, was conducted based on examination of fecal smears, flotations, and sedimentations. At least 1 type of parasite was detected in 97% of the 96 fecal samples screened across 19 howler monkey groups using these techniques. Samples averaged 3.6 parasite species per individual (±1.4 SD). Parasites included species representing genera of 2 apicomplexans: Cyclospora sp. (18% of individual samples) and Isospora sp. (3%); 6 other protozoa: Balantidium sp. (9%), Blastocystis sp. (60%), Chilomastix sp. (4%), Dientamoeba sp. (3%), Entamoeba species (56%), Iodamoeba sp. (5%); 4 nematodes: Enterobius sp. (3%), Capillaria sp. (78%), Strongyloides spp. (88%) which included 2 morphotypes, Trypanoxyuris sp. (12%); and the platyhelminth Controrchis sp. (15%). A statistically significant positive correlation was found between group size and each of 3 different estimators of parasite species richness adjusted for sampling effort (ICE: r(2) = 0.24, P = 0.05; Chao2: r(2) = 0.25, P = 0.05, and Jackknife: r(2) = 0.31, P = 0.03). Two significant associations between co-infecting parasites were identified. Based on the prevalence data, individuals infected with Balantidium sp. were more likely to also be infected with Isospora sp. (χ(2) = 6.02, P = 0.01), while individuals harboring Chilomastix sp. were less likely to have Capillaria sp. present (χ(2) = 4.03, P = 0.04).

The neuropathology observed in wild-type mice inoculated with human poliovirus mirrors human paralytic poliomyelitis.

PubMed

Ford, Dayton J; Ropka, Stacie L; Collins, George H; Jubelt, Burk

2002-09-01

Human paralytic poliomyelitis results from the destruction of spinal cord anterior horn motor neurons by human poliovirus (PV). CNS disease pathology similar to human poliomyelitis has been observed in experimentally infected chimpanzees, monkeys and wild-type mice. In this study we present a detailed examination of the clinical and histopathological features in the wild-type mouse after intracranial (i.c.) and novel intramuscular (i.m.) injection of poliovirus. Either route of poliovirus administration results in a clinical disease characterized predominately by flaccid paralysis. The observed histopathological features are compared with the histopathology reported for human paralytic poliomyelitis, experimentally infected chimpanzees, monkeys and transgenic mice expressing the human poliovirus receptor (hPVR). The observation of flaccid paralysis and anterior horn motor neuron destruction mirrors what is observed in human paralytic poliomyelitis. Our results suggest that the neuropathology observed in the wild-type mouse model is similar to what has been observed in both the human disease and in other experimental animal models, with the possible exception of the transgenic mouse model. The observed neuropathology of the wild-type mouse model more closely reflects what has been observed in human poliomyelitis, as well as in experimentally infected chimpanzees and monkeys, than does the hPVR transgenic mouse model. The previously reported poliovirus-induced white matter demyelinating disease was not observed.

CXCR6-Mediated Simian Immunodeficiency Virus SIVagmSab Entry into Sabaeus African Green Monkey Lymphocytes Implicates Widespread Use of Non-CCR5 Pathways in Natural Host Infections

PubMed Central

Wetzel, Katherine S.; Yi, Yanjie; Elliott, Sarah T. C.; Romero, Dino; Jacquelin, Beatrice; Hahn, Beatrice H.; Muller-Trutwin, Michaela; Apetrei, Cristian; Pandrea, Ivona

2016-01-01

ABSTRACT African green monkeys (AGM) and sooty mangabeys (SM) are well-studied natural hosts of simian immunodeficiency virus (SIV) that do not progress to AIDS when infected with their species-specific viruses. Natural hosts of SIV express very low levels of the canonical entry coreceptor CCR5, and recent studies have shown that CCR5 is dispensable for SIV infection of SM in vivo and that blocking of CCR5 does not prevent ex vivo infection of peripheral blood mononuclear cells (PBMC) from SM or vervet AGM. In both hosts, CXCR6 is an efficient entry pathway in vitro. Here we investigated the use of species-matched CXCR6 and other alternative coreceptors by SIVagmSab, which infects sabaeus AGM. We cloned sabaeus CD4 and 10 candidate coreceptors. Species-matched CXCR6, CCR5, and GPR15 mediated robust entry into transfected cells by pseudotypes carrying SIVagmSab92018ivTF Env, with lower-level entry through GPR1 and APJ. We cloned genetically divergent env genes from the plasma of two wild-infected sabaeus AGM and found similar patterns of coreceptor use. Titration experiments showed that CXCR6 and CCR5 were more efficient than other coreceptors when tested at limiting CD4/coreceptor levels. Finally, blocking of CXCR6 with its ligand CXCL16 significantly inhibited SIVagmSab replication in sabaeus PBMC and had a greater impact than did the CCR5 blocker maraviroc, confirming the use of CXCR6 in primary lymphocyte infection. These data suggest a new paradigm for SIV infection of natural host species, whereby a shared outcome of virus-host coevolution is the use of CXCR6 or other alternative coreceptors for entry, which may direct SIV toward CD4+ T cell subsets and anatomical sites that support viral replication without disrupting immune homeostasis and function. IMPORTANCE Natural hosts of SIV do not progress to AIDS, in stark contrast to pathogenic human immunodeficiency virus type 1 (HIV-1)-human and SIVmac-macaque infections. Identifying how natural hosts avoid immunodeficiency can elucidate key mechanisms of pathogenesis. It is known that despite high viral loads, natural hosts have a low frequency of CD4+ cells expressing the SIV coreceptor CCR5. In this study, we demonstrate the efficient use of the coreceptor CXCR6 by SIVagmSab to infect sabaeus African green monkey lymphocytes. In conjunction with studies of SIVsmm, which infects sooty mangabeys, and SIVagmVer, which infects vervet monkeys, our data suggest a unifying model whereby in natural hosts, in which the CCR5 expression level is low, the use of CXCR6 or other coreceptors to mediate infection may target SIV toward distinct cell populations that are able to support high-level viral replication without causing a loss of CD4+ T cell homeostasis and lymphoid tissue damage that lead to AIDS in HIV-1 and SIVmac infections. PMID:27903799

CXCR6-Mediated Simian Immunodeficiency Virus SIVagmSab Entry into Sabaeus African Green Monkey Lymphocytes Implicates Widespread Use of Non-CCR5 Pathways in Natural Host Infections.

PubMed

Wetzel, Katherine S; Yi, Yanjie; Elliott, Sarah T C; Romero, Dino; Jacquelin, Beatrice; Hahn, Beatrice H; Muller-Trutwin, Michaela; Apetrei, Cristian; Pandrea, Ivona; Collman, Ronald G

2017-02-15

African green monkeys (AGM) and sooty mangabeys (SM) are well-studied natural hosts of simian immunodeficiency virus (SIV) that do not progress to AIDS when infected with their species-specific viruses. Natural hosts of SIV express very low levels of the canonical entry coreceptor CCR5, and recent studies have shown that CCR5 is dispensable for SIV infection of SM in vivo and that blocking of CCR5 does not prevent ex vivo infection of peripheral blood mononuclear cells (PBMC) from SM or vervet AGM. In both hosts, CXCR6 is an efficient entry pathway in vitro Here we investigated the use of species-matched CXCR6 and other alternative coreceptors by SIVagmSab, which infects sabaeus AGM. We cloned sabaeus CD4 and 10 candidate coreceptors. Species-matched CXCR6, CCR5, and GPR15 mediated robust entry into transfected cells by pseudotypes carrying SIVagmSab92018ivTF Env, with lower-level entry through GPR1 and APJ. We cloned genetically divergent env genes from the plasma of two wild-infected sabaeus AGM and found similar patterns of coreceptor use. Titration experiments showed that CXCR6 and CCR5 were more efficient than other coreceptors when tested at limiting CD4/coreceptor levels. Finally, blocking of CXCR6 with its ligand CXCL16 significantly inhibited SIVagmSab replication in sabaeus PBMC and had a greater impact than did the CCR5 blocker maraviroc, confirming the use of CXCR6 in primary lymphocyte infection. These data suggest a new paradigm for SIV infection of natural host species, whereby a shared outcome of virus-host coevolution is the use of CXCR6 or other alternative coreceptors for entry, which may direct SIV toward CD4 + T cell subsets and anatomical sites that support viral replication without disrupting immune homeostasis and function. Natural hosts of SIV do not progress to AIDS, in stark contrast to pathogenic human immunodeficiency virus type 1 (HIV-1)-human and SIVmac-macaque infections. Identifying how natural hosts avoid immunodeficiency can elucidate key mechanisms of pathogenesis. It is known that despite high viral loads, natural hosts have a low frequency of CD4 + cells expressing the SIV coreceptor CCR5. In this study, we demonstrate the efficient use of the coreceptor CXCR6 by SIVagmSab to infect sabaeus African green monkey lymphocytes. In conjunction with studies of SIVsmm, which infects sooty mangabeys, and SIVagmVer, which infects vervet monkeys, our data suggest a unifying model whereby in natural hosts, in which the CCR5 expression level is low, the use of CXCR6 or other coreceptors to mediate infection may target SIV toward distinct cell populations that are able to support high-level viral replication without causing a loss of CD4 + T cell homeostasis and lymphoid tissue damage that lead to AIDS in HIV-1 and SIVmac infections. Copyright © 2017 American Society for Microbiology.

Vitamin A toxicity in wild-caught African green vervet monkeys (Chlorocebus aethiops) after 2 years in captivity.

PubMed

Mills, Jordan P; Tanumihardjo, Sherry A

2006-10-01

Primate lab diets typically contain high vitamin A concentrations when compared with human recommended intakes. In this study, we analyzed the vitamin A contents of liver and serum from 13 adult female African green vervet monkeys (Chlorocebus aethiops). These monkeys were wild-caught and held in captivity for 2 y, during which time they consumed a standard primate diet. Liver vitamin A concentration (mean +/- 1 standard deviation) was 14.6 +/- 2.3 micromol retinol/g liver; subtoxicity in humans is defined as at least 1 micromol/g liver. The serum retinol concentration (0.93 +/- 0.21 microM) was not elevated. Hypertrophy and hyperplasia of hepatic stellate cells were present which, in conjunction with elevated hepatic vitamin A concentrations, are evidence of toxicity. Although the ramifications of chronically toxic vitamin A status in experimental monkeys have not been defined, this state may influence nonhuman primate research outcomes and confound data interpretation. The validity of bone mineral research using nonhuman primates is of greatest concern, in light of the association between vitamin A toxicity and compromised bone health.

Wireless Cortical Brain-Machine Interface for Whole-Body Navigation in Primates

NASA Astrophysics Data System (ADS)

Rajangam, Sankaranarayani; Tseng, Po-He; Yin, Allen; Lehew, Gary; Schwarz, David; Lebedev, Mikhail A.; Nicolelis, Miguel A. L.

2016-03-01

Several groups have developed brain-machine-interfaces (BMIs) that allow primates to use cortical activity to control artificial limbs. Yet, it remains unknown whether cortical ensembles could represent the kinematics of whole-body navigation and be used to operate a BMI that moves a wheelchair continuously in space. Here we show that rhesus monkeys can learn to navigate a robotic wheelchair, using their cortical activity as the main control signal. Two monkeys were chronically implanted with multichannel microelectrode arrays that allowed wireless recordings from ensembles of premotor and sensorimotor cortical neurons. Initially, while monkeys remained seated in the robotic wheelchair, passive navigation was employed to train a linear decoder to extract 2D wheelchair kinematics from cortical activity. Next, monkeys employed the wireless BMI to translate their cortical activity into the robotic wheelchair’s translational and rotational velocities. Over time, monkeys improved their ability to navigate the wheelchair toward the location of a grape reward. The navigation was enacted by populations of cortical neurons tuned to whole-body displacement. During practice with the apparatus, we also noticed the presence of a cortical representation of the distance to reward location. These results demonstrate that intracranial BMIs could restore whole-body mobility to severely paralyzed patients in the future.

Effect of chronic administration of Tamoxifen on fertility in male bonnet monkeys (Macaca radiata).

PubMed

Rao, A J; Ramachandra, S G; Ramesh, V; Krishnamurthy, H N; Jayaraman, S; Gopalakrishnan, K; Juneja, H S

1998-01-01

Administration of Tamoxifen via the Alzet pump at a rate of 50 micrograms hr-1 for 90 days in the adult male bonnet monkeys Macaca radiata had no effect on the serum testosterone concentration determined at 10 AM and 10 PM as well as total sperm count determined at 15-day intervals over a period of 260 days. However, a significant reduction in sperm motility was observed beyond 90 days up until the 225th day. Breeding studies conducted from day 90 to 260 revealed that these males were infertile.

Treatment Strategies for Human Arboviral Infections Applicable to Veterinary Medicine

DTIC Science & Technology

1992-06-16

16. MORILL , J. C., G. B. JENNINGS, T. M. COSGRIFF, P. H. GIBBS & C. J. PETERS. 1989. Prevention of Rift Valley fever in rhesus monkeys with interferon...alpha. Rev. Infect. Dis. 2(Suppl. 4): 815. 17. MORILL , J. C., C. W. CZARNECKI & C. J. PETERS. 1991. Recombinant human interferon- gamma modulates

Long-term protection against SHIV89.6P replication in HIV-1 Tat vaccinated cynomolgus monkeys.

PubMed

Maggiorella, Maria Teresa; Baroncelli, Silvia; Michelini, Zuleika; Fanales-Belasio, Emanuele; Moretti, Sonia; Sernicola, Leonardo; Cara, Andrea; Negri, Donatella R M; Buttò, Stefano; Fiorelli, Valeria; Tripiciano, Antonella; Scoglio, Arianna; Caputo, Antonella; Borsetti, Alessandra; Ridolfi, Barbara; Bona, Roberta; ten Haaft, Peter; Macchia, Iole; Leone, Pasqualina; Pavone-Cossut, Maria Rosaria; Nappi, Filomena; Ciccozzi, Massimo; Heeney, Jonathan; Titti, Fausto; Cafaro, Aurelio; Ensoli, Barbara

2004-09-03

Vaccination with a biologically active Tat protein or tat DNA contained infection with the highly pathogenic SHIV89.6P virus, preventing CD4 T-cell decline and disease onset. Here we show that protection was prolonged, since neither CD4 T-cell decline nor active virus replication was observed in all vaccinated animals that controlled virus replication up to week 104 after the challenge. In contrast, virus persisted and replicated in peripheral blood mononuclear cells and lymph nodes of infected animals, two of which died. Tat-specific antibody, CD4 and CD8 T-cell responses were high and stable only in the animals controlling the infection. In contrast, Gag-specific antibody production and CD4 and CD8 T-cell responses were consistently and persistently positive only in the monkeys that did not control primary virus replication. These results indicate that vaccination with Tat protein or DNA induced long-term memory Tat-specific immune responses and controlled primary infection at its early stages allowing a long-term containment of virus replication and spread in blood and tissues.

Detailed Analysis of the African Green Monkey Model of Nipah Virus Disease

PubMed Central

Johnston, Sara C.; Briese, Thomas; Bell, Todd M.; Pratt, William D.; Shamblin, Joshua D.; Esham, Heather L.; Donnelly, Ginger C.; Johnson, Joshua C.; Hensley, Lisa E.; Lipkin, W. Ian; Honko, Anna N.

2015-01-01

Henipaviruses are implicated in severe and frequently fatal pneumonia and encephalitis in humans. There are no approved vaccines or treatments available for human use, and testing of candidates requires the use of well-characterized animal models that mimic human disease. We performed a comprehensive and statistically-powered evaluation of the African green monkey model to define parameters critical to disease progression and the extent to which they correlate with human disease. African green monkeys were inoculated by the intratracheal route with 2.5×104 plaque forming units of the Malaysia strain of Nipah virus. Physiological data captured using telemetry implants and assessed in conjunction with clinical pathology were consistent with shock, and histopathology confirmed widespread tissue involvement associated with systemic vasculitis in animals that succumbed to acute disease. In addition, relapse encephalitis was identified in 100% of animals that survived beyond the acute disease phase. Our data suggest that disease progression in the African green monkey is comparable to the variable outcome of Nipah virus infection in humans. PMID:25706617

T-Cell Tropism of Simian Varicella Virus during Primary Infection

PubMed Central

Ouwendijk, Werner J. D.; Mahalingam, Ravi; de Swart, Rik L.; Haagmans, Bart L.; van Amerongen, Geert; Getu, Sarah; Gilden, Don; Osterhaus, Albert D. M. E.; Verjans, Georges M. G. M.

2013-01-01

Varicella-zoster virus (VZV) causes varicella, establishes a life-long latent infection of ganglia and reactivates to cause herpes zoster. The cell types that transport VZV from the respiratory tract to skin and ganglia during primary infection are unknown. Clinical, pathological, virological and immunological features of simian varicella virus (SVV) infection of non-human primates parallel those of primary VZV infection in humans. To identify the host cell types involved in virus dissemination and pathology, we infected African green monkeys intratracheally with recombinant SVV expressing enhanced green fluorescent protein (SVV-EGFP) and with wild-type SVV (SVV-wt) as a control. The SVV-infected cell types and virus kinetics were determined by flow cytometry and immunohistochemistry, and virus culture and SVV-specific real-time PCR, respectively. All monkeys developed fever and skin rash. Except for pneumonitis, pathology produced by SVV-EGFP was less compared to SVV-wt. In lungs, SVV infected alveolar myeloid cells and T-cells. During viremia the virus preferentially infected memory T-cells, initially central memory T-cells and subsequently effector memory T-cells. In early non-vesicular stages of varicella, SVV was seen mainly in perivascular skin infiltrates composed of macrophages, dendritic cells, dendrocytes and memory T-cells, implicating hematogenous spread. In ganglia, SVV was found primarily in neurons and occasionally in memory T-cells adjacent to neurons. In conclusion, the data suggest the role of memory T-cells in disseminating SVV to its target organs during primary infection of its natural and immunocompetent host. PMID:23675304

Selection of attenuated dengue 4 viruses by serial passage in primary kidney cells. II. Attributes of virus cloned at different dog kidney passage levels.

PubMed

Halstead, S B; Marchette, N J; Diwan, A R; Palumbo, N E; Putvatana, R

1984-07-01

Uncloned dengue (DEN) 4 (H-241) which had been passaged 15, 30 and 50 times in primary dog kidney (PDK) cells were subjected to two successive terminal dilution procedures. In the first (3Cl), virus was diluted in 10-fold steps in 10 replicate tubes. An infected tube from a dilution row with three or fewer virus-infected tubes was selected for two further passages. In the second (TD3), virus was triple terminal diluted using 2-fold dilution steps and selecting one positive tube out of 10. Both procedures selected virus population which differed from antecedents. Plaque size of PDK 15 was medium, PDK 30, small and PDK 50, pin-point. PDK 19-3Cl were medium and 56-3Cl, 24-TD3, 35-TD3 and 61-TD3 were all small. All cloned virus replication was completely shut-off at 38.5 degrees C; PDK 15 and 30 continued to replicate at this temperature. Uncloned viruses showed a graduated decrease in monkey virulence with PDK passage; cloned viruses were either avirulent for monkeys (19-3Cl, 56-31Cl, 24-TD3 and 35-TD3) or produced revertant large plaque parental-type viremia (35-3Cl and 61-TD3). Those cloned viruses which exhibited temperature sensitivity, reduced monkey virulence and stability after monkey passage may be suitable as vaccine candidates for evaluation in human beings.

Pathogenesis of Ebola Hemorrhagic Fever in Primate Models In Vivo and In Vitro

DTIC Science & Technology

2003-01-01

from the Philippine Islands (Jahrling et al., 1990). Hundreds of monkeys were infected (with high mortality) in this episode, but no human cases...reported that EBOV sGP binds to human neutrophils and inhibits early neutrophil activation . This study concluded that sGP diminished innate immunity...necrosis or apoptosis. However, viral infections can also exert changes in vascular endothelia indirectly, for example, by infecting and activating

Infection of Cultured Human and Monkey Cell Lines with Extract of Penaeid Shrimp Infected with Taura Syndrome Virus

PubMed Central

Audelo-del-Valle, Josefina; Clement-Mellado, Oliva; Magaña-Hernández, Anastasia; Flisser, Ana; Briseño-García, Baltasar

2003-01-01

Taura syndrome virus (TSV) affects shrimp cultured for human consumption. Although TSV is related to the Cricket Paralysis virus, it belongs to the “picornavirus superfamily,” the most common cause of viral illnesses. Here we demonstrate that TSV also infects human cell lines, which may suggest that Penaeus is a potential reservoir of this virus. PMID:12604003

Modeling vocalization with ECoG cortical activity recorded during vocal production in the macaque monkey.

PubMed

Fukushima, Makoto; Saunders, Richard C; Fujii, Naotaka; Averbeck, Bruno B; Mishkin, Mortimer

2014-01-01

Vocal production is an example of controlled motor behavior with high temporal precision. Previous studies have decoded auditory evoked cortical activity while monkeys listened to vocalization sounds. On the other hand, there have been few attempts at decoding motor cortical activity during vocal production. Here we recorded cortical activity during vocal production in the macaque with a chronically implanted electrocorticographic (ECoG) electrode array. The array detected robust activity in motor cortex during vocal production. We used a nonlinear dynamical model of the vocal organ to reduce the dimensionality of `Coo' calls produced by the monkey. We then used linear regression to evaluate the information in motor cortical activity for this reduced representation of calls. This simple linear model accounted for circa 65% of the variance in the reduced sound representations, supporting the feasibility of using the dynamical model of the vocal organ for decoding motor cortical activity during vocal production.

Remote and chronic access to the third cerebral ventricle of the unrestrained prepubertal rhesus monkey.

PubMed

Gay, V L; Mikuma, N; Plant, T M

1993-03-01

One channel of a commercially available standard-size three-channel fluid swivel was modified to permit continuous access to the brain of unrestrained prepubertal rhesus monkeys via a continuous length of small-bore Teflon tube originating from a swivel device on top of the animal's cage and terminating in the third cerebral ventricle. This system was employed to achieve continuous access to the third cerebroventricle in four monkeys for periods of up to 12 mo. The value of the system for studies of the neurochemical control of hypothalamic-releasing factor secretion was established by monitoring adenohypophysial responses to neurotransmitter receptor agonists infused into the third ventricle. Specifically, repetitive infusions of morphine (30 micrograms/infusion) elicited a robust train of prolactin discharges, and third ventricular administration of N-methyl-DL-aspartic acid (NMA; 20 micrograms) resulted in striking discharges of LH.

Dyscoria associated with herpesvirus infection in owl monkeys (Aotus nancymae)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gozalo, Alfonso S.; Montoya, Enrique J.; Weller, Richard E.

2008-08-16

Abstract Dyscoria was observed in a female owl monkey and her two offspring. A third offspring was found dead with necrohemorrhagic encephalitis. Two males paired with the female died, one of which showed oral ulcers at necropsy. Histologic examination of the oral ulcers revealed syncytia and eosinophilic intranuclear inclusion bodies in epithelial cells. Ocular examination revealed posterior synechia associated with the dyscoria in all three animals. Serum samples from the female and her offspring were positive for Herpesvirus simplex antibodies by enzyme-linked immunosorbent assay. The clinical history, gross and microscopic lesions, and serology results suggests a herpesviral etiology, possibly, H.more » simplex or H. saimiri-1. This report underscores the risks associated with introducing animals into breeding or research colonies that were previously kept as pets or those from unknown origin that could carry asymptomatic pathogenic Herpesvirus infections. In addition, herpesviral infection should be considered among the differential diagnoses if dyscoria is observed in nonhuman primates.« less

An enzootic outbreak of acute disease associated with pathogenic E. coli in Adler monkey colony.

PubMed

Lapin, Boris A; Yakovleva, Lelita A; Dzhikidze, Eteri K; Gvozdik, Tatiana E; Agumava, Aslan A; Stasilevich, Zinaida K; Danilova, Irina G

2015-12-01

In spring 2009 in Adler colony of the Institute of Medical Primatology, a large enzootic outbreak of acute intestine infection associated with pathogenic E. coli occurred and caused 5% mortality of population (209 animals). The epidemiological analysis, bacteriological investigation, postmortem examination, histological analysis, and PCR were used to identify the infectious agent. Marked hemorrhagic diathesis, lethargy, dehydration, diarrhea with blood, wasting, and sometimes dystrophic changes in articular cartilages were noted. Morphologically, hemorrhagic enterocolitis and massive hemorrhages were found. PCR investigation of bacteriologically isolated E. coli characterized it as enteropathogenic and enteroinvasive E. coli. The outbreak in Adler colony slightly differed from similar outbreak in Florida in 2014 by more marked hemorrhagic diathesis and articular changes in some monkeys caused by polyavitaminosis developed in the course of infection. Sensitive to infection were M. mulatta, M. fascicularis, Cercopithecus aethiops, P. hamadryas and anubis, and Cebus capucinus. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Emergence of Cryptosporidium hominis Monkey Genotype II and Novel Subtype Family Ik in the Squirrel Monkey (Saimiri sciureus) in China.

PubMed

Liu, Xuehan; Xie, Na; Li, Wei; Zhou, Ziyao; Zhong, Zhijun; Shen, Liuhong; Cao, Suizhong; Yu, Xingming; Hu, Yanchuan; Chen, Weigang; Peng, Gangneng

2015-01-01

A single Cryptosporidium isolate from a squirrel monkey with no clinical symptoms was obtained from a zoo in Ya'an city, China, and was genotyped by PCR amplification and DNA sequencing of the small-subunit ribosomal RNA (SSU rRNA), 70-kDa heat shock protein (HSP70), Cryptosporidium oocyst wall protein, and actin genes. This multilocus genetic characterization determined that the isolate was Cryptosporidium hominis, but carried 2, 10, and 6 nucleotide differences in the SSU rRNA, HSP70, and actin loci, respectively, which is comparable to the variations at these loci between C. hominis and the previously reported monkey genotype (2, 3, and 3 nucleotide differences). Phylogenetic studies, based on neighbor-joining and maximum likelihood methods, showed that the isolate identified in the current study had a distinctly discordant taxonomic status, distinct from known C. hominis and also from the monkey genotype, with respect to the three loci. Restriction fragment length polymorphisms of the SSU rRNA gene obtained from this study were similar to those of known C. hominis but clearly differentiated from the monkey genotype. Further subtyping was performed by sequence analysis of the gene encoding the 60-kDa glycoprotein (gp60). Maximum homology of only 88.3% to C. hominis subtype IdA10G4 was observed for the current isolate, and phylogenetic analysis demonstrated that this particular isolate belonged to a novel C. hominis subtype family, IkA7G4. This study is the first to report C. hominis infection in the squirrel monkey and, based on the observed genetic characteristics, confirms a new C. hominis genotype, monkey genotype II. Thus, these results provide novel insights into genotypic variation in C. hominis.

[Explantation method of isolating a persistent tick-borne encephalitis virus from the organs of infected monkeys].

PubMed

Levina, L S; Pogodina, V V

1981-01-01

The method of explantation was used to examine 63 organs from M. rhesus monkeys 92-783 days after intracerebral and subcutaneous inoculation with the Vasilchenko, Aina/1448 and 41/65 strains of tick-borne encephalitis virus. The optimal time for examination of the explants by tests of the hemagglutinating, cytopathogenic activity of the virus and its pathogenicity for mice was found to be the 15th day of cultivation. A comparative study of the properties of 3 isolates obtained from explants of the spleen, liver and subcortical cerebral ganglia 202 and 307 days after inoculation of monkeys was carried out. The isolates differed from the parental TBE virus strains by their capacity to form small plaques in PEKV cell cultures (pig embryo kidney cells in versen medium).

The subtype-selective nicotinic acetylcholine receptor agonist SIB-1553A improves both attention and memory components of a spatial working memory task in chronic low dose 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated monkeys.

PubMed

Schneider, J S; Tinker, J P; Menzaghi, F; Lloyd, G K

2003-07-01

Monkeys that receive chronic low dose (CLD) 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration develop deficits in spatial delayed-response task performance. The present study examined the extent to which SIB-1553A [(+/-)-4-[[2-(1-methyl-2-pyrrolidinyl)ethyl]thio]phenol hydrochloride], a novel neuronal nicotinic acetylcholine receptor (nAChR) agonist with selectivity for beta4 subunit-containing nAChRs, could counteract this cognitive deficit produced by CLD MPTP exposure. Prior to MPTP treatment, monkeys displayed a delay-dependent decrement in performance on a variable delayed response task. CLD MPTP treatment caused a shift to a delay-independent pattern of responding on this task, such that short-delay trials were performed as poorly as long-delay trials. At lower doses (e.g., 0.025 mg/kg), SIB-1553A significantly improved performance on short-delay trials but only at 24 h after drug administration. At higher doses (e.g., 0.50 mg/kg), SIB-1553A significantly improved performance on both short- and long-delay trials at both 20 min and 24 h after drug administration. When tested 24 h after drug administration, monkeys performed long-delay trials with greater accuracy than they did under normal (pre-MPTP) conditions. These results suggest that at lower doses, SIB-1553A may be more effective in improving attentional deficits associated with CLD MPTP exposure, whereas at higher doses, SIB-1553A may effectively improve both attentional and memory performance.

Blood levels do not predict behavioral or physiological effects of Δ9-tetrahydrocannabinol in rhesus monkeys with different patterns of exposure

PubMed Central

Ginsburg, Brett C.; Hruba, Lenka; Zaki, Armia; Javors, Martin; McMahon, Lance R.

2014-01-01

Background Recent changes in the legality of cannabis have prompted evaluation of whether blood levels of Δ9-tetrahydrocannabinol (THC) or its metabolites could be used to substantiate impairment, particularly related to behavioral tasks such as driving. However, because marked tolerance develops to behavioral effects of THC, the applicability of a particular threshold of blood THC as an index of impairment in people with different patterns of use remains unclear. Studies relevant to this issue are difficult to accomplish in humans, as prior drug exposure is difficult to control. Methods Here, effects of THC to decrease rectal temperature and operant response rate compared to levels of THC and its metabolites were studied in blood in two groups of monkeys: one received intermittent treatment with THC (0.1 mg/kg i.v.) and another received chronic THC (1 mg/kg/12 h s.c.) for several years. Results In monkeys with intermittent THC exposure, a single dose of THC (3.2 mg/kg s.c.) decreased rectal temperature and response rate. The same dose did not affect response rate or rectal temperature in chronically exposed monkeys, indicative of greater tolerance. In both groups, blood levels of THC peaked 20–60 min post-injection and had a similar half life of elimination, indicating no tolerance to the pharmacokinetics of THC. Notably, in both groups, the behavioral effects of THC were not apparent when blood levels were maximal (20-min post-administration). Conclusion These data indicate that thresholds for blood levels of THC do not provide a consistent index of behavioral impairment across individuals with different patterns of THC exposure. PMID:24703610

Mitochondrial and Nuclear Ribosomal DNA Evidence Supports the Existence of a New Trichuris Species in the Endangered François’ Leaf-Monkey

PubMed Central

Liu, Guo-Hua; Gasser, Robin B.; Nejsum, Peter; Wang, Yan; Chen, Qiang; Song, Hui-Qun; Zhu, Xing-Quan

2013-01-01

The whipworm of humans, Trichuris trichiura, is responsible for a neglected tropical disease (NTD) of major importance in tropical and subtropical countries of the world. Whipworms also infect animal hosts, including pigs, dogs and non-human primates, cause clinical disease (trichuriasis) similar to that of humans. Although Trichuris species are usually considered to be host specific, it is not clear whether non-human primates are infected with T. trichiura or other species. In the present study, we sequenced the complete mitochondrial (mt) genome as well as the first and second internal transcribed spacers (ITS-1 and ITS-2) of Trichuris from the François’ leaf-monkey (langur), and compared them with homologous sequences from human- and pig-derived Trichuris. In addition, sequence comparison of a conserved mt ribosomal gene among multiple individual whipworms revealed substantial nucleotide differences among these three host species but limited sequence variation within each of them. The molecular data indicate that the monkey-derived whipworm is a separate species from that of humans. Future work should focus on detailed population genetic and morphological studies (by electron microscopy) of whipworms from various non-humans primates and humans. PMID:23840431

Mitochondrial and nuclear ribosomal DNA evidence supports the existence of a new Trichuris species in the endangered françois' leaf-monkey.

PubMed

Liu, Guo-Hua; Gasser, Robin B; Nejsum, Peter; Wang, Yan; Chen, Qiang; Song, Hui-Qun; Zhu, Xing-Quan

2013-01-01

The whipworm of humans, Trichuris trichiura, is responsible for a neglected tropical disease (NTD) of major importance in tropical and subtropical countries of the world. Whipworms also infect animal hosts, including pigs, dogs and non-human primates, cause clinical disease (trichuriasis) similar to that of humans. Although Trichuris species are usually considered to be host specific, it is not clear whether non-human primates are infected with T. trichiura or other species. In the present study, we sequenced the complete mitochondrial (mt) genome as well as the first and second internal transcribed spacers (ITS-1 and ITS-2) of Trichuris from the François' leaf-monkey (langur), and compared them with homologous sequences from human- and pig-derived Trichuris. In addition, sequence comparison of a conserved mt ribosomal gene among multiple individual whipworms revealed substantial nucleotide differences among these three host species but limited sequence variation within each of them. The molecular data indicate that the monkey-derived whipworm is a separate species from that of humans. Future work should focus on detailed population genetic and morphological studies (by electron microscopy) of whipworms from various non-humans primates and humans.

Genetic Characterization of Simian Foamy Viruses Infecting Humans

PubMed Central

Rua, Réjane; Betsem, Edouard; Calattini, Sara; Saib, Ali

2012-01-01

Simian foamy viruses (SFVs) are retroviruses that are widespread among nonhuman primates (NHPs). SFVs actively replicate in their oral cavity and can be transmitted to humans after NHP bites, giving rise to a persistent infection even decades after primary infection. Very few data on the genetic structure of such SFVs found in humans are available. In the framework of ongoing studies searching for SFV-infected humans in south Cameroon rainforest villages, we studied 38 SFV-infected hunters whose times of infection had presumably been determined. By long-term cocultures of peripheral blood mononuclear cells with BHK-21 cells, we isolated five new SFV strains and obtained complete genomes of SFV strains from chimpanzee (Pan troglodytes troglodytes; strains BAD327 and AG15), monkey (Cercopithecus nictitans; strain AG16), and gorilla (Gorilla gorilla; strains BAK74 and BAD468). These zoonotic strains share a very high degree of similarity with their NHP counterparts and have a high degree of conservation of the genetic elements important for viral replication. Interestingly, analysis of FV DNA sequences obtained before cultivation revealed variants with deletions in both the U3 region and tas that may correlate with in vivo chronicity in humans. Genomic changes in bet (a premature stop codon) and gag were also observed. To determine if such changes were specific to zoonotic strains, we studied local SFV-infected chimpanzees and found the same genomic changes. Our study reveals that natural polymorphism of SFV strains does exist at both the intersubspecies level (gag, bet) and the intrasubspecies (U3, tas) levels but does not seem to reflect a viral adaptation specific to zoonotic SFV strains. PMID:23015714

Loss of CXCR6 coreceptor usage characterizes pathogenic lentiviruses

PubMed Central

Wetzel, Katherine S.; Yi, Yanjie; Bauer, Anya M.; Bibollet-Ruche, Frederic; Hahn, Beatrice H.; Paiardini, Mirko; Silvestri, Guido; Peeters, Martine; Collman, Ronald G.

2018-01-01

Pandemic HIV-1 originated from the cross-species transmission of SIVcpz, which infects chimpanzees, while SIVcpz itself emerged following the cross-species transmission and recombination of monkey SIVs, with env contributed by the SIVgsn/mus/mon lineage that infects greater spot-nosed, mustached and mona monkeys. SIVcpz and HIV-1 are pathogenic in their respective hosts, while the phenotype of their SIVgsn/mus/mon ancestors is unknown. However, two well-studied SIV infected natural hosts, sooty mangabeys (SMs) and African green monkeys (AGMs), typically remain healthy despite high viral loads; these species express low levels of the canonical coreceptor CCR5, and recent work shows that CXCR6 is a major coreceptor for SIV in these hosts. It is not known what coreceptors were used by the precursors of SIVcpz, whether coreceptor use changed during emergence of the SIVcpz/HIV-1 lineage, and what T cell subsets express CXCR6 in natural hosts. Using species-matched coreceptors and CD4, we show here that SIVcpz uses only CCR5 for entry and, like HIV-1, cannot use CXCR6. In contrast, SIVmus efficiently uses both CXCR6 and CCR5. Coreceptor selectivity was determined by Env, with CXCR6 use abrogated by Pro326 in the V3 crown, which is absent in monkey SIVs but highly conserved in SIVcpz/HIV-1. To characterize which cells express CXCR6, we generated a novel antibody that recognizes CXCR6 of multiple primate species. Testing lymphocytes from SM, the best-studied natural host, we found that CXCR6 is restricted to CD4+ effector memory cells, and is expressed by a sub-population distinct from those expressing CCR5. Thus, efficient CXCR6 use, previously identified in SM and AGM infection, also characterizes a member of the SIV lineage that gave rise to SIVcpz/HIV-1. Loss of CXCR6 usage by SIVcpz may have altered its cell tropism, shifting virus from CXCR6-expressing cells that may support replication without disrupting immune function or homeostasis, towards CCR5-expressing cells with pathogenic consequences. PMID:29659623

Loss of CXCR6 coreceptor usage characterizes pathogenic lentiviruses.

PubMed

Wetzel, Katherine S; Yi, Yanjie; Yadav, Anjana; Bauer, Anya M; Bello, Ezekiel A; Romero, Dino C; Bibollet-Ruche, Frederic; Hahn, Beatrice H; Paiardini, Mirko; Silvestri, Guido; Peeters, Martine; Collman, Ronald G

2018-04-01

Pandemic HIV-1 originated from the cross-species transmission of SIVcpz, which infects chimpanzees, while SIVcpz itself emerged following the cross-species transmission and recombination of monkey SIVs, with env contributed by the SIVgsn/mus/mon lineage that infects greater spot-nosed, mustached and mona monkeys. SIVcpz and HIV-1 are pathogenic in their respective hosts, while the phenotype of their SIVgsn/mus/mon ancestors is unknown. However, two well-studied SIV infected natural hosts, sooty mangabeys (SMs) and African green monkeys (AGMs), typically remain healthy despite high viral loads; these species express low levels of the canonical coreceptor CCR5, and recent work shows that CXCR6 is a major coreceptor for SIV in these hosts. It is not known what coreceptors were used by the precursors of SIVcpz, whether coreceptor use changed during emergence of the SIVcpz/HIV-1 lineage, and what T cell subsets express CXCR6 in natural hosts. Using species-matched coreceptors and CD4, we show here that SIVcpz uses only CCR5 for entry and, like HIV-1, cannot use CXCR6. In contrast, SIVmus efficiently uses both CXCR6 and CCR5. Coreceptor selectivity was determined by Env, with CXCR6 use abrogated by Pro326 in the V3 crown, which is absent in monkey SIVs but highly conserved in SIVcpz/HIV-1. To characterize which cells express CXCR6, we generated a novel antibody that recognizes CXCR6 of multiple primate species. Testing lymphocytes from SM, the best-studied natural host, we found that CXCR6 is restricted to CD4+ effector memory cells, and is expressed by a sub-population distinct from those expressing CCR5. Thus, efficient CXCR6 use, previously identified in SM and AGM infection, also characterizes a member of the SIV lineage that gave rise to SIVcpz/HIV-1. Loss of CXCR6 usage by SIVcpz may have altered its cell tropism, shifting virus from CXCR6-expressing cells that may support replication without disrupting immune function or homeostasis, towards CCR5-expressing cells with pathogenic consequences.

Performance norms for a rhesus monkey neuropsychological testing battery: acquisition and long-term performance.

PubMed

Weed, M R; Taffe, M A; Polis, I; Roberts, A C; Robbins, T W; Koob, G F; Bloom, F E; Gold, L H

1999-10-25

A computerized behavioral battery based upon human neuropsychological tests (CANTAB, CeNeS, Cambridge, UK) has been developed to assess cognitive behaviors of rhesus monkeys. Monkeys reliably performed multiple tasks, providing long-term assessment of changes in a number of behaviors for a given animal. The overall goal of the test battery is to characterize changes in cognitive behaviors following central nervous system (CNS) manipulations. The battery addresses memory (delayed non-matching to sample, DNMS; spatial working memory, using a self-ordered spatial search task, SOSS), attention (intra-/extra-dimensional shift, ID/ED), motivation (progressive-ratio, PR), reaction time (RT) and motor coordination (bimanual task). As with human neuropsychological batteries, different tasks are thought to involve different neural substrates, and therefore performance profiles should assess function in particular brain regions. Monkeys were tested in transport cages, and responding on a touch sensitive computer monitor was maintained by food reinforcement. Parametric manipulations of several tasks demonstrated the sensitivity of performance to increases in task difficulty. Furthermore, the factors influencing difficulty for rhesus monkeys were the same as those shown to affect human performance. Data from this study represent performance of a population of healthy normal monkeys that will be used for comparison in subsequent studies of performance following CNS manipulations such as infection with simian immunodeficiency virus (NeuroAIDS) or drug administration.

Comparative analysis of field-isolate and monkey-adapted Plasmodium vivax genomes.

PubMed

Chan, Ernest R; Barnwell, John W; Zimmerman, Peter A; Serre, David

2015-03-01

Significant insights into the biology of Plasmodium vivax have been gained from the ability to successfully adapt human infections to non-human primates. P. vivax strains grown in monkeys serve as a renewable source of parasites for in vitro and ex vivo experimental studies and functional assays, or for studying in vivo the relapse characteristics, mosquito species compatibilities, drug susceptibility profiles or immune responses towards potential vaccine candidates. Despite the importance of these studies, little is known as to how adaptation to a different host species may influence the genome of P. vivax. In addition, it is unclear whether these monkey-adapted strains consist of a single clonal population of parasites or if they retain the multiclonal complexity commonly observed in field isolates. Here we compare the genome sequences of seven P. vivax strains adapted to New World monkeys with those of six human clinical isolates collected directly in the field. We show that the adaptation of P. vivax parasites to monkey hosts, and their subsequent propagation, did not result in significant modifications of their genome sequence and that these monkey-adapted strains recapitulate the genomic diversity of field isolates. Our analyses also reveal that these strains are not always genetically homogeneous and should be analyzed cautiously. Overall, our study provides a framework to better leverage this important research material and fully utilize this resource for improving our understanding of P. vivax biology.

Comparative Analysis of Field-Isolate and Monkey-Adapted Plasmodium vivax Genomes

PubMed Central

Chan, Ernest R.; Barnwell, John W.; Zimmerman, Peter A.; Serre, David

2015-01-01

Significant insights into the biology of Plasmodium vivax have been gained from the ability to successfully adapt human infections to non-human primates. P. vivax strains grown in monkeys serve as a renewable source of parasites for in vitro and ex vivo experimental studies and functional assays, or for studying in vivo the relapse characteristics, mosquito species compatibilities, drug susceptibility profiles or immune responses towards potential vaccine candidates. Despite the importance of these studies, little is known as to how adaptation to a different host species may influence the genome of P. vivax. In addition, it is unclear whether these monkey-adapted strains consist of a single clonal population of parasites or if they retain the multiclonal complexity commonly observed in field isolates. Here we compare the genome sequences of seven P. vivax strains adapted to New World monkeys with those of six human clinical isolates collected directly in the field. We show that the adaptation of P. vivax parasites to monkey hosts, and their subsequent propagation, did not result in significant modifications of their genome sequence and that these monkey-adapted strains recapitulate the genomic diversity of field isolates. Our analyses also reveal that these strains are not always genetically homogeneous and should be analyzed cautiously. Overall, our study provides a framework to better leverage this important research material and fully utilize this resource for improving our understanding of P. vivax biology. PMID:25768941

Synaptic adaptations to chronic ethanol intake in male rhesus monkey dorsal striatum depend on age of drinking onset.

PubMed

Cuzon Carlson, Verginia C; Grant, Kathleen A; Lovinger, David M

2018-03-15

One in 12 adults suffer with alcohol use disorder (AUD). Studies suggest the younger the age in which alcohol consumption begins the higher the probability of being diagnosed with AUD. Binge/excessive alcohol drinking involves a transition from flexible to inflexible behavior likely involving the dorsal striatum (caudate and putamen nuclei). A major focus of this study was to examine the effect of age of drinking onset on subsequent chronic, voluntary ethanol intake and dorsal striatal circuitry. Data from rhesus monkeys (n = 45) that started drinking as adolescents, young adults or mature adults confirms an age-related risk for heavy drinking. Striatal neuroadaptations were examined using whole-cell patch clamp electrophysiology to record AMPA receptor-mediated miniature excitatory postsynaptic currents (mEPSCs) and GABA A receptor-mediated miniature inhibitory postsynaptic currents (mIPSCs) from medium-sized spiny projection neurons located in the caudate or putamen nuclei. In controls, greater GABAergic transmission (mIPSC frequency and amplitude) was observed in the putamen compared to the caudate. With advancing age, in the absence of ethanol, an increase in mIPSC frequency concomitant with changes in mIPSC amplitude was observed in both regions. Chronic ethanol drinking decreased mIPSC frequency in the putamen regardless of age of onset. In the caudate, an ethanol drinking-induced increase in mIPSC frequency was only observed in monkeys that began drinking as young adults. Glutamatergic transmission did not differ between the dorsal striatal subregions in controls. With chronic ethanol drinking there was a decrease in the postsynaptic characteristics of rise time and area of mEPSCs in the putamen but an increase in mEPSC frequency in the caudate. Together, the observed changes in striatal physiology indicate a combined disinhibition due to youth and ethanol leading to abnormally strong activation of the putamen that could contribute to the increased risk for problem drinking in younger drinkers. Published by Elsevier Ltd.

Immunocyte Response to Experimental Mumps Virus Infection in Rhesus Monkeys

PubMed Central

Genco, R. J.; Flanagan, T. D.; Emmings, F. G.

1973-01-01

Nineteen rhesus monkeys were inoculated with mumps virus by retrograde ductal instillation into the parotid gland. Evidence of infection was obtained in all instances. Virus was isolated from buccal swabbings and parotid biopsies for 1 week after inoculation. A vigorous serum-neutralizing antibody response occurred within 3 weeks, and there was marked monocytic infiltration of the parotid stroma. The monocytic infiltrate comprised as much as 60% of the total gland volume 1 week after infection. The predominant inflammatory cells were non-immunoglobulin-containing mononuclear cells resembling lymphocytes. Plasma cells containing immunoglobulin G (IgG), IgA, IgM, and IgE increased in numbers in the gland after infection, the greatest increase occurring in IgG-containing cells. Neutralizing antibodies and interferon were found in extracts prepared from the infected glands. Neutralizing activity was highest in samples taken 3 weeks after infection but was detectable in samples taken as soon as 36 to 48 h after infection. Interferon activity was detected in significant amounts 36 to 48 h after infection. Challenge of previously infected animals resulted in an increase in the monocytic infiltrate as well as an increase in numbers of immunoglobulin-containing plasma cells. However, reinfection did not occur as evidenced by the inability to culture shed virus after challenge. This model should be useful for in vivo study of biochemical mediators which evoke inflammatory cell infiltration and which may be significant both in protection and in tissue damage. PMID:4202659

Isolation of Ancestral Sylvatic Dengue Virus Type 1, Malaysia

PubMed Central

Teoh, Boon-Teong; Sam, Sing-Sin; Abd-Jamil, Juraina

2010-01-01

Ancestral sylvatic dengue virus type 1, which was isolated from a monkey in 1972, was isolated from a patient with dengue fever in Malaysia. The virus is neutralized by serum of patients with endemic DENV-1 infection. Rare isolation of this virus suggests a limited spillover infection from an otherwise restricted sylvatic cycle. PMID:21029545

Subtle changes in brain functions produced by single doses of mevinphos (Phosdrin).

DOT National Transportation Integrated Search

1973-02-01

Mevinphos (Phosdrin) was found to inhibit the amplitude of hippocampal evoked potentials in unanesthetized squirrel monkeys with chronically indwelling electrodes. The threshold dose was 0.050 mg/kg and the maximal dose studied was 0.200 mg/kg. Doses...

Marburg Hemorrhagic Fever (Marburg HF)

MedlinePlus

... infected had been exposed to imported African green monkeys or their tissues while conducting research. One additional ... OIG 1600 Clifton Road Atlanta , GA 30329-4027 USA 800-CDC-INFO (800-232-4636) , TTY: 888- ...

Transplantation of micro- and macroencapsulated piglet islets into mice and monkeys.

PubMed

Elliott, R B; Escobar, L; Calafiore, R; Basta, G; Garkavenko, O; Vasconcellos, A; Bambra, C

2005-01-01

Neonatal porcine islets within alginate microcapsules transplanted intraperitoneally (IP) or within semi-permeable macrocapsules (TheraCyte) and transplanted subcutaneously (SC) survive and reverse diabetes for up to 16 weeks in diabetic autoimmune nonobese diabetic (NOD) mice. The islets in microcapsules transplanted IP into nondiabetic cynomolgus monkeys survived for 8 weeks. Similar results were shown with islets transplanted in TheraCytes. Neither species showed adverse effects or evidence of infection with porcine endogenous retroviruses or other endemic pig viruses. Proof of principle is illustrated for successful xenotransplantation in humans.

Glycerol Monolaurate Does Not Alter Rhesus Macaque (Macaca mulatta) Vaginal Lactobacilli and Is Safe for Chronic Use▿

PubMed Central

Schlievert, Patrick M.; Strandberg, Kristi L.; Brosnahan, Amanda J.; Peterson, Marnie L.; Pambuccian, Stefan E.; Nephew, Karla R.; Brunner, Kevin G.; Schultz-Darken, Nancy J.; Haase, Ashley T.

2008-01-01

Glycerol monolaurate (GML) is a fatty acid monoester that inhibits growth and exotoxin production of vaginal pathogens and cytokine production by vaginal epithelial cells. Because of these activities, and because of the importance of cytokine-mediated immune activation in human immunodeficiency virus type 1 (HIV-1) transmission to women, our laboratories are performing studies on the potential efficacy of GML as a topical microbicide to interfere with HIV-1 transmission in the simian immunodeficiency virus-rhesus macaque model. While GML is generally recognized as safe by the FDA for topical use, its safety for chronic use and effects on normal vaginal microflora in this animal model have not been evaluated. GML was therefore tested both in vitro for its effects on vaginal flora lactobacilli and in vivo as a 5% gel administered vaginally to monkeys. In vitro studies demonstrated that lactobacilli are not killed by GML; GML blocks the loss of their viability in stationary phase and does not interfere with lactic acid production. GML (5% gel) does not quantitatively alter monkey aerobic vaginal microflora compared to vehicle control gel. Lactobacilli and coagulase-negative staphylococci are the dominant vaginal aerobic microflora, with beta-hemolytic streptococci, Staphylococcus aureus, and yeasts sporadically present; gram-negative rods are not part of their vaginal flora. Colposcopy and biopsy studies indicate that GML does not alter normal mucosal integrity and does not induce inflammation; instead, GML reduces epithelial cell production of interleukin 8. The studies suggest that GML is safe for chronic use in monkeys when applied vaginally; it does not alter either mucosal microflora or integrity. PMID:18838587

Biotransformation of Daclatasvir In Vitro and in Nonclinical Species: Formation of the Main Metabolite by Pyrrolidine δ-Oxidation and Rearrangement.

PubMed

Li, Wenying; Zhao, Weiping; Liu, Xiaohong; Huang, Xiaohua; Lopez, Omar D; Leet, John E; Fancher, R Marcus; Nguyen, Van; Goodrich, Jason; Easter, John; Hong, Yang; Caceres-Cortes, Janet; Chang, Shu Y; Ma, Li; Belema, Makonen; Hamann, Lawrence G; Gao, Min; Zhu, Mingshe; Shu, Yue-Zhong; Humphreys, W Griffith; Johnson, Benjamin M

2016-06-01

Daclatasvir is a first-in-class, potent, and selective inhibitor of the hepatitis C virus nonstructural protein 5A replication complex. In support of nonclinical studies during discovery and exploratory development, liquid chromatography-tandem mass spectrometry and nuclear magnetic resonance were used in connection with synthetic and radiosynthetic approaches to investigate the biotransformation of daclatasvir in vitro and in cynomolgus monkeys, dogs, mice, and rats. The results of these studies indicated that disposition of daclatasvir was accomplished mainly by the release of unchanged daclatasvir into bile and feces and, secondarily, by oxidative metabolism. Cytochrome P450s were the main enzymes involved in the metabolism of daclatasvir. Oxidative pathways included δ-oxidation of the pyrrolidine moiety, resulting in ring opening to an aminoaldehyde intermediate followed by an intramolecular reaction between the aldehyde and the proximal imidazole nitrogen atom. Despite robust formation of the resulting metabolite in multiple systems, rates of covalent binding to protein associated with metabolism of daclatasvir were modest (55.2-67.8 pmol/mg/h) in nicotinamide adenine dinucleotide phosphate (reduced form)-supplemented liver microsomes (human, monkey, rat), suggesting that intramolecular rearrangement was favored over intermolecular binding in the formation of this metabolite. This biotransformation profile supported the continued development of daclatasvir, which is now marketed for the treatment of chronic hepatitis C virus infection. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

Prevention of renal scarring from pyelonephritis in nonhuman primates by vaccination with a synthetic Escherichia coli serotype O8 oligosaccharide-protein conjugate.

PubMed Central

Roberts, J A; Kaack, M B; Baskin, G; Svenson, S B

1993-01-01

Rhesus monkeys were vaccinated with a synthetic Escherichia coli serotype O8 oligosaccharide-protein conjugate. Using our experimental pyelonephritis monkey model, we tested whether such immunization was protective against the renal damage from inflammation following experimental infection with a P-fimbriated O-antigenically homologous E. coli strain. The vaccination did not significantly alter the duration of bacteriuria or interfere with the infection. However, the vaccine was efficient in renal protection, as vaccinated animals showed significantly less intratubular infiltration of neutrophils (P < 0.02) and the degree of renal scarring was also significantly less in these animals (P > 0.005) than in the control animals. Total kidney involvement in the vaccinated animals was 16.9%, compared with 32.5% in the control animals (P = 0.07). PMID:8225595

From the mouths of monkeys: Detection of Mycobacterium tuberculosis complex DNA from buccal swabs of synanthropic macaques

PubMed Central

Wilbur, AK; Engel, G; Rompis, A; Putra, IGA A; Lee, BP Y-H; Aggimarangsee, N; Chalise, M; Shaw, E; Oh, G; Schillaci, MA; Jones-Engel, L

2012-01-01

Although the Mycobacterium tuberculosis complex (MTBC) infects a third of all humans, little is known regarding the prevalence of mycobacterial infection in nonhuman primates (NHP). For more than a century, tuberculosis has been regarded as a serious infectious threat to NHP species. Advances in the detection of MTBC open new possibilities for investigating the effects of this poorly understood pathogen in diverse populations of NHP. Here we report results of a cross-sectional study using well-described molecular methods to detect a nucleic acid sequence (IS6110) unique to the MTBC. Sample collection was focused on the oral cavity, the presumed route of transmission of MTBC. Buccal swabs were collected from 263 macaques representing 11 species in four Asian countries and Gibraltar. Contexts of contact with humans included free ranging, pets, performing monkeys, zoos, and monkey temples. Following DNA isolation from buccal swabs, the PCR amplified IS6110 from 84 (31.9%) of the macaques. In general, prevalence of MTBC DNA was higher among NHP in countries where the World Health Organization reports higher prevalence of humans infected with MTBC. This is the first demonstration of MTBC DNA in the mouths of macaques. Further research is needed to establish the significance of this finding at both the individual and population levels. PCR of buccal samples holds promise as a method to elucidate the mycobacterial landscape among NHP, particularly macaques that thrive in areas of high human MTBC prevalence. PMID:22644580

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gokumakulapalle, Madhuri; Mei, Ya-Fang, E-mail: ya-fang.mei@umu.se

The use of continuous cell lines derived from the African green monkey kidney (AGMK) has led to major advances in virus vaccine development. However, to date, these cells have not been used to facilitate the creation of human adenoviruses because most human adenoviruses undergo abortive infections in them. Here, we report the susceptibility of AGMK-derived cells to adenovirus 11p (Ad11p) infection. First, we showed that CD46 molecules, which act as receptors for Ad11p, are expressed in AGMK cells. We then monitored Ad11p replication by measuring GFP expression as an indicator of viral transcription. We found that AGMK-derived cells were asmore » capable as carcinoma cells at propagating full-length replication-competent Ad11p (RCAd11p) DNA. Of the AGMK cell lines tested, Vero cells had the greatest capacity for adenovirus production. Thus, AGMK cells can be used to evaluate RCAd11p-mediated gene delivery, and Vero cells can be used for the production of RCAd11pGFP vectors at relatively high yields. - Highlights: • Africa green monkey cell lines were monitored for human adenovirus 11p GFP vector infection. • Human CD46 molecules were detectable in these monkey cell lines. • Adenovirus 11p GFP vector can be propagated in Vero cells increases the safety of Ad11p-based vectors for clinical trials. • To use Vero cells for preparation of Ad11p vector avoids the potential inclusion of oncogenes from tumor cells.« less

3B11-N, a monoclonal antibody against MERS-CoV, reduces lung pathology in rhesus monkeys following intratracheal inoculation of MERS-CoV Jordan-n3/2012

DOE Office of Scientific and Technical Information (OSTI.GOV)

Johnson, Reed F., E-mail: johnsonreed@mail.nih.gov; Bagci, Ulas; Center for Research in Computer Vision

Middle East Respiratory Syndrome Coronavirus (MERS-CoV) was identified in 2012 as the causative agent of a severe, lethal respiratory disease occurring across several countries in the Middle East. To date there have been over 1600 laboratory confirmed cases of MERS-CoV in 26 countries with a case fatality rate of 36%. Given the endemic region, it is possible that MERS-CoV could spread during the annual Hajj pilgrimage, necessitating countermeasure development. In this report, we describe the clinical and radiographic changes of rhesus monkeys following infection with 5×10{sup 6} PFU MERS-CoV Jordan-n3/2012. Two groups of NHPs were treated with either a humanmore » anti-MERS monoclonal antibody 3B11-N or E410-N, an anti-HIV antibody. MERS-CoV Jordan-n3/2012 infection resulted in quantifiable changes by computed tomography, but limited other clinical signs of disease. 3B11-N treated subjects developed significantly reduced lung pathology when compared to infected, untreated subjects, indicating that this antibody may be a suitable MERS-CoV treatment. - Highlights: • MERS-CoV Jordan-n3/2012 challenge of rhesus monkeys results in a mild disease. • CT can be used to monitor disease progression to aid models of human disease. • Treatment with the human monoclonal antibody 3B11-N resulted in decreased disease.« less

Sertraline inhibits increases in body fat and carbohydrate dysregulation in adult female cynomolgus monkeys

PubMed Central

Silverstein-Metzler, Marnie G.; Shively, Carol A.; Clarkson, Thomas B.; Appt, Susan E.; Carr, J.Jeffrey; Kritchevsky, Stephen B.; Jones, Sara R.; Register, Thomas C.

2017-01-01

Selective serotonin reuptake inhibitor (SSRI) antidepressants are widely prescribed for depression and other disorders. SSRIs have become one of the most commonly used drugs in the United States, particularly by women. Acute effects on body composition and carbohydrate metabolism have been reported, but little is known regarding the effects of chronic SSRI use. We evaluated the effects of chronic administration of a commonly prescribed SSRI, sertraline HCl, on body weight and composition, fat distribution, carbohydrate metabolism, as well as activity, in adult female depressed and nondepressed cynomolgus monkeys (Macaca fascicularis; n = 42) using a placebo-controlled, longitudinal, randomized study design. Phenotypes were evaluated prior to and after 18 months of oral sertraline (20 mg/kg) or placebo. Over the 18 month treatment period, the placebo group experienced increases in body weight, body fat (visceral and subcutaneous) fasting insulin concentrations, and homeostasis model assessment of insulin resistance scores (HOMA-IR). Sertraline treatment prevented increases in body weight, fat, insulin, and HOMA-IR (all p < 0.05), without significantly altering activity levels. Sertraline treatment altered adiponectin in an unusual way — reducing circulating adiponectin in depressed monkeys without affecting fat mass or body weight. Deleterious effects on adiponectin, a potentially insulin-sensitizing and atheroprotective protein, may result in adverse effects on cardiovascular health despite otherwise beneficial effects on body composition and carbohydrate metabolism. PMID:26939086

High prevalences and a wide genetic diversity of simian retroviruses in non-human primate bushmeat in rural areas of the Democratic Republic of Congo

PubMed Central

Steve, Ahuka-Mundeke; Ahidjo, Ayouba; Placide, Mbala-Kingebeni; Caroline, Foncelle; Mukulumanya, Mubonga; Simon-Pierre, Ndimbo-Kumugo; Octavie, Lunguya-Metila; Valentin, Mbenzo-Abokome; Jean-Jacques, Muyembe-Tamfum; Eric, Delaporte; Martine, Peeters

2017-01-01

Like the majority of emerging infectious diseases, HIV and HTLV are of zoonotic origin. Here we assess the risk of cross-species transmissions of their simian counterparts, SIV and STLV, from nonhuman primates (NHP) to humans in the Democratic Republic of Congo (DRC). A total of 331 samples, derived from NHP bushmeat, were collected as dried blood spots (DBS, n=283) or as tissue samples (n=36) at remote forest sites in northern and eastern DRC. SIV antibody prevalences in DBS were estimated with a novel high throughput immune assay with antigens representing the actual known diversity of HIV/SIV lineages. Antibody positive samples were confirmed by PCR and sequence analysis. Screening for STLV infection was done with universal primers in tax and new strains were further characterized in LTR. SIV and STLV infection in tissue samples was done by PCR only. Overall, 5% and 15.4% of NHP bushmeat was infected with SIV and STLV respectively. A new SIV lineage was identified in Allen's swamp monkeys (Allenopithecus nigroviridis). Three new STLV-1 subtypes were identified in Allen's swamp monkeys (Allenopithecus nigroviridis), blue monkeys (Cercopithecus mitis), red tailed guenons (Cercopithecus ascanius schmidti) and agile mangabeys (Cercocebus agilis). SIV and STLV prevalences varied according to species and geographic region. Our study illustrates clearly, even on a small sample size from a limited number of geograhic areas, that our knowledge on the genetic diversity and geographic distribution of simian retroviruses is still limited and that humans continue to be exposed to relative high proportions on infected NHP bushmeat. PMID:28050688

Effect of physical exercise prelabyrinthectomy on locomotor balance compensation in the squirrel monkey

NASA Technical Reports Server (NTRS)

Igarashi, M.; Ohashi, K.; Yoshihara, T.; MacDonald, S.

1989-01-01

This study examines the effectiveness of physical exercise, during a prepathology state, on locomotor balance compensation after subsequent unilateral labyrinthectomy in squirrel monkeys. An experimental group underwent 3 hr. of daily running exercise on a treadmill for 3 mo. prior to the surgery, whereas a control group was not exercised. Postoperatively, the locomotor balance function of both groups was tested for 3 mo. There was no significant difference in gait deviation counts in the acute phase of compensation. However, in the chronic compensation maintenance phase, the number of gait deviation counts was fewer in the exercise group, which showed significantly better performance stability.

Tonic control of kisspeptin release in prepubertal monkeys: implications to the mechanism of puberty onset.

PubMed

Kurian, Joseph R; Keen, Kim L; Guerriero, Kathryn A; Terasawa, Ei

2012-07-01

Previously we have shown that a reduction in γ-amino butyric acid (GABA) inhibition is critical for the mechanism initiating puberty onset because chronic infusion of the GABA(A) receptor antagonist, bicuculline, significantly increased GnRH release and accelerated the timing of menarche and first ovulation in female rhesus monkeys. Because previous studies in our laboratory indicate that in prepubertal female monkeys, kisspeptin release in the medial basal hypothalamus is low, whereas kisspeptin-10 can stimulate GnRH release, we hypothesized that a low level of kisspeptin release prior to puberty onset is due to tonic GABA inhibition. To test this hypothesis we examined the effects of bicuculline infusion on kisspeptin release using a microdialysis method. We found that bicuculline at 1 μM dramatically stimulates kisspeptin release in the medial basal hypothalamus of prepubertal monkeys but had little effect on kisspeptin release in midpubertal monkeys. We further examined whether bicuculline-induced GnRH release is blocked by the presence of the kisspeptin antagonist, peptide 234. We found that inhibition of kisspeptin signaling blocked the bicuculline-induced stimulation of GnRH release, suggesting that kisspeptin neurons may relay inhibitory GABA signals to GnRH neurons. This implies that a reduction in tonic GABA inhibition of GnRH release is, at least in part, mediated through kisspeptin neurons.

Two separable functional domains of simian virus 40 large T antigen: carboxyl-terminal region of simian virus 40 large T antigen is required for efficient capsid protein synthesis.

PubMed Central

Tornow, J; Polvino-Bodnar, M; Santangelo, G; Cole, C N

1985-01-01

The carboxyl-terminal portion of simian virus 40 large T antigen is essential for productive infection of CV-1 and CV-1p green monkey kidney cells. Mutant dlA2459, lacking 14 base pairs at 0.193 map units, was positive for viral DNA replication, but unable to form plaques in CV-1p cells (J. Tornow and C.N. Cole, J. Virol. 47:487-494, 1983). In this report, the defect of dlA2459 is further defined. Simian virus 40 late mRNAs were transcribed, polyadenylated, spliced, and transported in dlA2459-infected cells, but the level of capsid proteins produced in infected CV-1 green monkey kidney cells was extremely low. dlA2459 large T antigen lacks those residues known to be required for adenovirus helper function, and the block to productive infection by dlA2459 occurs at the same stage of infection as the block to productive adenovirus infection of CV-1 cells. These results suggest that the adenovirus helper function is required for productive infection by simian virus 40. Mutant dlA2459 was able to grow on the Vero and BSC-1 lines of African green monkey kidney cells. Additional mutants affecting the carboxyl-terminal portion of large T were prepared. Mutant inv2408 contains an inversion of the DNA between the BamHI and BclI sites (0.144 to 0.189 map units). This inversion causes transposition of the carboxyl-terminal 26 amino acids of large T antigen and the carboxyl-terminal 18 amino acids of VP1. This mutant was viable, even though the essential information absent from dlA2459 large T antigen has been transferred to the carboxyl terminus of VP1 of inv2408. The VP1 polypeptide carrying this carboxyl-terminal portion of large T could overcome the defect of dlA2459. This indicates that the carboxyl terminus of large T antigen is a separate and separable functional domain. Images PMID:2982029

Experimental poliomyelitis in bonnet monkey. Clinical features, virology and pathology.

PubMed

Samuel, B U; Ponnuraj, E; Rajasingh, J; John, T J

1993-01-01

We have investigated the distribution of virus and the pathology in the spinal cords of bonnet monkeys (Macaca radiata) with experimental paralytic poliomyelitis induced by inoculating poliovirus type 1 (Mahoney) into the right ulnar nerve. Viraemia and alimentary tract infection due to the inoculated virus were found in all monkeys. Between two and seven days after the onset of limb paralysis, the animals were killed and the spinal cord examined. Virus was isolated from the cervical enlargement, thoracic region and lumbar enlargement in titres ranging from 10(2.5) to 10(6.4) TCID50/gram of tissue. Cellular infiltrate, perivascular cuffing, early and late neuronal damage such as chromatolysis, nuclear pyknosis, retraction of the cytoplasm and neuronophagia were seen distributed throughout the spinal cord. This experimental animal model resembles human paralytic poliomyelitis clinically and pathologically.

Antigenic Relationships Among Four Herpesviruses

PubMed Central

Blue, W. T.; Plummer, G.

1973-01-01

Common viral antigens were detected, by fluorescent-antibody studies, in cells infected with herpes simplex virus 1, squirrel monkey herpesvirus 1, bovine rhinotracheitis, and equine abortion viruses. The two primate viruses showed slight cross-neutralization. PMID:4351969

Olive baboons: a non-human primate model for testing dengue virus type 2 replication.

PubMed

Valdés, Iris; Gil, Lázaro; Castro, Jorge; Odoyo, Damián; Hitler, Rikoi; Munene, Elephas; Romero, Yaremis; Ochola, Lucy; Cosme, Karelia; Kariuki, Thomas; Guillén, Gerardo; Hermida, Lisset

2013-12-01

This study evaluated the use of a non-human primate, the olive baboon (Papio anubis), as a model of dengue infection. Olive baboons closely resemble humans genetically and physiologically and have been used extensively for assessing novel vaccine formulations. Two doses of dengue virus type 2 (DENV-2) were tested in baboons: 10(3) and 10(4) pfu. Similarly, African green monkeys received the same quantity of virus and acted as positive controls. Following exposure, high levels of viremia were detected in both animal species. There was a trend to detect more days of viremia and more homogeneous viral titers in animals receiving the low viral dose. In addition, baboons infected with the virus generally exhibited positive virus isolation 1 day later than African green monkeys. Humoral responses consisting of antiviral and neutralizing antibodies were detected in all animals after infection. We conclude that baboons provide an alternative non-human primate species for experimental DENV-2 infection and we recommend their use for further tests of vaccines, administering the lowest dose assayed: 10(3) pfu. Copyright © 2013 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Chromobacterium violaceum Infection in a free-ranging howler monkey in Costa Rica.

PubMed

Baldi, Mario; Morales, Juan A; Hernández, Giovanna; Jiménez, Mauricio; Alfaro, Alejandro; Barquero-Calvo, Elias

2010-01-01

Chromobacterium violaceum is a gram-negative saprobe bacterium that is a rare opportunistic pathogen in mammals. There are numerous reports in humans including fatalities, but no record exists in free-ranging nonhuman primates. Here we report an infection by C. violaceum in a wild adult male howler monkey (Alouatta palliata) captured at Ballena Marine National Park, in southwestern Costa Rica. The individual had severe skin lesions over its extremities; gross findings included multiple skin ulcers, white foci in liver, and lymphoid hyperplasia. Histologic results included deep dermatitis with presence of necrotic epithelial cells where clusters of coccoid-shaped bacteria were detected. In the liver, numerous neutrophils forming microabscesses, telangiectasia, and focal necrotic areas were observed. Necrotic liver tissue sampled for bacteriologic culture resulted in the isolation of C. violaceum. We could not ascertain the source or mechanism of infection in this case, although infection through skin microabrasions is suspected. To the best of our knowledge, this is the first report for this pathogen in a wild, nonhuman primate. This report also draws attention to this infectious agent as a potential emerging wildlife disease and consideration should be paid by regional veterinary and epidemiologic vigilance services.

Effect of vaccination schedule on immune response of Macaca mulatta to cell culture-grown Rocky Mountain spotted fever vaccine.

PubMed Central

Sammons, L S; Kenyon, R H; Pedersen, C E

1976-01-01

The effect of vaccination schedule on the immune response of Macaca mulatta to formalin-inactivated chicken embryo cell culture (CEC)-grown Rickettsia rickettsii vaccine was studied. Schedules consisted of inoculation on day 1 only, on days 1 and 15, on days 1 and 30, on days 1, 8, and 15, or on days 1, 15, and 45. Humoral antibody measured by microagglutination and indirect immunofluorescence and resistance to challenge with 10(4) plaque-forming units of yolk sac-grown R. rickettsii were assessed. Seroconversion was noted in all monkeys after the first dose of vaccine. A second dose administered 8 or 15 days after the primary infection, or a third given 7 or 30 days after the second, produced no long-term effect on antibody titer. Only monkeys given two doses of vaccine at a 30-day interval showed an increase in antibody titer during the period before challenge. Vaccination with one, two, or three doses of CEC vaccine prevented development of rash and rickettsemia after challenge. The two-dose schedules appeared to induce the highest degree of resistance to challenge, as indicated by unaltered hematological parameters and body temperature in monkeys. The one- and three-dose schedules were somewhat less effective, in that some challenged monkeys within each group displayed febrile and leukocyte responses associated with Rocky Mountain spotted fever infection. Our data suggest that administration of two doses of CEC vaccine at 15- or 30-day intervals is the immunization schedule of choice. PMID:823173

Preclinical Characterization and Human Microdose Pharmacokinetics of ITMN-8187, a Nonmacrocyclic Inhibitor of the Hepatitis C Virus NS3 Protease.

PubMed

Rajagopalan, Ravi; Pan, Lin; Schaefer, Caralee; Nicholas, John; Lim, Sharlene; Misialek, Shawn; Stevens, Sarah; Hooi, Lisa; Aleskovski, Natalia; Ruhrmund, Donald; Kossen, Karl; Huang, Lea; Yap, Sophia; Beigelman, Leonid; Serebryany, Vladimir; Liu, Jyanwei; Sastry, Srikonda; Seiwert, Scott; Buckman, Brad

2017-01-01

The current paradigm for the treatment of chronic hepatitis C virus (HCV) infection involves combinations of agents that act directly on steps of the HCV life cycle. Here we report the preclinical characteristics of ITMN-8187, a nonmacrocyclic inhibitor of the NS3/4A HCV protease. X-ray crystallographic studies of ITMN-8187 and simeprevir binding to NS3/4A protease demonstrated good agreement between structures. Low nanomolar biochemical potency was maintained against NS3/4A derived from HCV genotypes 1, 2b, 4, 5, and 6. In cell-based potency assays, half-maximal reduction of genotype 1a and 1b HCV replicon RNA was afforded by 11 and 4 nM doses of ITMN-8187, respectively. Combinations of ITMN-8187 with other directly acting antiviral agents in vitro displayed additive antiviral efficacy. A 30-mg/kg of body weight dose of ITMN-8187 administered for 4 days yielded significant viral load reductions through day 5 in a chimeric mouse model of HCV. A 3-mg/kg oral dose administered to rats, dogs, or monkeys yielded concentrations in plasma 16 h after dosing that exceeded the half-maximal effective concentration of ITMN-8187. Human microdose pharmacokinetics showed low intersubject variability and prolonged oral absorption with first-order elimination kinetics compatible with once-daily dosing. These preclinical characteristics compare favorably with those of other NS3/4A inhibitors approved for the treatment of chronic HCV infection. Copyright © 2016 American Society for Microbiology.

Chemotherapy of Second Stage Human African Trypanosomiasis: Comparison between the Parenteral Diamidine DB829 and Its Oral Prodrug DB868 in Vervet Monkeys

PubMed Central

Thuita, John K.; Wolf, Kristina K.; Murilla, Grace A.; Bridges, Arlene S.; Boykin, David W.; Mutuku, James N.; Liu, Qiang; Jones, Susan K.; Gem, Charles O.; Ching, Shelley; Tidwell, Richard R.; Wang, Michael Z.; Paine, Mary F.; Brun, Reto

2015-01-01

Human African trypanosomiasis (HAT, sleeping sickness) ranks among the most neglected tropical diseases based on limited availability of drugs that are safe and efficacious, particularly against the second stage (central nervous system [CNS]) of infection. In response to this largely unmet need for new treatments, the Consortium for Parasitic Drug Development developed novel parenteral diamidines and corresponding oral prodrugs that have shown cure of a murine model of second stage HAT. As a rationale for selection of one of these compounds for further development, the pharmacokinetics and efficacy of intramuscular (IM) active diamidine 2,5-bis(5-amidino-2-pyridyl)furan (DB829; CPD-0802) and oral prodrug2,5-bis[5-(N-methoxyamidino)-2-pyridyl]furan (DB868) were compared in the vervet monkey model of second stage HAT. Treatment was initiated 28 days post-infection of monkeys with T. b. rhodesiense KETRI 2537. Results showed that IM DB829 at 5 mg/kg/day for 5 consecutive days, 5 mg/kg/day every other day for 5 doses, or 2.5 mg/kg/day for 5 consecutive days cured all monkeys (5/5). Oral DB868 was less successful, with no cures (0/2) at 3 mg/kg/day for 10 days and cure rates of 1/4 at 10 mg/kg/day for 10 days and 20 mg/kg/day for 10 days; in total, only 2/10 monkeys were cured with DB868 dose regimens. The geometric mean plasma Cmax of IM DB829 at 5 mg/kg following the last of 5 doses was 25-fold greater than that after 10 daily oral doses of DB868 at 20 mg/kg. These data suggest that the active diamidine DB829, administered IM, should be considered for further development as a potential new treatment for second stage HAT. PMID:25654243

Parallel evolution of a self-signal: humans and new world monkeys independently lost the cell surface sugar Neu5Gc.

PubMed

Springer, Stevan A; Diaz, Sandra L; Gagneux, Pascal

2014-11-01

Human sialic acid biology is unusual and thought to be unique among mammals. Humans lack a functional cytidine monophosphate-N-acetylneuraminic acid hydroxylase (CMAH) protein and cannot synthesize the sugar Neu5Gc, an innate mammalian signal of self. Losing this sugar changed how humans interact with some of our deadliest pathogens: malaria, influenza, and streptococcus among others. We show that the New World monkeys, comprising the third of all primate species, have human-like sialic acid biology. They have lost Neu5Gc because of an independent CMAH inactivation ~30 million years ago (mya) (compared to ~3 mya in hominids). This parallel loss of Neu5Gc opens sialic acid biology to comparative phylogenetic analysis and reveals an unexpected conservation priority. New World monkeys risk infection by human pathogens that can recognize cells in the absence of Neu5Gc. This striking molecular convergence provides a mechanism that could explain the long-standing observation that New World monkeys are susceptible to some human diseases that cannot be transmitted to other primates.

Single subcutaneous dosing of cefovecin in rhesus monkeys (Macaca mulatta): a pharmacokinetic study.

PubMed

Bakker, J; Thuesen, L R; Braskamp, G; Skaanild, M T; Ouwerling, B; Langermans, J A M; Bertelsen, M F

2011-10-01

Cefovecin is a third-generation cephalosporin approved for antibacterial treatment with a 14-day dosing interval in dogs and cats. This antibiotic may also be useful for zoo and wildlife veterinary medicine, because of its broad spectrum and long duration of activity. The aim of the study was to determine whether cefovecin is a suitable antibiotic to prevent skin wound infection in rhesus monkeys. Therefore, the pharmacokinetics (PK) of cefovecin after a single subcutaneous injection at 8 mg/kg bodyweight in four rhesus monkeys (Macaca mulatta) and sensitivity of bacterial isolates from fresh skin wounds were determined. After administration, blood, urine, and feces were collected, and concentrations of cefovecin were determined. Further, the minimum inhibitory concentrations (MIC) for bacteria isolated from fresh skin wounds of monkeys during a health control program were determined. The mean maximum plasma concentration (C(max) ) of cefovecin was 78 μg/mL and was achieved after 57 min. The mean apparent long elimination half-life (t½) was 6.6 h and excretion occurred mainly via urine. The MIC for the majority of the bacteria examined was >100 μg/mL. The PK of cefovecin in rhesus monkeys is substantially different than for dogs and cats. Cefovecin rapidly reached C(max) which however was lower than most of the MIC levels and with a very short t½. Therefore, cefovecin is not recommended for treating skin wounds in rhesus monkeys. © 2011 Blackwell Publishing Ltd.

Protein phosphorylations in poliovirus infected cells.

PubMed

James, L A; Tershak, D R

1981-01-01

In vivo phosphorylation of proteins that are associated with polysomes of poliovirus-infected VERO (African green monkey kidney) and HeLa (Henrietta Lacks) cells differed from phosphorylations observed with uninfected cells that were fed fresh medium. With both types of cells infection stimulated phosphorylation of proteins with molecular weights of 40 000-41 000, 39 000, 34 000, 32 000, and 24 000. Similarities of phosphorylations in VERO and HeLa cells suggest that they are a specific consequence of infection and might serve a regulatory function during protein synthesis.

Tuberculosis Caused by Mycobacterium orygis in Dairy Cattle and Captured Monkeys in Bangladesh: a New Scenario of Tuberculosis in South Asia.

PubMed

Rahim, Z; Thapa, J; Fukushima, Y; van der Zanden, A G M; Gordon, S V; Suzuki, Y; Nakajima, C

2017-12-01

Mycobacterium orygis, commonly known as the oryx bacillus and a newly proposed Mycobacterium tuberculosis complex subspecies, was isolated from 18 cattle in a dairy farm and two captured rhesus monkeys in a zoo in Bangladesh. All the infected animals had tuberculosis lesions in their lungs, suggesting transmission and infection with M. orygis by an airborne route. The 20 isolates were analysed using a range of conventional and molecular typing methods, and RD-deletion typing and sequencing of selected genes confirmed the isolates as M. orygis. Multiple-locus variable-number tandem repeat analysis (MLVA) allowed the isolates to be divided into three clusters based on the relatedness of their MLVA profiles. The two monkey isolates shared the same MLVA pattern with 15 of the cattle isolates, whereas the remaining three cattle isolates had different patterns, even though the latter animals had been kept in the same dairy farm. The diversity observed among isolates may suggest the bacteria have been established in this area for a long period. This study along with other recent findings that report the detection of M. orygis from animals as well as humans originating from South Asia potentially indicate endemic distribution of M. orygis in South Asia. © 2016 Blackwell Verlag GmbH.

Pathophysiology of shock and hemorrhage in a fulminating viral infection (Ebola).

PubMed

Fisher-Hoch, S P; Platt, G S; Neild, G H; Southee, T; Baskerville, A; Raymond, R T; Lloyd, G; Simpson, D I

1985-11-01

Eleven rhesus monkeys were monitored intensively during experimental infection with Ebola virus. Prominent neutrophilia with left shift and lymphopenia were the earliest abnormalities and were statistically significant by day 4 (P less than .02 and P less than .01, respectively). By day 4 falls in platelet counts were not statistically significant, whereas in vitro platelet aggregation was markedly depressed, progressing rapidly to complete failure by the time of maximum illness. Intraplatelet protein studies suggested this event was the result of in vivo activation and degranulation. Coagulation cascade defects were mainly in the intrinsic system and were surprisingly mild, with no evidence of selective consumption or production deficit of factor VII or VIII. When the possibility of indirectly mediated damage to endothelium possibly by a nonspecific immune response was examined, weight loss was less severe in drug-treated monkeys, and all had detectable plasma prostacyclin metabolites, but there was no improvement in survival.

Social Behaviours and Networks of Vervet Monkeys Are Influenced by Gastrointestinal Parasites

PubMed Central

Friant, Sagan; Godfrey, Kathleen; Liu, Cynthia; Sakar, Dipto; Schoof, Valérie A. M.; Sengupta, Raja; Twinomugisha, Dennis; Valenta, Kim; Goldberg, Tony L.

2016-01-01

Substantial research has shown that while some parasite infections can be fatal to hosts, most infections are sub-clinical and non-lethal. Such sub-clinical infections can nonetheless have negative consequences for the long-term fitness of the host such as reducing juvenile growth and the host’s ability to compete for food and mates. With such effects, infected individuals are expected to exhibit behavioural changes. Here we use a parasite removal experiment to quantify how gastrointestinal parasite infections affect the behaviour of vervet monkeys (Chlorocebus aethiops) at Lake Nabugabo, Uganda. Behavioural profiles and the structure of nearest neighbour relationships varied significantly. As predicted, after deworming the duration of the resting events decreased, which is consistent with the idea that parasite infections are energetically costly. In contrast to what was predicted, we could not reject the null hypothesis and we observed no change in either the frequency or duration of grooming, but we found that the duration of travel events increased. A network analysis revealed that after deworming, individuals tended to have more nearest neighbours and hence probably more frequent interactions, with this effect being particularly marked for juveniles. The heightened response by juveniles may indicate that they are avoiding infected individuals more than other age classes because it is too costly to move energy away from growth. We consider that populations with high parasite burden may have difficulties developing social networks and behaviours that could have cascading effects that impact the population in general. PMID:27580121

Kyasanur Forest Disease (KFD): Rare Disease of Zoonotic Origin.

PubMed

Muraleedharan, M

2016-09-01

Kyasanur forest disease (KFD) is a rare tick borne zoonotic disease that causes acute febrile hemorrhagic illness in humans and monkeys especially in southern part of India. The disease is caused by highly pathogenic KFD virus (KFDV) which belongs to member of the genus Flavivirus and family Flaviviridae. The disease is transmitted to monkeys and humans by infective tick Haemaphysalisspinigera. Seasonal outbreaks are expected to occur during the months of January to June. The aim of this paper is to briefly summarize the epidemiology, mode of transmission of KFD virus, clinical findings, diagnosis, treatment, control and prevention of the disease..

POSSIBILITY OF HEREDITARY TRANSMISSION OF YELLOW FEVER VIRUS BY AEDES AEGYPTI (LINN.)

PubMed Central

Philip, Cornelius B.

1929-01-01

Attempts to obtain passage of yellow fever virus from one generation to the next in A. aegypti were unsuccessful. Subcutaneous injections at varying intervals of a saline emulsion of 200 eggs laid by an infective lot of mosquitoes produced no reaction in six normal M. rhesus monkeys. Negative results were also obtained in five biting and two injection experiments with progeny of the same infective lot of mosquitoes in which seven normal monkeys were used. The eggs consisted of batches laid after the first, second and fourth blood-meals of the original lot; the latter feeding occurred 41 days after the initial infecting meal. The imaginal offspring represented rearings following the first, second and fifth blood-meals of the parent lot. The last feeding occurred 54 days after the first. It is concluded that under the conditions of the experiments here reported hereditary transmission of yellow fever by A. aegypti is improbable. Variations in age and in number of blood-meals of parent and offspring mosquitoes had no effect in achieving passage of the virus from one stage of the insect to another. PMID:19869656

Differential gene expression in HIV/SIV-associated and spontaneous lymphomas

PubMed Central

2005-01-01

Diffuse large B-cell lymphoma (DLBCL) is more prevalent and more often fatal in HIV-infected patients and SIV-infected monkeys compared to immune-competent individuals. Molecular, biological, and immunological data indicate that virus-associated lymphomagenesis is similar in both infected hosts. To find genes specifically overexpressed in HIV/SIV-associated and non-HIV/SIV-associated DLBCL we compared gene expression profiles of HIV/SIV-related and non-HIV-related lymphomas using subtractive hybridization and Northern blot analysis. Our experimental approach allowed us to detect two genes (a-myb and pub) upregulated solely in HIV/SIV-associated DLBCLs potentially involved in virus-specific lymphomagenesis in human and monkey. Downregulation of the pub gene was observed in all non-HIV-associated lymphomas investigated. In addition, we have found genes upregulated in both non-HIV- and HIV-associated lymphomas. Among those were genes both with known (set, ND4, SMG-1) and unknown functions. In summary, we have demonstrated that simultaneous transcriptional upregulation of at least two genes (a-myb and pub) was specific for AIDS-associated lymphomas. PMID:16239949

Animal studies on Spacelab-3

NASA Technical Reports Server (NTRS)

Schatte, C.; Grindeland, R.; Callahan, P.; Berry, W.; Funk, G.; Lencki, W.

1987-01-01

The flight of two squirrel monkeys and 24 rats on Spacelab-3 was the first mission to provide hands-on maintenance on animals in a laboratory environment. With few exceptions, the animals grew and behaved normally, were free of chronic stress, and differed from ground controls only for gravity dependent parameters. One of the monkeys exhibited symptoms of space sickness similar to those observed in humans, which suggests squirrel monkeys may be good models for studying the space adaptation syndrome. Among the wide variety of parameters measured in the rats, most notable was the dramatic loss of muscle mass and increased fragility of long bones. Other interesting rat findings were those of suppressed interferom production by spleen cells, defective release of growth hormone by somatrophs, possible dissociation of circadian pacemakers, changes in hepatic lipid and carbohydrate metabolism, and hypersensitivity of marrow cells to erythropoietin. These results portend a strong role for animals in identifying and elucidating the physiological and anatomical responses of mammals to microgravity.

Animal studies on Spacelab-3

NASA Technical Reports Server (NTRS)

Schatte, C.; Grindeland, R.; Callahan, P.; Funk, G.; Lencki, W.; Berry, W.

1986-01-01

The flight of two squirrel monkeys and 24 rates on Spacelab-3 was the first mission to provide hand-on maintenance on animals in a laboratory environment. With few exceptions, the animals grew and behaved normally, were free of chronic stress, and differed from ground controls only for gravity-dependent parameters. One of the monkeys exhibited symptoms of space sickness similar to those observed in humans, which suggests squirrel monkeys may be good models for studying the space-adaptation syndrome. Among the wide variety of parameters measured in the rats, most notable was the dramatic loss of muscle mass and increased fragility of long bones. Other interesting rat findings were those of suppressed interferon production by spleen cells, defective release of growth hormone by somatotrophs, possible dissociation of circadian pacemakers, changes in hepatic lipid and carbohydrate metabolism, and hypersensitivity of marrow cells to erythopoietin. These results portend a strong role for animals in identifying and elucidating the physiological and anatomical responses of mammals to microgravity.

Molecular Ecology and Natural History of Simian Foamy Virus Infection in Wild-Living Chimpanzees

PubMed Central

Liu, Weimin; Worobey, Michael; Li, Yingying; Keele, Brandon F.; Bibollet-Ruche, Frederic; Guo, Yuanyuan; Goepfert, Paul A.; Santiago, Mario L.; Ndjango, Jean-Bosco N.; Neel, Cecile; Clifford, Stephen L.; Sanz, Crickette; Kamenya, Shadrack; Wilson, Michael L.; Pusey, Anne E.; Gross-Camp, Nicole; Boesch, Christophe; Smith, Vince; Zamma, Koichiro; Huffman, Michael A.; Mitani, John C.; Watts, David P.; Peeters, Martine; Shaw, George M.; Switzer, William M.; Sharp, Paul M.; Hahn, Beatrice H.

2008-01-01

Identifying microbial pathogens with zoonotic potential in wild-living primates can be important to human health, as evidenced by human immunodeficiency viruses types 1 and 2 (HIV-1 and HIV-2) and Ebola virus. Simian foamy viruses (SFVs) are ancient retroviruses that infect Old and New World monkeys and apes. Although not known to cause disease, these viruses are of public health interest because they have the potential to infect humans and thus provide a more general indication of zoonotic exposure risks. Surprisingly, no information exists concerning the prevalence, geographic distribution, and genetic diversity of SFVs in wild-living monkeys and apes. Here, we report the first comprehensive survey of SFVcpz infection in free-ranging chimpanzees (Pan troglodytes) using newly developed, fecal-based assays. Chimpanzee fecal samples (n = 724) were collected at 25 field sites throughout equatorial Africa and tested for SFVcpz-specific antibodies (n = 706) or viral nucleic acids (n = 392). SFVcpz infection was documented at all field sites, with prevalence rates ranging from 44% to 100%. In two habituated communities, adult chimpanzees had significantly higher SFVcpz infection rates than infants and juveniles, indicating predominantly horizontal rather than vertical transmission routes. Some chimpanzees were co-infected with simian immunodeficiency virus (SIVcpz); however, there was no evidence that SFVcpz and SIVcpz were epidemiologically linked. SFVcpz nucleic acids were recovered from 177 fecal samples, all of which contained SFVcpz RNA and not DNA. Phylogenetic analysis of partial gag (616 bp), pol-RT (717 bp), and pol-IN (425 bp) sequences identified a diverse group of viruses, which could be subdivided into four distinct SFVcpz lineages according to their chimpanzee subspecies of origin. Within these lineages, there was evidence of frequent superinfection and viral recombination. One chimpanzee was infected by a foamy virus from a Cercopithecus monkey species, indicating cross-species transmission of SFVs in the wild. These data indicate that SFVcpz (i) is widely distributed among all chimpanzee subspecies; (ii) is shed in fecal samples as viral RNA; (iii) is transmitted predominantly by horizontal routes; (iv) is prone to superinfection and recombination; (v) has co-evolved with its natural host; and (vi) represents a sensitive marker of population structure that may be useful for chimpanzee taxonomy and conservation strategies. PMID:18604273

New Animal Model Could Boost Research on AIDS Drugs and Vaccines | Poster

Cancer.gov

By Frank Blanchard, Staff Writer, and Jeff Lifson, Guest Writer In a research milestone reported in the June 20 issue of the journal Science, scientists have developed a minimally modified version of HIV-1, the virus that causes AIDS in infected humans, that is capable of causing progressive infection and AIDS in monkeys. The advance should help create more authentic animal

Establishment of an In Vitro Assay for Assessing the Effects of Drugs on the Liver Stages of Plasmodium vivax Malaria

DTIC Science & Technology

2010-06-01

Materials and Methods Pv spz A chimpanzee at the Yerkes Primate Center, Emory University, Atlanta, GA was infected with Pv (India VII strain) in order to have...a source of Pv gametocytes. This strain of Pv was earlier adapted to infect and grow in various new world monkeys and chimpanzees [23]. Multiple...batches of Anopheles dirus mosquitoes were fed on blood from the infected chimpanzee , and it was documented at Center for Disease Control & Prevention

An electrocorticographic electrode array for simultaneous recording from medial, lateral, and intrasulcal surface of the cortex in macaque monkeys.

PubMed

Fukushima, Makoto; Saunders, Richard C; Mullarkey, Matthew; Doyle, Alexandra M; Mishkin, Mortimer; Fujii, Naotaka

2014-08-15

Electrocorticography (ECoG) permits recording electrical field potentials with high spatiotemporal resolution over a large part of the cerebral cortex. Application of chronically implanted ECoG arrays in animal models provides an opportunity to investigate global spatiotemporal neural patterns and functional connectivity systematically under various experimental conditions. Although ECoG is conventionally used to cover the gyral cortical surface, recent studies have shown the feasibility of intrasulcal ECoG recordings in macaque monkeys. Here we developed a new ECoG array to record neural activity simultaneously from much of the medial and lateral cortical surface of a single hemisphere, together with the supratemporal plane (STP) of the lateral sulcus in macaque monkeys. The ECoG array consisted of 256 electrodes for bipolar recording at 128 sites. We successfully implanted the ECoG array in the left hemisphere of three rhesus monkeys. The electrodes in the auditory and visual cortex detected robust event related potentials to auditory and visual stimuli, respectively. Bipolar recording from adjacent electrode pairs effectively eliminated chewing artifacts evident in monopolar recording, demonstrating the advantage of using the ECoG array under conditions that generate significant movement artifacts. Compared with bipolar ECoG arrays previously developed for macaque monkeys, this array significantly expands the number of cortical target areas in gyral and intralsulcal cortex. This new ECoG array provides an opportunity to investigate global network interactions among gyral and intrasulcal cortical areas. Published by Elsevier B.V.

Biomechanical Changes in the Sclera of Monkey Eyes Exposed to Chronic IOP Elevations

PubMed Central

Girard, Michaël J. A.; Suh, J.-K. Francis; Bottlang, Michael; Burgoyne, Claude F.

2011-01-01

Purpose. To characterize scleral biomechanics in both eyes of eight monkeys in which chronic intraocular pressure (IOP) elevation was induced in one eye. Methods. Each posterior sclera was mounted on a pressurization apparatus, IOP was elevated from 5 to 45 mm Hg while the 3D displacements of the scleral surface were measured by speckle interferometry. Finite element (FE) models of each scleral shell were constructed that incorporated stretch-induced stiffening and multidirectionality of the collagen fibers. FE model predictions were then iteratively matched to experimental displacements to extract unique sets of scleral biomechanical properties. Results. For all eyes, the posterior sclera exhibited inhomogeneous, anisotropic, nonlinear biomechanical behavior. Biomechanical changes caused by chronic IOP elevation were complex and specific to each subject. Specifically: (1) Glaucomatous eyes in which the contralateral normal eyes displayed large modulus or thickness were less prone to biomechanical changes; (2) glaucomatous scleral modulus associated with an IOP of 10 mm Hg decreased (when compared with that of the contralateral normal) after minimal chronic IOP elevation; (3) glaucomatous scleral modulus associated with IOPs of 30 and 45 mm Hg increased (when compared with that of the contralateral normal) after moderate IOP elevation; and (4) FE-based estimates of collagen fiber orientation demonstrated no change in the glaucomatous eyes. Conclusions. Significant stiffening of the sclera follows exposure to moderate IOP elevations in most eyes. Scleral hypercompliance may precede stiffening or be a unique response to minimal chronic IOP elevation in some eyes. These biomechanical changes are likely to be the result of scleral extracellular matrix remodeling. PMID:21519033

Effects of Chronic Buspirone Treatment on Cocaine Self-Administration

PubMed Central

Mello, Nancy K; Fivel, Peter A; Kohut, Stephen J; Bergman, Jack

2013-01-01

Cocaine abuse and dependence is a major public health problem that continues to challenge medication-based treatment. Buspirone (Buspar) is a clinically available, non-benzodiazepine anxiolytic medication that acts on both serotonin and dopamine systems. In recent preclinical studies, acute buspirone treatment reduced cocaine self-administration at doses that did not also decrease food-reinforced behavior in rhesus monkeys (Bergman et al, 2012). The present study evaluated the effectiveness of chronic buspirone treatment on self-administration of cocaine and food. Five adult rhesus monkeys (Macaca mulatta) were trained to self-administer cocaine and food during four 1-h daily sessions under a second-order schedule of reinforcement (FR2 [VR 16:S]). Buspirone (0.32 and 0.56 mg/kg/h) was administered intravenously through one lumen of a double-lumen catheter every 20 min for 23 h each day for 7–10 consecutive days. Each buspirone treatment period was followed by saline control treatment until drug- and food-maintained responding returned to baseline levels. Buspirone significantly reduced responding maintained by cocaine, and shifted the dose–effect curve downwards. Buspirone had minimal effects on food-maintained responding. In cocaine discrimination studies, buspirone (0.1–0.32 mg/kg, IM) did not antagonize the discriminative stimulus and rate-altering effects of cocaine in four of six monkeys. These findings indicate that buspirone selectively attenuates the reinforcing effects of cocaine in a nonhuman primate model of cocaine self-administration, and has variable effects on cocaine discrimination. PMID:23072835

[Mechanisms of viral emergence and interspecies transmission: the exemple of simian foamy viruses in Central Africa].

PubMed

Gessain, Antoine

2013-12-01

A large proportion of viral pathogens that have emerged during the last decades in humans are considered to have originated from various animal species. This is well exemplified by several recent epidemics such as those of Nipah, Severe Acute Respiratory Syndrome, Avian flu, Ebola, Monkeypox, and Hantaviruses. After the initial interspecies transmission per se, the viruses can disseminate into the human population through various and distinct mechanisms. Some of them are well characterized and understood, thus allowing a certain level of risk control and prevention. Surprisingly and in contrast, the initial steps that lead to the emergence of several viruses, and of their associated diseases, remain still poorly understood. Epidemiological field studies conducted in certain specific high-risk populations are thus necessary to obtain new insights into the early events of this emergence process. Human infections by simian viruses represent increasing public health concerns. Indeed, by virtue of their genetic andphysiological similarities, non-human primates (NHPs) are considered to be likely the sources of viruses that can infect humans and thus may pose a significant threat to human population. This is well illustrated by retroviruses, which have the ability to cross species, adapt to a new host and sometimes spread within these new species. Sequence comparison and phylogenetic studies have thus clearly showed that the emergence of human immunodeficiency virus type 1 (HIV-1) and HIV-2 in humans have resulted from several independent interspecies transmissions of different SIV types from Chimpanzees and African monkeys (including sooty mangabeys), respectively, probably during the first part of the last century. The situation for Human T cell Lymphotropic virus type 1 (HTLV-1) is, for certain aspects, quite comparable. Indeed, the origin of most HTLV-1 subtypes appears to be linked to interspecies transmission between STLV-1-infected monkeys and humans, followed by variable periods of evolution in the human host. In this review, after an introduction on emerging viruses, we will briefly present the results of a large epidemiological study performed in groups of Bantus and Pygmies living in villages and settlements located in the rain forest of the South region of Cameroon. These populations are living nearby the habitats of several monkeys and apes, often naturally infected by different retroviruses including SIV, STLV and simianfoamy virus. Most of the persons included in this study were hunters of such NHPs, thus at high risk of contact with infected body fluids (blood, saliva,...) during hunting activities. After reviewing the current available data on the discovery, cross-species transmission from monkeys and apes to humans of the simian foamy retroviruses, we will report the results of our study. Such infection is a unique natural model to study the different mechanisms of restriction of retroviral emergence in Humans.

Gene-environment interactions and the neurobiology of social conflict.

PubMed

Suomi, Stephen J

2003-12-01

Recent research has disclosed marked individual differences in biobehavioral responses to social conflicts exhibited by rhesus monkeys across the life span. For example, approximately 5-10% of rhesus monkeys growing up in the wild consistently exhibit impulsive and/or inappropriately aggressive responses to mildly stressful situations throughout development; those same individuals also show chronic deficits in their central serotonin metabolism. These characteristic patterns of biobehavioral response emerge early in life and remain remarkably stable from infancy to adulthood. Laboratory studies have demonstrated that although these characteristics are highly heritable, they are also subject to major modification by specific early experiences, particularly those involving early social attachment relationships. Moreover, genetic and early experience factors can interact, often in dramatic fashion. For example, a specific polymorphism in the serotonin transporter gene is associated with deficits in early neurobehavioral functioning and serotonin metabolism, extreme aggression, and excessive alcohol consumption among monkeys who experienced insecure early attachment relationships, but not in monkeys who developed secure attachment relationships with their mothers during infancy. Because daughters tend to develop the same type of attachment relationships with their own offspring that they experienced with their mothers early in life, such early experiences provide a possible nongenetic mechanism for transmitting these patterns to subsequent generations.

Cognitive performance of juvenile monkeys after chronic fluoxetine treatment.

PubMed

Golub, Mari S; Hackett, Edward P; Hogrefe, Casey E; Leranth, Csaba; Elsworth, John D; Roth, Robert H

2017-08-01

Potential long term effects on brain development are a concern when drugs are used to treat depression and anxiety in childhood. In this study, male juvenile rhesus monkeys (three-four years of age) were dosed with fluoxetine or vehicle (N=16/group) for two years. Histomorphometric examination of cortical dendritic spines conducted after euthanasia at one year postdosing (N=8/group) suggested a trend toward greater dendritic spine synapse density in prefrontal cortex of the fluoxetine-treated monkeys. During dosing, subjects were trained for automated cognitive testing, and evaluated with a test of sustained attention. After dosing was discontinued, sustained attention, recognition memory and cognitive flexibility were evaluated. Sustained attention was affected by fluoxetine, both during and after dosing, as indexed by omission errors. Response accuracy was not affected by fluoxetine in post-dosing recognition memory and cognitive flexibility tests, but formerly fluoxetine-treated monkeys compared to vehicle controls had more missed trial initiations and choices during testing. Drug treatment also interacted with genetic and environmental variables: MAOA genotype (high- and low transcription rate polymorphisms) and testing location (upper or lower tier of cages). Altered development of top-down cortical regulation of effortful attention may be relevant to this pattern of cognitive test performance after juvenile fluoxetine treatment. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Characterization of Bacteroides forsythus Strains from Cat and Dog Bite Wounds in Humans and Comparison with Monkey and Human Oral Strains

PubMed Central

Hudspeth, M. K.; Gerardo, S. Hunt; Maiden, M. F. J.; Citron, D. M.; Goldstein, E. J. C.

1999-01-01

Bacteroides forsythus strains recovered from cat and dog bite wound infections in humans (n = 3), monkey oral strains (n = 3), and the human oral ATCC 43037 type strain were characterized by using phenotypic characteristics, enzymatic tests, whole cell fatty acid analysis, sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) analysis, PCR fingerprinting, and 16S rDNA (genes coding for rRNA) sequencing. All three bite wound isolates grew on brucella agar supplemented with 5% sheep blood, vitamin K1, and hemin. These strains, unlike the ATCC strain and previously described monkey oral and human clinical strains, did not require N-acetylmuramic acid supplementation for growth as pure cultures. However, their phenotypic characteristics, except for catalase production, were similar to those of previously identified strains. PCR fingerprinting analysis showed differences in band patterns from the ATCC strain. Also, SDS-PAGE and whole cell fatty acid analysis indicated that the dog and cat bite wound strains were similar but not identical to the human B. forsythus ATCC 43037 type strain and the monkey oral strains. The rDNA sequence analysis indicated that the three bite wound isolates had 99.93% homology with each other and 98.9 and 99.22% homology with the human ATCC 43037 and monkey oral strains, respectively. These results suggest that there are host-specific variations within each group. PMID:10325363

Histopathology of Incidental Findings in Cynomolgus Monkeys (Macaca Fascicularis) Used in Toxicity Studies

PubMed Central

Sato, Junko; Doi, Takuya; Kanno, Takeshi; Wako, Yumi; Tsuchitani, Minoru; Narama, Isao

2012-01-01

The purpose of our publication is to widely communicate pictures of spontaneous findings occurring in cynomolgus monkeys. Focal lymphoplasmacytic infiltration is commonly seen in the general organs. The frequency and severity of these lesions may be influenced by the administration of drugs with an effect on the immune system. Lymphoplasmacytic infiltration in the lamina propria of the stomach is also frequently seen in cynomolgus monkeys, and it is caused mainly by a Helicobacter pylori infection. Various degrees of brown pigments are observed in various organs, and it is possible to distinguish the material of the pigments by its morphological features and site. A focal/segmental glomerular lesion is occasionally seen in a section of the kidney, and the minimal lesion has no influence on the urinalysis. We showed the common glomerular lesions in HE-stained sections, as well as in PAM- or PAS-stained sections, for understanding the details. Young and pubertal monkeys are usually used in toxicity studies; therefore, understanding various maturation stages of the genital system is important. In particular, the female genital system needs to be understood in the morphology, because their cyclic changes are different from other laboratory animals. Thus, we present the normal features of the cyclic changes of the female genital organs. Furthermore, we provide more information on spontaneous findings in cynomolgus monkeys for exact diagnoses in toxicity studies. PMID:22481861

Assessing chronic exposure to fumonisin mycotoxins: the use of hair as a suitable noninvasive matrix.

PubMed

Sewram, V; Nair, J J; Nieuwoudt, T W; Gelderblom, W C; Marasas, W F; Shephard, G S

2001-09-01

This study describes for the first time the accumulation of measurable levels of fumonisin mycotoxins in the hair of nonhuman primates (vervet monkeys, Cercopithecus aethiops) and rats exposed to contaminated feed. Hair was subjected to reflux with methanol, and the resulting extract was cleaned up on strong anion exchange (SAX) and C18 solid-phase sorbents. Fumonisins FB1, FB2, and FB3 as well as their hydrolysis products commonly known as aminopolyols, AP1 and AP2, were detected in monkey hair using high-performance liquid chromatography coupled to electrospray ionization mass spectrometry (HPLC-ESI-MS). Despite matrix interferences, the two-stage mass spectrometric process (MS-MS) yielded product ion mass spectra, which served as diagnostic indicators thus providing unequivocal identification of FB1, FB2, and FB3 as well as AP1 and AP2. In vervet monkeys, the levels of exposure related well to the levels of toxin detected in hair, and levels as high as 5.98 mg FB1, 33.77 mg FB1, and 65.93 mg FB1/kg of hair were found in monkeys receiving control, low-dose, and high-dose contaminated diets, respectively. Hair was also analyzed from rats given either single gavage doses of 1 and 10 mg FB1/kg body weight or contaminated feed (50 mg FB1/kg), resulting in an exposure of approximately 4.25 mg FB1/kg body weight/day based on the measured daily feed intake. Analysis of rat hair over a four-week period indicated that mean levels up to 34.50 mg/kg and 42.20 mg/kg were detectable by the fourth week in the rats treated by gavage (10 mg FB1/kg body weight) and those receiving contaminated feed, respectively. This relationship indicates that hair can provide an easily applicable non-invasive matrix for assessing chronic exposure to fumonisin mycotoxins.

IMMUNOTOXICOLOGY: THIRTY YEARS AND COUNTING

EPA Science Inventory

The science of immunotoxicology arguably began in the early 1970s, following the recognition of increased sensitivity to infection following exposure of test species, including guinea pigs, [1] mice, [2, 3] rats, [4] ducks, [5] hamsters and monkeys [6] to various xenobiotics. Re...

Analysis of the cross-talk of Epstein–Barr virus-infected B cells with T cells in the marmoset

PubMed Central

Dunham, Jordon; van Driel, Nikki; Eggen, Bart JL; Paul, Chaitali; ‘t Hart, Bert A; Laman, Jon D; Kap, Yolanda S

2017-01-01

Despite the well-known association of Epstein–Barr virus (EBV), a lymphocryptovirus (LCV), with multiple sclerosis, a clear pathogenic role for disease progression has not been established. The translationally relevant experimental autoimmune encephalomyelitis (EAE) model in marmoset monkeys revealed that LCV-infected B cells have a central pathogenic role in the activation of T cells that drive EAE progression. We hypothesized that LCV-infected B cells induce T-cell functions relevant for EAE progression. In the current study, we examined the ex vivo cross-talk between lymph node mononuclear cells (MNCs) from EAE marmosets and (semi-) autologous EBV-infected B-lymphoblastoid cell lines (B-LCLs). Results presented here demonstrate that infection with EBV B95-8 has a strong impact on gene expression profile of marmoset B cells, particularly those involved with antigen processing and presentation or co-stimulation to T cells. At the cellular level, we observed that MNC co-culture with B-LCLs induced decrease of CCR7 expression on T cells from EAE responder marmosets, but not in EAE monkeys without clinically evident disease. B-LCL interaction with T cells also resulted in significant loss of CD27 expression and reduced expression of IL-23R and CCR6, which coincided with enhanced IL-17A production. These results highlight the profound impact that EBV-infected B-LCL cells can have on second and third co-stimulatory signals involved in (autoreactive) T-cell activation. PMID:28243437

Pathogenesis of Ebola Hemorrhagic Fever in Cynomolgus Macaques

DTIC Science & Technology

2003-12-01

Pathogenesis of Ebola Hemorrhagic Fever in Cynomolgus Macaques Evidence that Dendritic Cells Are Early and Sustained Targets of Infection Thomas W...is known about the development of EBOV hemorrhagic fever . In the present study, 21 cynomol- gus monkeys were experimentally infected with EBOV and...Am J Pathol 2003, 163:2347–2370) Among viruses causing hemorrhagic fever (HF), and among emerging infectious diseases with global impact in general

Computational and empirical studies predict Mycobacterium tuberculosis-specific T cells as a biomarker for infection outcome

DOE PAGES

Marino, Simeone; Gideon, Hannah P.; Gong, Chang; ...

2016-04-11

Identifying biomarkers for tuberculosis (TB) is an ongoing challenge in developing immunological correlates of infection outcome and protection. Biomarker discovery is also necessary for aiding design and testing of new treatments and vaccines. To effectively predict biomarkers for infection progression in any disease, including TB, large amounts of experimental data are required to reach statistical power and make accurate predictions. We took a two-pronged approach using both experimental and computational modeling to address this problem. We first collected 200 blood samples over a 2-year period from 28 non-human primates (NHP) infected with a low dose of Mycobacterium tuberculosis. We identifiedmore » T cells and the cytokines that they were producing (single and multiple) from each sample along with monkey status and infection progression data. Machine learning techniques were used to interrogate the experimental NHP datasets without identifying any potential TB biomarker. In parallel, we used our extensive novel NHP datasets to build and calibrate a multi-organ computational model that combines what is occurring at the site of infection (e.g., lung) at a single granuloma scale with blood level readouts that can be tracked in monkeys and humans. We then generated a large in silico repository of in silico granulomas coupled to lymph node and blood dynamics and developed an in silico tool to scale granuloma level results to a full host scale to identify what best predicts Mycobacterium tuberculosis (Mtb) infection outcomes. The analysis of in silico blood measures identifies Mtb-specific frequencies of effector T cell phenotypes at various time points post infection as promising indicators of infection outcome. As a result, we emphasize that pairing wetlab and computational approaches holds great promise to accelerate TB biomarker discovery.« less

Computational and empirical studies predict Mycobacterium tuberculosis-specific T cells as a biomarker for infection outcome

DOE Office of Scientific and Technical Information (OSTI.GOV)

Marino, Simeone; Gideon, Hannah P.; Gong, Chang

Identifying biomarkers for tuberculosis (TB) is an ongoing challenge in developing immunological correlates of infection outcome and protection. Biomarker discovery is also necessary for aiding design and testing of new treatments and vaccines. To effectively predict biomarkers for infection progression in any disease, including TB, large amounts of experimental data are required to reach statistical power and make accurate predictions. We took a two-pronged approach using both experimental and computational modeling to address this problem. We first collected 200 blood samples over a 2-year period from 28 non-human primates (NHP) infected with a low dose of Mycobacterium tuberculosis. We identifiedmore » T cells and the cytokines that they were producing (single and multiple) from each sample along with monkey status and infection progression data. Machine learning techniques were used to interrogate the experimental NHP datasets without identifying any potential TB biomarker. In parallel, we used our extensive novel NHP datasets to build and calibrate a multi-organ computational model that combines what is occurring at the site of infection (e.g., lung) at a single granuloma scale with blood level readouts that can be tracked in monkeys and humans. We then generated a large in silico repository of in silico granulomas coupled to lymph node and blood dynamics and developed an in silico tool to scale granuloma level results to a full host scale to identify what best predicts Mycobacterium tuberculosis (Mtb) infection outcomes. The analysis of in silico blood measures identifies Mtb-specific frequencies of effector T cell phenotypes at various time points post infection as promising indicators of infection outcome. As a result, we emphasize that pairing wetlab and computational approaches holds great promise to accelerate TB biomarker discovery.« less

Number of Grooming Partners Is Associated with Hookworm Infection in Wild Vervet Monkeys (Chlorocebus aethiops).

PubMed

Wren, Brandi T; Remis, Melissa J; Camp, Joseph W; Gillespie, Thomas R

2016-01-01

There are many known benefits of social grooming among primates, including maintenance of social relationships, removal of ectoparasites, and improved physiological condition. Recently, however, researchers have noted that social grooming and social contact may also present a significant cost by facilitating transmission of some parasites and pathogens. We investigated whether the number of social grooming partners varied based on infection status for gastrointestinal parasites. We used focal animal sampling and continuous recording to collect data on the number of grooming partners for known individual vervet monkeys (Chlorocebus aethiops). We collected non-invasive faecal samples and examined them using faecal flotation, faecal sedimentation, and immunofluorescence microscopy. We detected 6 parasites: Trichuris sp. (92%), hookworm (71%), spirurids (68%), Oesophagostomum sp. (84%), Strongyloides sp. (24%), and Entamoeba coli (92%). The number of grooming partners varied significantly based on infection with hookworm and sex. No significant relationships were detected for other parasites. Associations between host behavioural variation and some parasite taxa (specifically Trichuris, Oesophagostomum, and Entamoeba spp.) were impossible to explore due to an extremely high prevalence among hosts. This is the first report that we are aware of that has detected an association between social grooming behaviours and infection with hookworm. © 2016 S. Karger AG, Basel.

Behavioral changes from chronic exposure to pesticides used in aerial application : effects of Phosdrin on the performance of monkeys and pigeons on variable interval reinforcement schedules.

DOT National Transportation Integrated Search

1972-08-01

The need for study of behavioral difficulties resulting from exposure to pesticides is based upon reports of behavioral difficulties in aerial applicators following organophosphate poisoning and is underscored by a recent plane crash of a cropduster ...

The natural history of violence.

PubMed Central

Russell, C; Russell, W M

1979-01-01

In the past, human violence was associated with food shortage, but recently it has increased even in relatively well-fed societies. The reason appears from studies of monkeys under relaxed, spacious conditions and under crowding stress. Uncrowded monkeys have unaggressive leaders, rarely quarrel, and protect females and young. Crowded monkeys (even well-fed) have brutal bosses, often quarrel, and wound and kill each other, including females and young. Crowding has similar behaviour effects on other mammals, with physiological disturbances including greater susceptibility to infections. All this appears to be a regular response to overpopulation, reducing the population before it has depleted its natural resources. Human beings, like monkeys and other mammals, need ample space, and become more violent when crowded. Human history is marked by population cycles: population outgrows resources, the resulting violence, stress and disease mortality cuts down the population, leading to a relief period of social and cultural progress, till renewed population growth produces the next crisis. The modern population crisis is world-wide, and explains the increase of violence even in well-fed societies. The solution to the problem of violence is to substitute voluntary birth control for involuntary death control, and bring about relaxed conditions for a reduced world population. PMID:114662

Choriodecidual Group B Streptococcal Inoculation Induces Fetal Lung Injury without Intra-Amniotic Infection and Preterm Labor in Macaca nemestrina

PubMed Central

Adams Waldorf, Kristina M.; Gravett, Michael G.; McAdams, Ryan M.; Paolella, Louis J.; Gough, G. Michael; Carl, David J.; Bansal, Aasthaa; Liggitt, H. Denny; Kapur, Raj P.; Reitz, Frederick B.; Rubens, Craig E.

2011-01-01

Background Early events leading to intrauterine infection and fetal lung injury remain poorly defined, but may hold the key to preventing neonatal and adult chronic lung disease. Our objective was to establish a nonhuman primate model of an early stage of chorioamnionitis in order to determine the time course and mechanisms of fetal lung injury in utero. Methodology/Principal Findings Ten chronically catheterized pregnant monkeys (Macaca nemestrina) at 118–125 days gestation (term = 172 days) received one of two treatments: 1) choriodecidual and intra-amniotic saline (n = 5), or 2) choriodecidual inoculation of Group B Streptococcus (GBS) 1×106 colony forming units (n = 5). Cesarean section was performed regardless of labor 4 days after GBS or 7 days after saline infusion to collect fetal and placental tissues. Only two GBS animals developed early labor with no cervical change in the remaining animals. Despite uterine quiescence in most cases, blinded review found histopathological evidence of fetal lung injury in four GBS animals characterized by intra-alveolar neutrophils and interstitial thickening, which was absent in controls. Significant elevations of cytokines in amniotic fluid (TNF-α, IL-8, IL-1β, IL-6) and fetal plasma (IL-8) were detected in GBS animals and correlated with lung injury (p<0.05). Lung injury was not directly caused by GBS, because GBS was undetectable in amniotic fluid (∼10 samples tested/animal), maternal and fetal blood by culture and polymerase chain reaction. In only two cases was GBS cultured from the inoculation site in low numbers. Chorioamnionitis occurred in two GBS animals with lung injury, but two others with lung injury had normal placental histology. Conclusions/Significance A transient choriodecidual infection can induce cytokine production, which is associated with fetal lung injury without overt infection of amniotic fluid, chorioamnionitis or preterm labor. Fetal lung injury may, thus, occur silently without symptoms and before the onset of the fetal systemic inflammatory response syndrome. PMID:22216148

The Effects of Chronic Alcohol Self-Administration on Serotonin-1A Receptor Binding in Nonhuman Primates

PubMed Central

Hillmer, Ansel T.; Wooten, Dustin W.; Tudorascu, Dana L.; Barnhart, Todd E.; Ahlers, Elizabeth O.; Resch, Leslie M.; Larson, Julie A.; Converse, Alexander K.; Moore, Colleen F.; Schneider, Mary L.; Christian, Bradley T.

2014-01-01

Background Previous studies have found interrelationships between the serotonin system and alcohol self-administration. The goal of this work was to directly observe in vivo effects of chronic ethanol self-administration on serotonin 5-HT1A receptor binding with [18F]mefway PET neuroimaging in rhesus monkeys. Subjects were first imaged alcohol-naïve and again during chronic ethanol self-administration to quantify changes in 5-HT1A receptor binding. Methods Fourteen rhesus monkey subjects (10.7-12.8 years) underwent baseline [18F]mefway PET scans prior to alcohol exposure. Subjects then drank gradually increasing ethanol doses over four months as an induction period, immediately followed by at least nine months ad libidum ethanol access. A post [18F]mefway PET scan was acquired during the final three months of ad libidum ethanol self-administration. 5-HT1A receptor binding was assayed with binding potential (BPND) using the cerebellum as a reference region. Changes in 5-HT1A binding during chronic ethanol self-administration were examined. Relationships of binding metrics with daily ethanol self-administration were also assessed. Results Widespread increases in 5-HT1A binding were observed during chronic ethanol self-administration, independent of the amount of ethanol consumed. A positive correlation between 5-HT1A binding in the raphe nuclei and average daily ethanol self-administration was also observed, indicating that baseline 5-HT1A binding in this region predicted drinking levels. Conclusions The increase in 5-HT1A binding levels during chronic ethanol self-administration demonstrates an important modulation of the serotonin system due to chronic alcohol exposure. Furthermore, the correlation between 5-HT1A binding in the raphe nuclei and daily ethanol self-administration indicates a relationship between the serotonin system and alcohol self-administration. PMID:25220896

Decrease in health-related quality of life associated with awareness of hepatitis C virus infection among people who inject drugs in Scotland.

PubMed

McDonald, Scott A; Hutchinson, Sharon J; Palmateer, Norah E; Allen, Elizabeth; Cameron, Sheila O; Goldberg, David J; Taylor, Avril

2013-03-01

Chronic hepatitis C virus (HCV) infection can significantly reduce health-related quality of life (QoL), but it is not clear if reduction is associated with the infection or with being aware of one's infection status. Understanding the impact of a HCV diagnosis on QoL is essential to inform decision-making regarding screening/testing and treatment. Using a cross-sectional design, we assessed QoL in 2898 people who inject drugs (PWID), surveyed in Scotland during 2010 using EQ-5D. Multifactorial regression compared self-reported QoL between PWID who were (i) chronically HCV-infected and aware of their infected status, (ii) chronically HCV-infected but unaware, and (iii) not chronically infected. Median time since onset of injecting was 10years; not chronically infected PWID were younger and had shorter injecting careers than chronically infected PWID. Median EQ-5D was highest for the not chronically infected and the chronic/unaware groups (0.73) compared with the chronic/aware group (0.66). After adjustment for demographic and behavioural co-factors, QoL was significantly reduced in chronic/aware compared with chronic/unaware PWID (adjusted B=-0.09, p=0.005); there was no evidence for a difference in QoL between not chronically infected and chronic/unaware PWID (adjusted B=-0.03, p=0.13). Awareness of one's chronic HCV status was associated with reduced health-related QoL, but there was no evidence for further reduction attributable to chronic infection itself after adjusting for important covariate differences. Copyright © 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

An electrocorticographic electrode array for simultaneous recording from medial, lateral, and intrasulcal surface of the cortex in macaque monkeys

PubMed Central

Fukushima, Makoto; Saunders, Richard C.; Mullarkey, Matthew; Doyle, Alexandra M.; Mishkin, Mortimer; Fujii, Naotaka

2014-01-01

Background Electrocorticography (ECoG) permits recording electrical field potentials with high spatiotemporal resolution over a large part of the cerebral cortex. Application of chronically implanted ECoG arrays in animal models provides an opportunity to investigate global spatiotemporal neural patterns and functional connectivity systematically under various experimental conditions. Although ECoG is conventionally used to cover the gyral cortical surface, recent studies have shown the feasibility of intrasulcal ECoG recordings in macaque monkeys. New Method Here we developed a new ECoG array to record neural activity simultaneously from much of the medial and lateral cortical surface of a single hemisphere, together with the supratemporal plane (STP) of the lateral sulcus in macaque monkeys. The ECoG array consisted of 256 electrodes for bipolar recording at 128 sites. Results We successfully implanted the ECoG array in the left hemisphere of three rhesus monkeys. The electrodes in the auditory and visual cortex detected robust event related potentials to auditory and visual stimuli, respectively. Bipolar recording from adjacent electrode pairs effectively eliminated chewing artifacts evident in monopolar recording, demonstrating the advantage of using the ECoG array under conditions that generate significant movement artifacts. Comparison with Existing Methods Compared with bipolar ECoG arrays previously developed for macaque monkeys, this array significantly expands the number of cortical target areas in gyral and intralsulcal cortex. Conclusions This new ECoG array provides an opportunity to investigate global network interactions among gyral and intrasulcal cortical areas. PMID:24972186

One-trial memory for object-place associations after separate lesions of hippocampus and posterior parahippocampal region in the monkey.

PubMed

Malkova, Ludise; Mishkin, Mortimer

2003-03-01

In earlier studies of one-trial spatial memory in monkeys (Parkinson et al., 1988; Angeli et al., 1993), severe and chronic memory impairment for both object-place association and place alone was found after ablation of the hippocampal formation. The results appeared to provide the first clear-cut evidence in the monkey of the essential role of the hippocampus in spatial memory, but that interpretation neglected the inclusion in the lesion of the underlying posterior parahippocampal region. To determine the separate contributions of the hippocampus and posterior parahippocampal region to these spatial forms of one-trial memory, we trained 10 rhesus monkeys, as before, to remember the spatial positions of either two different trial-unique objects overlying two of the wells in a three-well test tray (object-place trials) or simply two of the three wells (place trials). Six of the monkeys then received ibotenic acid lesions restricted to the hippocampal formation (group H), and the four others received selective ablations of the posterior parahippocampal region (group P), comprising mainly parahippocampal cortex, parasubiculum, and presubiculum. Group H was found to be completely unaffected postoperatively on both types of trials, whereas group P sustained an impairment on both types equal in magnitude to that observed after the combined lesions in the original studies. Thus, contrary to the previous interpretation, one-trial memory for object-place association and, perhaps more fundamentally, one-trial memory for two different places appear to be critically dependent not on the hippocampal formation but rather on the posterior parahippocampal region.

Lorcaserin Reduces the Discriminative Stimulus and Reinforcing Effects of Cocaine in Rhesus Monkeys.

PubMed

Collins, Gregory T; Gerak, Lisa R; Javors, Martin A; France, Charles P

2016-01-01

Cocaine abuse and obesity are serious public health problems, and studies suggest that both dopamine and serotonin systems are involved in regulating the consumption of drugs and food. Lorcaserin has serotonin (5-HT)2C receptor agonist actions, is approved by the U.S. Food and Drug Administration for treating obesity, and might be effective for treating cocaine abuse. These studies characterized the pharmacokinetic and behavioral profiles of lorcaserin (intragastric administration) and determined the effectiveness of lorcaserin to alter discriminative stimulus and reinforcing effects of cocaine (intravenous administration) in rhesus monkeys. Administered acutely, lorcaserin dose-dependently increased the occurrence of yawning while decreasing spontaneous activity and operant responding for food. These effects appeared within 30-60 minutes of administration and began to dissipate by 240 minutes, a time course closely matching plasma concentrations of lorcaserin. In monkeys discriminating cocaine from saline, lorcaserin alone did not occasion cocaine-appropriate responding but shifted the cocaine dose-response curve to the right and down in two of three monkeys. When administered acutely, lorcaserin dose-dependently decreased the rate at which monkeys responded for infusions of cocaine. When administered chronically, 3.2 mg/kg lorcaserin reduced the rate of cocaine-maintained responding by 50% for the duration of a 14-day treatment period. Together, these results show that lorcaserin attenuates the discriminative stimulus effects of cocaine after acute administration and the reinforcing effects of cocaine after acute and repeated administration, consistent with the view that it might have utility in treating cocaine abuse. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

Lorcaserin Reduces the Discriminative Stimulus and Reinforcing Effects of Cocaine in Rhesus Monkeys

PubMed Central

Collins, Gregory T.; Gerak, Lisa R.; Javors, Martin A.

2016-01-01

Cocaine abuse and obesity are serious public health problems, and studies suggest that both dopamine and serotonin systems are involved in regulating the consumption of drugs and food. Lorcaserin has serotonin (5-HT)2C receptor agonist actions, is approved by the U.S. Food and Drug Administration for treating obesity, and might be effective for treating cocaine abuse. These studies characterized the pharmacokinetic and behavioral profiles of lorcaserin (intragastric administration) and determined the effectiveness of lorcaserin to alter discriminative stimulus and reinforcing effects of cocaine (intravenous administration) in rhesus monkeys. Administered acutely, lorcaserin dose-dependently increased the occurrence of yawning while decreasing spontaneous activity and operant responding for food. These effects appeared within 30–60 minutes of administration and began to dissipate by 240 minutes, a time course closely matching plasma concentrations of lorcaserin. In monkeys discriminating cocaine from saline, lorcaserin alone did not occasion cocaine-appropriate responding but shifted the cocaine dose-response curve to the right and down in two of three monkeys. When administered acutely, lorcaserin dose-dependently decreased the rate at which monkeys responded for infusions of cocaine. When administered chronically, 3.2 mg/kg lorcaserin reduced the rate of cocaine-maintained responding by 50% for the duration of a 14-day treatment period. Together, these results show that lorcaserin attenuates the discriminative stimulus effects of cocaine after acute administration and the reinforcing effects of cocaine after acute and repeated administration, consistent with the view that it might have utility in treating cocaine abuse. PMID:26534942

A Brain-Machine Interface Instructed by Direct Intracortical Microstimulation

PubMed Central

O'Doherty, Joseph E.; Lebedev, Mikhail A.; Hanson, Timothy L.; Fitzsimmons, Nathan A.; Nicolelis, Miguel A. L.

2009-01-01

Brain–machine interfaces (BMIs) establish direct communication between the brain and artificial actuators. As such, they hold considerable promise for restoring mobility and communication in patients suffering from severe body paralysis. To achieve this end, future BMIs must also provide a means for delivering sensory signals from the actuators back to the brain. Prosthetic sensation is needed so that neuroprostheses can be better perceived and controlled. Here we show that a direct intracortical input can be added to a BMI to instruct rhesus monkeys in choosing the direction of reaching movements generated by the BMI. Somatosensory instructions were provided to two monkeys operating the BMI using either: (a) vibrotactile stimulation of the monkey's hands or (b) multi-channel intracortical microstimulation (ICMS) delivered to the primary somatosensory cortex (S1) in one monkey and posterior parietal cortex (PP) in the other. Stimulus delivery was contingent on the position of the computer cursor: the monkey placed it in the center of the screen to receive machine–brain recursive input. After 2 weeks of training, the same level of proficiency in utilizing somatosensory information was achieved with ICMS of S1 as with the stimulus delivered to the hand skin. ICMS of PP was not effective. These results indicate that direct, bi-directional communication between the brain and neuroprosthetic devices can be achieved through the combination of chronic multi-electrode recording and microstimulation of S1. We propose that in the future, bidirectional BMIs incorporating ICMS may become an effective paradigm for sensorizing neuroprosthetic devices. PMID:19750199

Reduced cortical innervation of the subthalamic nucleus in MPTP-treated parkinsonian monkeys

PubMed Central

Mathai, Abraham; Ma, Yuxian; Paré, Jean-Francois; Villalba, Rosa M.; Wichmann, Thomas

2015-01-01

The striatum and the subthalamic nucleus are the main entry points for cortical information to the basal ganglia. Parkinson’s disease affects not only the function, but also the morphological integrity of some of these inputs and their synaptic targets in the basal ganglia. Significant morphological changes in the cortico-striatal system have already been recognized in patients with Parkinson’s disease and in animal models of the disease. To find out whether the primate cortico-subthalamic system is also subject to functionally relevant morphological alterations in parkinsonism, we used a combination of light and electron microscopy anatomical approaches and in vivo electrophysiological methods in monkeys rendered parkinsonian following chronic exposure to low doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). At the light microscopic level, the density of vesicular glutamate transporter 1-positive (i.e. cortico-subthalamic) profiles in the dorsolateral part of the subthalamic nucleus (i.e. its sensorimotor territory) was 26.1% lower in MPTP-treated parkinsonian monkeys than in controls. These results were confirmed by electron microscopy studies showing that the number of vesicular glutamate transporter 1-positive terminals and of axon terminals forming asymmetric synapses in the dorsolateral subthalamic nucleus was reduced by 55.1% and 27.9%, respectively, compared with controls. These anatomical findings were in line with in vivo electrophysiology data showing a 60% reduction in the proportion of pallidal neurons that responded to electrical stimulation of the cortico-subthalamic system in parkinsonian monkeys. These findings provide strong evidence for a partial loss of the hyperdirect cortico-subthalamic projection in MPTP-treated parkinsonian monkeys. PMID:25681412

Effective treatment with a tetrandrine/chloroquine combination for chloroquine-resistant falciparum malaria in Aotus monkeys

PubMed Central

2013-01-01

Background In vitro evidence indicates that tetrandrine (TT) can potentiate the action of chloroquine 40-fold against choloquine-resistant Plasmodium falciparum. The key question emanating from that study is “would tetrandine and chloroquine be highly effective in a live Aotus monkey model with chloroquine-resistant parasites”. This study was designed to closely mimic the pharmacological/anti-malarial activity in man. Methods The Vietnam Smith/RE strain of P. falciparum, which is chloroquine-resistant was used in this study. Previous experimental procedures were followed. Panamanian owl monkeys (Aotus) were inoculated with 5×106 erythrocytes parasitized with the CQ-resistant strain of P. falciparum. Oral drug treatment was with CQ (20 mg/kg) and/or tetrandrine at 15 mg/Kg, 30 mg/Kg or 60 mg/Kg or 25 mg/Kg depending on experimental conditions. Results and Discussion Parasitaemia was cleared rapidly with CQ and TT while CQ treatment alone was ineffective. Recrudescence of malaria occurred after seven days post-infection. However, four animals were treated orally with TT and CQ parasites were cleared. It is likely that monkeys were cured via a combination of both drug and host immune responses. A single Aotus monkey infected with P. falciparum and untreated with drugs, died. No side effects were observed with these drug treatments. Conclusions This combination of chloroquine and tetrandrine forms the basis of a new attack on chloroquine-resistant malaria - one based upon inhibition of the basis of chloroquine resistance, the multiple drug resistance pump. Previous studies demonstrated that the parasite MDR pump was found on parasite membranes using 3H azidopine photoaffinity labelling. Since MDR-based choloroquine resistance is induced by chloroquine, the basis of the action of tetrandrine is the following: 1) tetrandrine inhibits the MDR pump by stimulating MDR ATPase which limits the energy of the pump by depletion of parasite ATP, 2) tetrandrine blocks the genetic factor which controls the induction of the pump. Therefore, it appears that the parasite cannot outsmart these mechanisms and produce a new mode of resistance. Only time will tell if this is correct. PMID:23547773

Pig model mimicking chronic hepatitis E virus infection in immunocompromised patients to assess immune correlates during chronicity

PubMed Central

Cao, Dianjun; Cao, Qian M.; Subramaniam, Sakthivel; Yugo, Danielle M.; Heffron, C. Lynn; Rogers, Adam J.; Kenney, Scott P.; Tian, Debin; Matzinger, Shannon R.; Overend, Christopher; Catanzaro, Nicholas; LeRoith, Tanya; Wang, Heng; Piñeyro, Pablo; Lindstrom, Nicole; Clark-Deener, Sherrie; Yuan, Lijuan; Meng, Xiang-Jin

2017-01-01

Chronic hepatitis E virus (HEV) infection is a significant clinical problem in immunocompromised individuals such as organ transplant recipients, although the mechanism remains unknown because of the lack of an animal model. We successfully developed a pig model of chronic HEV infection and examined immune correlates leading to chronicity. The conditions of immunocompromised patients were mimicked by treating pigs with an immunosuppressive regimen including cyclosporine, azathioprine, and prednisolone. Immunocompromised pigs infected with HEV progressed to chronicity, because 8/10 drug-treated HEV-infected pigs continued fecal virus shedding beyond the acute phase of infection, whereas the majority (7/10) of mock-treated HEV-infected pigs cleared fecal viral shedding at 8 wk postinfection. During chronic infection, serum levels of the liver enzyme γ-glutamyl transferase and fecal virus shedding were significantly higher in immunocompromised HEV-infected pigs. To identify potential immune correlates of chronic infection, we determined serum levels of cytokines and cell-mediated immune responses in pigs. Results showed that HEV infection of immunocompromised pigs reduced the serum levels of Th1 cytokines IL-2 and IL-12, and Th2 cytokines IL-4 and IL-10, particularly during the acute phase of infection. Furthermore IFN-γ–specific CD4+ T-cell responses were reduced in immunocompromised pigs during the acute phase of infection, but TNF-α–specific CD8+ T-cell responses increased during the chronic phase of infection. Thus, active suppression of cell-mediated immune responses under immunocompromised conditions may facilitate the establishment of chronic HEV infection. This pig model will aid in delineating the mechanisms of chronic HEV infection and in developing effective therapeutics against chronic hepatitis E. PMID:28630341

Pig model mimicking chronic hepatitis E virus infection in immunocompromised patients to assess immune correlates during chronicity.

PubMed

Cao, Dianjun; Cao, Qian M; Subramaniam, Sakthivel; Yugo, Danielle M; Heffron, C Lynn; Rogers, Adam J; Kenney, Scott P; Tian, Debin; Matzinger, Shannon R; Overend, Christopher; Catanzaro, Nicholas; LeRoith, Tanya; Wang, Heng; Piñeyro, Pablo; Lindstrom, Nicole; Clark-Deener, Sherrie; Yuan, Lijuan; Meng, Xiang-Jin

2017-07-03

Chronic hepatitis E virus (HEV) infection is a significant clinical problem in immunocompromised individuals such as organ transplant recipients, although the mechanism remains unknown because of the lack of an animal model. We successfully developed a pig model of chronic HEV infection and examined immune correlates leading to chronicity. The conditions of immunocompromised patients were mimicked by treating pigs with an immunosuppressive regimen including cyclosporine, azathioprine, and prednisolone. Immunocompromised pigs infected with HEV progressed to chronicity, because 8/10 drug-treated HEV-infected pigs continued fecal virus shedding beyond the acute phase of infection, whereas the majority (7/10) of mock-treated HEV-infected pigs cleared fecal viral shedding at 8 wk postinfection. During chronic infection, serum levels of the liver enzyme γ-glutamyl transferase and fecal virus shedding were significantly higher in immunocompromised HEV-infected pigs. To identify potential immune correlates of chronic infection, we determined serum levels of cytokines and cell-mediated immune responses in pigs. Results showed that HEV infection of immunocompromised pigs reduced the serum levels of Th1 cytokines IL-2 and IL-12, and Th2 cytokines IL-4 and IL-10, particularly during the acute phase of infection. Furthermore IFN-γ-specific CD4 + T-cell responses were reduced in immunocompromised pigs during the acute phase of infection, but TNF-α-specific CD8 + T-cell responses increased during the chronic phase of infection. Thus, active suppression of cell-mediated immune responses under immunocompromised conditions may facilitate the establishment of chronic HEV infection. This pig model will aid in delineating the mechanisms of chronic HEV infection and in developing effective therapeutics against chronic hepatitis E.

3B11-N, a monoclonal antibody against MERS-CoV, reduces lung pathology in rhesus monkeys following intratracheal inoculation of MERS-CoV Jordan-n3/2012.

PubMed

Johnson, Reed F; Bagci, Ulas; Keith, Lauren; Tang, Xianchun; Mollura, Daniel J; Zeitlin, Larry; Qin, Jing; Huzella, Louis; Bartos, Christopher J; Bohorova, Natasha; Bohorov, Ognian; Goodman, Charles; Kim, Do H; Paulty, Michael H; Velasco, Jesus; Whaley, Kevin J; Johnson, Joshua C; Pettitt, James; Ork, Britini L; Solomon, Jeffrey; Oberlander, Nicholas; Zhu, Quan; Sun, Jiusong; Holbrook, Michael R; Olinger, Gene G; Baric, Ralph S; Hensley, Lisa E; Jahrling, Peter B; Marasco, Wayne A

2016-03-01

Middle East Respiratory Syndrome Coronavirus (MERS-CoV) was identified in 2012 as the causative agent of a severe, lethal respiratory disease occurring across several countries in the Middle East. To date there have been over 1600 laboratory confirmed cases of MERS-CoV in 26 countries with a case fatality rate of 36%. Given the endemic region, it is possible that MERS-CoV could spread during the annual Hajj pilgrimage, necessitating countermeasure development. In this report, we describe the clinical and radiographic changes of rhesus monkeys following infection with 5×10(6) PFU MERS-CoV Jordan-n3/2012. Two groups of NHPs were treated with either a human anti-MERS monoclonal antibody 3B11-N or E410-N, an anti-HIV antibody. MERS-CoV Jordan-n3/2012 infection resulted in quantifiable changes by computed tomography, but limited other clinical signs of disease. 3B11-N treated subjects developed significantly reduced lung pathology when compared to infected, untreated subjects, indicating that this antibody may be a suitable MERS-CoV treatment. Published by Elsevier Inc.

Purification and functional characterization of mucosal IgA from vaccinated and SIV-infected rhesus macaques.

PubMed

Musich, Thomas; Demberg, Thorsten; Morgan, Ian L; Estes, Jacob D; Franchini, Genoveffa; Robert-Guroff, Marjorie

2015-06-01

Vaccine-induced mucosal antibodies are often evaluated using small volumes of secretory fluids. However, fecal matter containing mucosal IgA is abundant. We purified fecal IgA from five SIV-vaccinated and five SIV-infected rhesus macaques by sequential affinity chromatography. The purified IgA was dimeric by native PAGE, contained secretory component, and was analogous to IgA in colostrum and vaginal fluid by western blot. IgA from one infected and four vaccinated animals neutralized H9-derived SIV(mac)251 with IC(50)s as low as 1 μg/mL. Purified IgAs inhibited transcytosis and exhibited phagocytic activity, the latter significantly correlated with SIV(mac)251 Env-specific IgA in the purified samples. Among different affinity resins, peptide M was optimal compared to jacalin, anti-monkey IgA and SSL7 for IgA purification, as confirmed using tandem peptide M/anti-monkey IgA columns. Fecal IgA provided material sufficient for several assays relevant to protective efficacy, and was shown to be multifunctional. Our approach is potentially applicable to human clinical studies. Published by Elsevier Inc.

Abnormal tuning of saccade-related cells in pontine reticular formation of strabismic monkeys.

PubMed

Walton, Mark M G; Mustari, Michael J

2015-08-01

Strabismus is a common disorder, characterized by a chronic misalignment of the eyes and numerous visual and oculomotor abnormalities. For example, saccades are often highly disconjugate. For humans with pattern strabismus, the horizontal and vertical disconjugacies vary with eye position. In monkeys, manipulations that disturb binocular vision during the first several weeks of life result in a chronic strabismus with characteristics that closely match those in human patients. Early onset strabismus is associated with altered binocular sensitivity of neurons in visual cortex. Here we test the hypothesis that brain stem circuits specific to saccadic eye movements are abnormal. We targeted the pontine paramedian reticular formation, a structure that directly projects to the ipsilateral abducens nucleus. In normal animals, neurons in this structure are characterized by a high-frequency burst of spikes associated with ipsiversive saccades. We recorded single-unit activity from 84 neurons from four monkeys (two normal, one exotrope, and one esotrope), while they made saccades to a visual target on a tangent screen. All 24 neurons recorded from the normal animals had preferred directions within 30° of pure horizontal. For the strabismic animals, the distribution of preferred directions was normal on one side of the brain, but highly variable on the other. In fact, 12/60 neurons recorded from the strabismic animals preferred vertical saccades. Many also had unusually weak or strong bursts. These data suggest that the loss of corresponding binocular vision during infancy impairs the development of normal tuning characteristics for saccade-related neurons in brain stem. Copyright © 2015 the American Physiological Society.

Activity of Two Chlorinated Lincomycin Analogues Against Chloroquine-Resistant Falciparum Malaria in Owl Monkeys1

PubMed Central

Powers, Kendall G.; Jacobs, Richard L.

1972-01-01

The chloroquine-resistant Oak Knoll strain of Plasmodium falciparum, recently adapted to the owl monkey (Aotus trivirgatus), was insusceptible to chloroquine therapy. Two chlorinated lincomycin analogues tested in this host-parasite system cured blood-induced infections. Acute infections were treated orally for 7 consecutive days with either 15 or 75 mg of clindamycin hydrochloride (U-21) per kg per day, 10 or 50 mg of N-demethyl-4′-pentyl clindamycin hydrochloride (U-24) per kg per day, or 20 mg of chloroquine base per kg per day. These lincomycin analogues cleared trophozoites from the peripheral blood by the end of the 7-day treatment period. The speed of clearance of parasites was not dose-related, but curative activity appeared dependent upon the amount of drug given as well as the number of daily treatments. The efficacy of U-21 and U-24 is of particular interest since they represent major structural departures from compounds commonly used in the treatment of malaria. PMID:4207758

Activity of two chlorinated lincomycin analogues against chloroquine-resistant falciparum malaria in owl monkeys.

PubMed

Powers, K G; Jacobs, R L

1972-01-01

The chloroquine-resistant Oak Knoll strain of Plasmodium falciparum, recently adapted to the owl monkey (Aotus trivirgatus), was insusceptible to chloroquine therapy. Two chlorinated lincomycin analogues tested in this host-parasite system cured blood-induced infections. Acute infections were treated orally for 7 consecutive days with either 15 or 75 mg of clindamycin hydrochloride (U-21) per kg per day, 10 or 50 mg of N-demethyl-4'-pentyl clindamycin hydrochloride (U-24) per kg per day, or 20 mg of chloroquine base per kg per day. These lincomycin analogues cleared trophozoites from the peripheral blood by the end of the 7-day treatment period. The speed of clearance of parasites was not dose-related, but curative activity appeared dependent upon the amount of drug given as well as the number of daily treatments. The efficacy of U-21 and U-24 is of particular interest since they represent major structural departures from compounds commonly used in the treatment of malaria.

Isolation and characterization of a Brazilian strain of yellow fever virus from an epizootic outbreak in 2009.

PubMed

Jorge, Taissa Ricciardi; Mosimann, Ana Luiza Pamplona; Noronha, Lucia de; Maron, Angela; Duarte Dos Santos, Claudia Nunes

2017-02-01

During a series of epizootics caused by Yellow fever virus in Brazil between 2007 and 2009, a monkey was found dead (May 2009) in a sylvatic area in the State of Paraná. Brain samples from this animal were used for immunohistochemical analysis and isolation of a wild-type strain of YFV. This viral strain was characterized, and sequence analyzes demonstrated that it is closely related with YFV strains of the recently identified subclade 1E of the South American genotype I. Further characterization included indirect-immunofluorescence of different infected cell lines and analysis of the kinetics of virus replication and infectivity inhibition by type I IFN. The generated data contributes to the knowledge of YFV evolution and phylogeny. Additionally, the reagents generated and characterized during this study, such as a panel of monoclonal antibodies, are useful tools for further studies on YFV. Lastly, this case stresses the importance of yellow fever surveillance through sentinel monkeys. Copyright © 2016 Elsevier B.V. All rights reserved.

Partial Molecular Characterization of Two Simian Immunodeficiency Viruses (SIV) from African Colobids: SIVwrc from Western Red Colobus (Piliocolobus badius) and SIVolc from Olive Colobus (Procolobus verus)

PubMed Central

Courgnaud, Valerie; Formenty, Pierre; Akoua-Koffi, Chantal; Noe, Ronald; Boesch, Christophe; Delaporte, Eric; Peeters, Martine

2003-01-01

In order to study primate lentivirus evolution in the Colobinae subfamily, in which only one simian immunodeficiency virus (SIV) has been described to date, we screened additional species from the three different genera of African colobus monkeys for SIV infection. Blood was obtained from 13 West African colobids, and HIV cross-reactive antibodies were observed in 5 of 10 Piliocolobus badius, 1 of 2 Procolobus verus, and 0 of 1 Colobus polykomos specimens. Phylogenetic analyses of partial pol sequences revealed that the new SIVs were more closely related to each other than to the other SIVs and especially did not cluster with the previously described SIVcol from Colobus guereza. This study presents evidence that the three genera of African colobus monkeys are naturally infected with an SIV and indicates also that there was no coevolution between virus and hosts at the level of the Colobinae subfamily. PMID:12477880

Cannabidiol Affects MK-801-Induced Changes in the PPI Learned Response of Capuchin Monkeys (Sapajus spp.).

PubMed

Saletti, Patricia G; Maior, Rafael S; Barros, Marilia; Nishijo, Hisao; Tomaz, Carlos

2017-01-01

There are several lines of evidence indicating a possible therapeutic action of cannabidiol (CBD) in schizophrenia treatment. Studies with rodents have demonstrated that CBD reverses MK-801 effects in prepulse inhibition (PPI) disruption, which may indicate that CBD acts by improving sensorimotor gating deficits. In the present study, we investigated the effects of CBD on a PPI learned response of capuchin monkeys ( Sapajus spp.). A total of seven monkeys were employed in this study. In Experiment 1, we evaluated the CBD (doses of 15, 30, 60 mg/kg, i.p.) effects on PPI. In Experiment 2, the effects of sub-chronic MK-801 (0.02 mg/kg, i.m.) on PPI were challenged by a CBD pre-treatment. No changes in PPI response were observed after CBD-alone administration. However, MK-801 increased the PPI response of our animals. CBD pre-treatment blocked the PPI increase induced by MK-801. Our findings suggest that CBD's reversal of the MK-801 effects on PPI is unlikely to stem from a direct involvement on sensorimotor mechanisms, but may possibly reflect its anxiolytic properties.

Ear infection - chronic

MedlinePlus

Middle ear infection - chronic; Otitis media - chronic; Chronic otitis media; Chronic ear infection ... Chole RA. Chronic otitis media, mastoiditis, and petrositis. In: Flint PW, Haughey BH, Lund V, et al, eds. Cummings Otolaryngology: Head & Neck Surgery . 6th ed. ...

Enhanced Viral Replication and Modulated Innate Immune Responses in Infant Airway Epithelium following H1N1 Infection

PubMed Central

Clay, Candice C.; Reader, J. Rachel; Gerriets, Joan E.; Wang, Theodore T.; Harrod, Kevin S.

2014-01-01

ABSTRACT Influenza is the cause of significant morbidity and mortality in pediatric populations. The contribution of pulmonary host defense mechanisms to viral respiratory infection susceptibility in very young children is poorly understood. As a surrogate to compare mucosal immune responses of infant and adult lungs, rhesus monkey primary airway epithelial cell cultures were infected with pandemic influenza A/H1N1 virus in vitro. Virus replication, cytokine secretion, cell viability, and type I interferon (IFN) pathway PCR array profiles were evaluated for both infant and adult cultures. In comparison with adult cultures, infant cultures showed significantly increased levels of H1N1 replication, reduced alpha interferon (IFN-α) protein synthesis, and no difference in cell death following infection. Age-dependent differences in expression levels of multiple genes associated with the type I IFN pathway were observed in H1N1-infected cultures. To investigate the pulmonary and systemic responses to H1N1 infection in early life, infant monkeys were inoculated with H1N1 by upper airway administration. Animals were monitored for virus and parameters of inflammation over a 14-day period. High H1N1 titers were recovered from airways at day 1, with viral RNA remaining detectable until day 9 postinfection. Despite viral clearance, bronchiolitis and alveolitis persisted at day 14 postinfection; histopathological analysis revealed alveolar septal thickening and intermittent type II pneumocyte hyperplasia. Our overall findings are consistent with the known susceptibility of pediatric populations to respiratory virus infection and suggest that intrinsic developmental differences in airway epithelial cell immune function may contribute to the limited efficacy of host defense during early childhood. IMPORTANCE To the best of our knowledge, this study represents the first report of intrinsic developmental differences in infant airway epithelial cells that may contribute to the increased susceptibility of the host to respiratory virus infections. Despite the global burden of influenza, there are currently no vaccine formulations approved for children <6 months of age. Given the challenges of conducting experimental studies involving pediatric patients, rhesus monkeys are an ideal laboratory animal model to investigate the maturation of pulmonary mucosal immune mechanisms during early life because they are most similar to those of humans with regard to postnatal maturation of the lung structure and the immune system. Thus, our findings are highly relevant to translational medicine, and these data may ultimately lead to novel approaches that enhance airway immunity in very young children. PMID:24741104

Relations among Acute and Chronic Nicotine Administration, Short-Term Memory, and Tactics of Data Analysis

ERIC Educational Resources Information Center

Kangas, Brian D.; Branch, Marc N.

2012-01-01

Emerging evidence suggests that nicotine may enhance short-term memory. Some of this evidence comes from nonhuman primate research using a procedure called delayed matching-to-sample, wherein the monkey is trained to select a comparison stimulus that matches some physical property of a previously presented sample stimulus. Delays between sample…

Intra-nasal infection of macaques with Yellow Fever (YF) vaccine strain 17D: a novel and economical approach for YF vaccination in man.

PubMed

Niedrig, M; Stolte, N; Fuchs, D; Hunsmann, G; Stahl-Hennig, C

1999-03-05

Investigating new and simple application routes for YF vaccine, four groups of 4-6 rhesus monkeys were vaccinated with live attenuated 17D YF-vaccine. In two groups the vaccine was administered either as spray into the oral cavity, or as an encapsulated form directly into the stomach. Only one out of eight animals developed a humoral immune response against 17D. In the third group receiving the vaccine intranasally by spray and in the fourth group serving as control all ten monkeys developed an immune response. From all except one of these seroconverted monkeys virus could be detected either by virus reisolation or RT-PCR. All these animals showed a serological immune response in immunofluorescence and neutralisation test. Parallel to viremia, an increase of neopterin as an unspecified immune activation marker could be demonstrated for these animals. Intra-nasal application of 17D-vaccine seems to be a good alternative to subcutaneous immunisation in mass vaccination campaigns.

Factors Associated with Siman Immunodeficiency Virus Transmission in a Natural African Nonhuman Primate Host in the Wild

PubMed Central

Ma, Dongzhu; Jasinska, Anna J.; Feyertag, Felix; Wijewardana, Viskam; Kristoff, Jan; He, Tianyu; Raehtz, Kevin; Schmitt, Christopher A.; Jung, Yoon; Cramer, Jennifer Danzy; Dione, Michel; Antonio, Martin; Tracy, Russell; Turner, Trudy; Robertson, David L.; Pandrea, Ivona; Freimer, Nelson

2014-01-01

ABSTRACT African green monkeys (AGMs) are naturally infected with simian immunodeficiency virus (SIV) at high prevalence levels and do not progress to AIDS. Sexual transmission is the main transmission route in AGM, while mother-to-infant transmission (MTIT) is negligible. We investigated SIV transmission in wild AGMs to assess whether or not high SIV prevalence is due to differences in mucosal permissivity to SIV (i.e., whether the genetic bottleneck of viral transmission reported in humans and macaques is also observed in AGMs in the wild). We tested 121 sabaeus AGMs (Chlorocebus sabaeus) from the Gambia and found that 53 were SIV infected (44%). By combining serology and viral load quantitation, we identified 4 acutely infected AGMs, in which we assessed the diversity of the quasispecies by single-genome amplification (SGA) and documented that a single virus variant established the infections. We thus show that natural SIV transmission in the wild is associated with a genetic bottleneck similar to that described for mucosal human immunodeficiency virus (HIV) transmission in humans. Flow cytometry assessment of the immune cell populations did not identify major differences between infected and uninfected AGM. The expression of the SIV coreceptor CCR5 on CD4+ T cells dramatically increased in adults, being higher in infected than in uninfected infant and juvenile AGMs. Thus, the limited SIV MTIT in natural hosts appears to be due to low target cell availability in newborns and infants, which supports HIV MTIT prevention strategies aimed at limiting the target cells at mucosal sites. Combined, (i) the extremely high prevalence in sexually active AGMs, (ii) the very efficient SIV transmission in the wild, and (iii) the existence of a fraction of multiparous females that remain uninfected in spite of massive exposure to SIV identify wild AGMs as an acceptable model of exposed, uninfected individuals. IMPORTANCE We report an extensive analysis of the natural history of SIVagm infection in its sabaeus monkey host, the African green monkey species endemic to West Africa. Virtually no study has investigated the natural history of SIV infection in the wild. The novelty of our approach is that we report for the first time that SIV infection has no discernible impact on the major immune cell populations in natural hosts, thus confirming the nonpathogenic nature of SIV infection in the wild. We also focused on the correlates of SIV transmission, and we report, also for the first time, that SIV transmission in the wild is characterized by a major genetic bottleneck, similar to that described for HIV-1 transmission in humans. Finally, we report here that the restriction of target cell availability is a major correlate of the lack of SIV transmission to the offspring in natural hosts of SIVs. PMID:24623416

Relationship of creatine kinase, aspartate aminotransferase, lactate dehydrogenase, and proteinuria to cardiomyopathy in the owl monkey (Aotus vociferans)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gozalo, Alfonso S.; Chavera, Alfonso; Montoya, Enrique J.

2008-02-01

The purpose of this study was to determine serum reference values for crea- tine kinase (CK), aspartate aminotransferase (AST), and lactate dehydroge- nase (LDH) in captive-born and wild-caught owl monkeys to assess their usefulness for diagnosing myocardial disease. Urine samples were also collected and semi-quantitative tests performed. There was no statistically significant difference between CK, AST, and LDH when comparing both groups. However, when comparing monkeys with proteinuria to those without proteinuria, a statistically significant difference in CK value was observed (P = 0.021). In addition, the CK/AST ratio revealed that 29% of the animals included in this study hadmore » values suggesting cardiac infarction. Grossly, cardiac concentric hypertrophy of the left ventricle and small, pitted kidneys were the most common findings. Microscopically, myocardial fibrosis, contraction band necrosis, hypertrophy and hyperplasia of coronary arteries, medium-sized renal arteries, and afferent glomerular arteriolae were the most significant lesions, along with increased mesangial matrix and hypercellularity of glomeruli, Bowman’s capsule, and peritubular space fibroplasia. These findings suggest that CK, AST, and LDH along with urinalysis provide a reliable method for diagnosing cardiomyopathies in the owl monkey. In addition, CK/AST ratio, proteinuria, and the observed histological and ultrastructural changes suggest that Aotus vociferans suffer from arterial hypertension and chronic myocardial infarction.« less

Effects of Monoclonal Antibodies against Nerve Growth Factor on Healthy Bone and Joint Tissues in Mice, Rats, and Monkeys: Histopathologic, Biomarker, and Microcomputed Tomographic Assessments.

PubMed

Gropp, Kathryn E; Carlson, Cathy S; Evans, Mark G; Bagi, Cedo M; Reagan, William J; Hurst, Susan I; Shelton, David L; Zorbas, Mark A

2018-01-01

Tanezumab, an anti-nerve growth factor (NGF) antibody, is in development for management of chronic pain. During clinical trials of anti-NGF antibodies, some patients reported unexpected adverse events requiring total joint replacements, resulting in a partial clinical hold on all NGF inhibitors. Three nonclinical toxicology studies were conducted to evaluate the effects of tanezumab or the murine precursor muMab911 on selected bone and joint endpoints and biomarkers in cynomolgus monkeys, Sprague-Dawley rats, and C57BL/6 mice. Joint and bone endpoints included histology, immunohistochemistry, microcomputed tomography (mCT) imaging, and serum biomarkers of bone physiology. Responses of bone endpoints to tanezumab were evaluated in monkeys at 4 to 30 mg/kg/week for 26 weeks and in rats at 0.2 to 10 mg/kg twice weekly for 28 days. The effects of muMab911 at 10 mg/kg/week for 12 weeks on selected bone endpoints were determined in mice. Tanezumab and muMab911 had no adverse effects on any bone or joint parameter. There were no test article-related effects on bone or joint histology, immunohistochemistry, or structure. Reversible, higher osteocalcin concentrations occurred only in the rat study. No deleterious effects were observed in joints or bones in monkeys, rats, or mice administered high doses of tanezumab or muMab911.

Evaluation of Drug and Vaccine Candidates in the Human Malaria/Aotus Monkey Model

DTIC Science & Technology

1998-03-01

parasitemia, resulting in infection cure without retreatment (10). Evaluation of two oil-soluble derivatives of artemisinin , artemether and arteether...Artelinic acid in Aotus. Artelinic acid an Artemisinin derivative is known to possess in vitro and in vivo antimalarial activity against strains of

Evaluation of the Reinforcing Effect of Quetiapine, Alone and in Combination with Cocaine, in Rhesus Monkeys.

PubMed

Brutcher, Robert E; Nader, Susan H; Nader, Michael A

2016-02-01

There are several case reports of nonmedicinal quetiapine abuse, yet there are very limited preclinical studies investigating quetiapine self-administration. The goal of this study was to investigate the reinforcing effects of quetiapine alone and in combination with intravenous cocaine in monkeys. In experiment 1, cocaine-experienced female monkeys (N = 4) responded under a fixed-ratio (FR) 30 schedule of food reinforcement (1.0-g banana-flavored pellets), and when responding was stable, quetiapine (0.003-0.1 mg/kg per injection) or saline was substituted for a minimum of five sessions; there was a return to food-maintained responding between doses. Next, monkeys were treated with quetiapine (25 mg, by mouth, twice a day) for approximately 30 days, and then the quetiapine self-administration dose-response curve was redetermined. In experiment 2, male monkeys (N = 6) self-administered cocaine under a concurrent FR schedule with food reinforcement (three food pellets) as the alternative to cocaine (0.003-0.3 mg/kg per injection) presentation. Once choice responding was stable, the effects of adding quetiapine (0.03 or 0.1 mg/kg per injection) to the cocaine solution were examined. In experiment 1, quetiapine did not function as a reinforcer, and chronic quetiapine treatment did not alter these effects. In experiment 2, cocaine choice increased in a dose-dependent fashion. The addition of quetiapine to cocaine resulted in increases in low-dose cocaine choice and number of cocaine injections in four monkeys, while not affecting high-dose cocaine preference. Thus, although quetiapine alone does not have abuse potential, there was evidence of enhancement of the reinforcing potency of cocaine. These results suggest that the use of quetiapine in cocaine-addicted patients should be monitored. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

Effects of chronic binge-like ethanol consumption on cocaine self-administration in rhesus monkeys.

PubMed

Czoty, Paul W

2015-08-01

Most cocaine abusers also abuse alcohol, but little is known about interactions that promote co-abuse. These experiments in rhesus monkeys determined the effects of >8 weeks of ethanol (EtOH) consumption on cocaine self-administration (n=6), effects of dopamine (DA) receptor antagonists on cocaine reinforcement (n=3-4 per drug) and the ability of the D2-like DA receptor agonist quinpirole to elicit yawning (n=3). Monkeys self-administered cocaine (0.0-1.0mg/kg/injection, i.v.) under a 300-s fixed-interval schedule and the above-listed variables were measured before EtOH exposure. Next, monkeys consumed a sweetened, 4% EtOH solution in the home cage under binge-like conditions: 1h, 5 days/week with daily intake equaling 2.0g/kg EtOH. After approximately 8 weeks, measures were re-determined, then EtOH drinking was discontinued. Finally, acute effects of EtOH on cocaine self-administration were determined by infusing EtOH (0.0-1.0g/kg. i.v.) prior to cocaine self-administration sessions (n=4). In five of six monkeys, EtOH drinking increased self-administration of low cocaine doses but did not alter reinforcing effects of higher doses. Self-administration returned to baseline after EtOH access was terminated (n=3). Effects of DA receptor antagonists on cocaine self-administration were not consistently altered after EtOH consumption, but the ability of quinpirole to induce yawning was enhanced in two of three monkeys. Acute EtOH infusions only decreased self-administration of lower cocaine doses. Taken together, the data suggest that long-term EtOH exposure can increase sensitivity to cocaine, possibly by increasing D3 receptor sensitivity. Data do not support a role for acute pharmacological interactions in promoting cocaine/EtOH co-abuse. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Lifespan Trajectories of White Matter Changes in Rhesus Monkeys.

PubMed

Kubicki, M; Baxi, M; Pasternak, O; Tang, Y; Karmacharya, S; Chunga, N; Lyall, A E; Rathi, Y; Eckbo, R; Bouix, S; Mortazavi, F; Papadimitriou, G; Shenton, M E; Westin, C F; Killiany, R; Makris, N; Rosene, D L

2018-04-26

Progress in neurodevelopmental brain research has been achieved through the use of animal models. Such models not only help understanding biological changes that govern brain development, maturation and aging, but are also essential for identifying possible mechanisms of neurodevelopmental and age-related chronic disorders, and to evaluate possible interventions with potential relevance to human disease. Genetic relationship of rhesus monkeys to humans makes those animals a great candidate for such models. With the typical lifespan of 25 years, they undergo cognitive maturation and aging that is similar to this observed in humans. Quantitative structural neuroimaging has been proposed as one of the candidate in vivo biomarkers for tracking white matter brain maturation and aging. While lifespan trajectories of white matter changes have been mapped in humans, such knowledge is not available for nonhuman primates. Here, we analyze and model lifespan trajectories of white matter microstructure using in vivo diffusion imaging in a sample of 44 rhesus monkeys. We report quantitative parameters (including slopes and peaks) of lifespan trajectories for 8 individual white matter tracts. We show different trajectories for cellular and extracellular microstructural imaging components that are associated with white matter maturation and aging, and discuss similarities and differences between those in humans and rhesus monkeys, the importance of our findings, and future directions for the field.Significance Statement: Quantitative structural neuroimaging has been proposed as one of the candidate in vivo biomarkers for tracking brain maturation and aging. While lifespan trajectories of structural white matter changes have been mapped in humans, such knowledge is not available for rhesus monkeys. We present here results of the analysis and modeling of the lifespan trajectories of white matter microstructure using in vivo diffusion imaging in a sample of 44 rhesus monkeys (age 4-27). We report and anatomically map lifespan changes related to cellular and extracellular microstructural components that are associated with white matter maturation and aging.

Changes in body temperature of the unanaesthetized monkey produced by sodium and calcium ions perfused through the cerebral ventricles

PubMed Central

Myers, R. D.; Veale, W. L.; Yaksh, T. L.

1971-01-01

1. In the unanaesthetized Rhesus monkey, solutions containing sodium, calcium, potassium or magnesium in excess of the normal concentration of extracellular fluid were perfused from a lateral to the fourth ventricle through chronically implanted cannulae. 2. Sodium (11·0-88·0 mM in excess of the physiological concentration) perfused through the ventricles, caused an immediate rise in body temperature which was accompanied by vasoconstriction, piloerection and shivering. The latency of the hyperthermia was related directly to the rate of perfusion and the concentration of sodium, whereas the magnitude of the response depended upon the concentration only. When the perfusion was terminated, shivering ceased and the temperature of the monkey returned to the base line level. 3. When calcium ions were perfused in concentrations 2·5-47·9 mM in excess of that of extracellular fluid, a fall in the temperature of the animal occurred. The magnitude of the decreases depended upon the concentration of calcium in the perfusion fluid. Vasodilatation, sedation and a reduction in withdrawal reflexes accompanied the calcium-induced hypothermia. After the perfusion ended, the temperature continued to fall until the monkey began to shiver and vasoconstriction was observed in many skin areas. 4. The perfusion through the cerebral ventricles with modified Krebs solution alone or with the Krebs solution which contained potassium or magnesium ions in concentrations five to ten times normal had virtually no effect on the temperature of the monkey. 5. Since the temperature of the monkey was unchanged as long as the physiological ratio of sodium to calcium in the perfusion fluid remained constant, we conclude that the balance between these two essential cations within the brain stem could determine the neural mechanism whereby the set-point for body temperature of the primate is established. PMID:4999638

The physiological disposition of the uricosuric-saluretic agent (6,7-dichloro-2-methyl-1-oxo-2-phenyl-5-indanyloxy)acetic acid (MK-196) in the rat, dog, and monkey.

PubMed

Zacchei, A G; Wishousky, T I

1976-01-01

The physiological disposition of a new saluretic-uricosuric agent, (6,7-dichloro-2-methyl-1-oxo-2-phenyl-5-indanyloxy)acetic acid (MK-196), was studied in the rat, dog, and monkey. MK-196 was well absorbed and showed minimal metabolism in these species. Peak plasma levels of radioactivity and drug occurred 0.5-2 hr after oral administration at a dose of 2.5 mg/kg. Essentially all of the radioactivity present in the plasma during the first day was intact MK-196. Following a single dose, a long terminal half-life for plasma radioactivity was observed in the dog (approximately 68 hr) and monkey (approximately 105 hr). The chronic administration of MK-196 to dogs resulted in a dose-related plasma profile and showed no tendency to increase or decrease with dosing. However, upon repeated drug administration to monkeys, the plasma levels of drug increased and then decreased, possibly due to hypochloremia and secondary metabolic alkalosis. Fecal excretion was the predominant route of tracer elimination in the dog (approximately 80%) and rat (approximately 94%), whereas the monkey eliminated the majority of the dose (approximately 60%) via the urine. Minimal metabolism was noted in the three lower species; most of the urinary, plasma, and fecal radioactivity was accounted for as intact drug and its glucuronide conjugate. Three minor metabolites, which were present in dog bile, plasma, and urine, were characterized as: (l,7-dichloro-1alpha-hydroxy-2-methyl-2-phenyl-5-indanyloxy)acetic acid, I; (6,7-dichloro-2-(4-hydroxyphenyl)-2-methyl-2-oxo-5-indanyloxy)acetic acid, II; and 2-methyl-2-phenyl-5-hydroxy-6,7-dichloro-1-indanone, III. The monkey urine and plasma also contained small amounts of II.

Broadly Neutralizing Human Immunodeficiency Virus Type 1 Antibody Gene Transfer Protects Nonhuman Primates from Mucosal Simian-Human Immunodeficiency Virus Infection

PubMed Central

Saunders, Kevin O.; Wang, Lingshu; Joyce, M. Gordon; Yang, Zhi-Yong; Balazs, Alejandro B.; Cheng, Cheng; Ko, Sung-Youl; Kong, Wing-Pui; Rudicell, Rebecca S.; Georgiev, Ivelin S.; Duan, Lijie; Foulds, Kathryn E.; Donaldson, Mitzi; Xu, Ling; Schmidt, Stephen D.; Todd, John-Paul; Baltimore, David; Roederer, Mario; Haase, Ashley T.; Kwong, Peter D.; Rao, Srinivas S.

2015-01-01

ABSTRACT Broadly neutralizing antibodies (bnAbs) can prevent lentiviral infection in nonhuman primates and may slow the spread of human immunodeficiency virus type 1 (HIV-1). Although protection by passive transfer of human bnAbs has been demonstrated in monkeys, durable expression is essential for its broader use in humans. Gene-based expression of bnAbs provides a potential solution to this problem, although immune responses to the viral vector or to the antibody may limit its durability and efficacy. Here, we delivered an adeno-associated viral vector encoding a simianized form of a CD4bs bnAb, VRC07, and evaluated its immunogenicity and protective efficacy. The expressed antibody circulated in macaques for 16 weeks at levels up to 66 μg/ml, although immune suppression with cyclosporine (CsA) was needed to sustain expression. Gene-delivered simian VRC07 protected against simian-human immunodeficiency virus (SHIV) infection in monkeys 5.5 weeks after treatment. Gene transfer of an anti-HIV antibody can therefore protect against infection by viruses that cause AIDS in primates when the host immune responses are controlled. IMPORTANCE Sustained interventions that can prevent HIV-1 infection are needed to halt the spread of the HIV-1 pandemic. The protective capacity of anti-HIV antibody gene therapy has been established in mouse models of HIV-1 infection but has not been established for primates. We show here a proof-of-concept that gene transfer of anti-HIV antibody genes can protect against infection by viruses that cause AIDS in primates when host immune responses are controlled. PMID:26041300

Identification of a Surrogate Marker for Infection in the African Green Monkey Model of Inhalation Anthrax

DTIC Science & Technology

2008-12-01

as well as condition and clarity of eyes and nose; clinical signs included breathing rate and pattern; natural behavior included peer interaction ...human cases, fatigue and/or mal- aise was a presenting symptom in only 64% of cases (26). While decreased activity and interaction were noted in some...experimental infection with Leishmania leishmania donovani and Leishmania leishmania infantum. Lab. Anim. Sci. 43:37–47. 5. Brachman, P. S. 1980

C-type lectins do not act as functional receptors for filovirus entry into cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Matsuno, Keita; Nakayama, Eri; Noyori, Osamu

2010-12-03

Research highlights: {yields} Filovirus glycoprotein (GP) having a deficient receptor binding region were generated. {yields} Mutant GPs mediated virus entry less efficiently than wild-type GP. {yields} Mutant GPs bound to C-type lectins but not mediated entire steps of cellular entry. {yields} C-type lectins do not independently mediate filovirus entry into cells. {yields} Other molecule(s) are required for C-type lectin-mediated entry of filoviruses. -- Abstract: Cellular C-type lectins have been reported to facilitate filovirus infection by binding to glycans on filovirus glycoprotein (GP). However, it is not clearly known whether interaction between C-type lectins and GP mediates all the steps ofmore » virus entry (i.e., attachment, internalization, and membrane fusion). In this study, we generated vesicular stomatitis viruses pseudotyped with mutant GPs that have impaired structures of the putative receptor binding regions and thus reduced ability to infect the monkey kidney cells that are routinely used for virus propagation. We found that infectivities of viruses with the mutant GPs dropped in C-type lectin-expressing cells, parallel with those in the monkey kidney cells, whereas binding activities of these GPs to the C-type lectins were not correlated with the reduced infectivities. These results suggest that C-type lectin-mediated entry of filoviruses requires other cellular molecule(s) that may be involved in virion internalization or membrane fusion.« less

Pharmacokinetics of IDX184, a liver-targeted oral prodrug of 2'-methylguanosine-5'-monophosphate, in the monkey and formulation optimization for human exposure.

PubMed

Pan-Zhou, Xin-Ru; Mayes, Benjamin A; Rashidzadeh, Hassan; Gasparac, Rahela; Smith, Steven; Bhadresa, Sanjeev; Gupta, Kusum; Cohen, Marita Larsson; Bu, Charlie; Good, Steven S; Moussa, Adel; Rush, Roger

2016-10-01

IDX184 is a phosphoramidate prodrug of 2'-methylguanosine-5'-monophosphate, developed to treat patients infected with hepatitis C virus. A mass balance study of radiolabeled IDX184 and pharmacokinetic studies of IDX184 in portal vein-cannulated monkeys revealed relatively low IDX184 absorption but higher exposure of IDX184 in the portal vein than in the systemic circulation, indicating >90 % of the absorbed dose was subject to hepatic extraction. Systemic exposures to the main metabolite, 2'-methylguanosine (2'-MeG), were used as a surrogate for liver levels of the pharmacologically active entity 2'-MeG triphosphate, and accordingly, systemic levels of 2'-MeG in the monkey were used to optimize formulations for further clinical development of IDX184. Capsule formulations of IDX184 delivered acceptable levels of 2'-MeG in humans; however, the encapsulation process introduced low levels of the genotoxic impurity ethylene sulfide (ES), which necessitated formulation optimization. Animal pharmacokinetic data guided the development of a tablet with trace levels of ES and pharmacokinetic performance equal to that of the clinical capsule in the monkey. Under fed conditions in humans, the new tablet formulation showed similar exposure to the capsule used in prior clinical trials.

Impairment of ovarian function and associated health-related abnormalities are attributable to low social status in premenopausal monkeys and not mitigated by a high-isoflavone soy diet.

PubMed

Kaplan, J R; Chen, H; Appt, S E; Lees, C J; Franke, A A; Berga, S L; Wilson, M E; Manuck, S B; Clarkson, T B

2010-12-01

Psychological stress may impair premenopausal ovarian function and contribute to risk for chronic disease. Soy isoflavones may also influence ovarian function and affect health. Here, we report the effects of a psychological stressor (subordinate social status) and dietary soy on reproductive function and related health indices in female monkeys. We hypothesized that reproductive compromise and adverse health outcomes would be induced in subordinate when compared with dominant monkeys and be mitigated by exposure to soy. Subjects were 95 adult cynomolgus monkeys (Macaca fascicularis) housed in social groups of five or six. Animals consumed a soy-free, animal protein-based diet during an 8-month Baseline phase and then, during a 32-month Treatment phase, consumed either the baseline diet or an identical diet that substituted high-isoflavone soy protein for animal protein. Across more than 1200 menstrual cycles, subordinate monkeys consistently exhibited ovarian impairment [increased cycle length (P < 0.02) and variability (P < 0.02) and reduced levels of progesterone (P < 0.04) and estradiol (P < 0.04)]. Subordinate status was confirmed behaviorally and was associated with elevated cortisol (P < 0.04) and relative osteopenia (P < 0.05). Consumption of the soy diet had no significant effects. (i) Psychological stress adversely affects ovarian function and related health indices in a well-accepted animal model of women's health; (ii) Similar effects may extend to women experiencing reproductive impairment of psychogenic origin; (iii) soy protein and isoflavones neither exacerbate nor mitigate the effects of an adverse psychosocial environment; and (iv) this study was limited by an inability to investigate the genetic and developmental determinants of social status.

Development of a translational model to screen medications for cocaine use disorder I: Choice between cocaine and food in rhesus monkeys.

PubMed

Johnson, Amy R; Banks, Matthew L; Blough, Bruce E; Lile, Joshua A; Nicholson, Katherine L; Negus, S Stevens

2016-08-01

Homologous cocaine self-administration procedures in laboratory animals and humans may facilitate translational research for medications development to treat cocaine dependence. This study, therefore, sought to establish choice between cocaine and an alternative reinforcer in rhesus monkeys responding under a procedure back-translated from previous human studies and homologous to a human laboratory procedure described in a companion paper. Four rhesus monkeys with chronic indwelling intravenous catheters had access to cocaine injections (0, 0.043, 0.14, or 0.43mg/kg/injection) and food (0, 1, 3, or 10 1g banana-flavored food pellets). During daily 5h sessions, a single cocaine dose and a single food-reinforcer magnitude were available in 10 30-min trials. During the initial "sample" trial, the available cocaine and food reinforcer were delivered non-contingently. During each of the subsequent nine "choice" trials, responding could produce either the cocaine or food reinforcer under an independent concurrent progressive-ratio schedule. Preference was governed by the cocaine dose and food-reinforcer magnitude, and increasing cocaine doses produced dose-dependent increases in cocaine choice at all food-reinforcer magnitudes. Effects of the candidate medication lisdexamfetamine (0.32-3.2mg/kg/day) were then examined on choice between 0.14mg/kg/injection cocaine and 10 pellets. Under baseline conditions, this reinforcer pair maintained an average of approximately 6 cocaine and 3 food choices. Lisdexamfetamine dose-dependently decreased cocaine choice in all monkeys, but food choice was not significantly altered. These results support utility of this procedure in rhesus monkeys as one component of a platform for translational research on medications development to treat cocaine use disorder. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Reduced cortical innervation of the subthalamic nucleus in MPTP-treated parkinsonian monkeys.

PubMed

Mathai, Abraham; Ma, Yuxian; Paré, Jean-Francois; Villalba, Rosa M; Wichmann, Thomas; Smith, Yoland

2015-04-01

The striatum and the subthalamic nucleus are the main entry points for cortical information to the basal ganglia. Parkinson's disease affects not only the function, but also the morphological integrity of some of these inputs and their synaptic targets in the basal ganglia. Significant morphological changes in the cortico-striatal system have already been recognized in patients with Parkinson's disease and in animal models of the disease. To find out whether the primate cortico-subthalamic system is also subject to functionally relevant morphological alterations in parkinsonism, we used a combination of light and electron microscopy anatomical approaches and in vivo electrophysiological methods in monkeys rendered parkinsonian following chronic exposure to low doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). At the light microscopic level, the density of vesicular glutamate transporter 1-positive (i.e. cortico-subthalamic) profiles in the dorsolateral part of the subthalamic nucleus (i.e. its sensorimotor territory) was 26.1% lower in MPTP-treated parkinsonian monkeys than in controls. These results were confirmed by electron microscopy studies showing that the number of vesicular glutamate transporter 1-positive terminals and of axon terminals forming asymmetric synapses in the dorsolateral subthalamic nucleus was reduced by 55.1% and 27.9%, respectively, compared with controls. These anatomical findings were in line with in vivo electrophysiology data showing a 60% reduction in the proportion of pallidal neurons that responded to electrical stimulation of the cortico-subthalamic system in parkinsonian monkeys. These findings provide strong evidence for a partial loss of the hyperdirect cortico-subthalamic projection in MPTP-treated parkinsonian monkeys. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Antibody-independent mechanisms regulate the establishment of chronic Plasmodium infection

PubMed Central

Lin, Jingwen; Cunningham, Deirdre; Tumwine, Irene; Kushinga, Garikai; McLaughlin, Sarah; Spence, Philip; Böhme, Ulrike; Sanders, Mandy; Conteh, Solomon; Bushell, Ellen; Metcalf, Tom; Billker, Oliver; Duffy, Patrick E.; Newbold, Chris; Berriman, Matthew; Langhorne, Jean

2017-01-01

Malaria is caused by parasites of the genus Plasmodium. All human-infecting Plasmodium species can establish long-lasting chronic infections1–5, creating an infectious reservoir to sustain transmission1,6. It is widely accepted that maintenance of chronic infection involves evasion of adaptive immunity by antigenic variation7. However, genes involved in this process have been identified in only two of five human-infecting species: P. falciparum and P. knowlesi. Furthermore, little is understood about the early events in establishment of chronic infection in these species. Using a rodent model we demonstrate that only a minority of parasites from among the infecting population, expressing one of several clusters of virulence-associated pir genes, establishes a chronic infection. This process occurs in different species of parasite and in different hosts. Establishment of chronicity is independent of adaptive immunity and therefore different from the mechanism proposed for maintainance of chronic P. falciparum infections7–9. Furthermore, we show that the proportions of parasites expressing different types of pir genes regulate the time taken to establish a chronic infection. Since pir genes are common to most, if not all, species of Plasmodium10, this process may be a common way of regulating the establishment of chronic infections. PMID:28165471

A western-style diet, with and without chronic androgen treatment, alters the number, structure and function of small antral follicles in ovaries of young adult monkeys

PubMed Central

Bishop, Cecily V.; Xu, Fuhua; Xu, Jing; Ting, Alison Y.; Galbreath, Etienne; McGee, Whitney K.; Zelinski, Mary B.; Hennebold, Jon D.; Cameron, Judy L.; Stouffer, Richard L.

2015-01-01

Objective To examine the small antral follicle (SAF) cohort in ovaries of adult rhesus monkeys following consumption of a western-style diet (WSD), with or without chronically elevated androgen levels since before puberty. Design Cholesterol or testosterone (T; n=6/group) implants were placed subcutaneously in female rhesus macaques beginning at 1 yr of age (pre-pubertal), with addition of a WSD (high fat/fructose) at 5.5 yrs (menarche ~2.6 yrs). Ovaries were collected at 7 yrs of age. One ovary/female was embedded in paraffin for morphological and immunohistochemical analyses. The SAFs (<2.5mm) were dissected from the other ovary obtained at/near menses in a subgroup of females (n=3/group), and processed for microarray analyses of the SAF transcriptome. Ovaries of adult monkeys consuming a standard macaque diet (low in fats and sugars) were obtained at similar stages of the menstrual cycle and used as controls for all analyses. Setting National primate research center Animals Adult, female rhesus monkeys (Macaca mulatta) Interventions None Main outcome measures Histological analyses, SAF counts and morphology, protein localization and abundance in SAFs, transcriptome in SAFs (mRNAs) Results Compared to controls, consumption of a WSD, with and without T treatment, increased the numbers of SAFs per ovary, due to the presence of more atretic follicles. Numbers of granulosa cells expressing cellular proliferation markers (pRb and pH3) was greater in healthy SAFs, while numbers of cells expressing the cell cycle inhibitor (p21) was higher in atretic SAFs. Intense CYP17A1 staining was observed in the theca cells of SAFs from WSD+/− T groups, compared to controls. Microarray analyses of the transcriptome in SAFs isolated from WSD and WSD+T treated females and controls consuming a standard diet, identified 1944 genes whose mRNA levels changed ≥2-fold among the three groups. Further analyses identified several gene pathways altered by WSD and/or WSD+T associated with steroid, carbohydrate and lipid metabolism, plus ovarian processes. Alterations in levels of several SAF mRNAs are similar to those observed in follicular cells from women with polycystic ovary syndrome (PCOS). Conclusion These data indicate that consumption of a WSD high in fats and sugars in the presence and absence of chronically elevated T alters the structure and function of SAFs within primate ovaries. PMID:26718060

An Ebola Filovirus Is Discovered in the USA: Reston, Virginia, USA, 1989.

PubMed

Jaax, Jerry; Jaax, Nancy K

2016-05-01

In December of 1989, a shipment Cynomolgus sp. monkeys into the U.S. infected with Ebola virus resulted in a potential public health crisis. An emergency interagency effort to control the outbreak was mounted in Reston Virginia, the site of the nonhuman primate quarantine facility.

A Review: The Current In Vivo Models for the Discovery and Utility of New Anti-leishmanial Drugs Targeting Cutaneous Leishmaniasis

PubMed Central

Mears, Emily Rose; Modabber, Farrokh; Don, Robert; Johnson, George E.

2015-01-01

The current in vivo models for the utility and discovery of new potential anti-leishmanial drugs targeting Cutaneous Leishmaniasis (CL) differ vastly in their immunological responses to the disease and clinical presentation of symptoms. Animal models that show similarities to the human form of CL after infection with Leishmania should be more representative as to the effect of the parasite within a human. Thus, these models are used to evaluate the efficacy of new anti-leishmanial compounds before human clinical trials. Current animal models aim to investigate (i) host–parasite interactions, (ii) pathogenesis, (iii) biochemical changes/pathways, (iv) in vivo maintenance of parasites, and (v) clinical evaluation of drug candidates. This review focuses on the trends of infection observed between Leishmania parasites, the predictability of different strains, and the determination of parasite load. These factors were used to investigate the overall effectiveness of the current animal models. The main aim was to assess the efficacy and limitations of the various CL models and their potential for drug discovery and evaluation. In conclusion, we found that the following models are the most suitable for the assessment of anti-leishmanial drugs: L. major–C57BL/6 mice (or–vervet monkey, or–rhesus monkeys), L. tropica–CsS-16 mice, L. amazonensis–CBA mice, L. braziliensis–golden hamster (or–rhesus monkey). We also provide in-depth guidance for which models are not suitable for these investigations. PMID:26334763

HIV-1 Tat-based vaccines: from basic science to clinical trials.

PubMed

Fanales-Belasio, Emanuele; Cafaro, Aurelio; Cara, Andrea; Negri, Donatella R M; Fiorelli, Valeria; Butto, Stefano; Moretti, Sonia; Maggiorella, Maria Teresa; Baroncelli, Silvia; Michelini, Zuleika; Tripiciano, Antonella; Sernicola, Leonardo; Scoglio, Arianna; Borsetti, Alessandra; Ridolfi, Barbara; Bona, Roberta; Ten Haaft, Peter; Macchia, Iole; Leone, Pasqualina; Pavone-Cossut, Maria Rosaria; Nappi, Filomena; Vardas, Eftyhia; Magnani, Mauro; Laguardia, Elena; Caputo, Antonella; Titti, Fausto; Ensoli, Barbara

2002-09-01

Vaccination against human immunodeficiency virus (HIV)-1 infection requires candidate antigen(s) (Ag) capable of inducing an effective, broad, and long-lasting immune response against HIV-1 despite mutation events leading to differences in virus clades. The HIV-1 Tat protein is more conserved than envelope proteins, is essential in the virus life cycle and is expressed very early upon virus entry. In addition, both humoral and cellular responses to Tat have been reported to correlate with a delayed progression to disease in both humans and monkeys. This suggested that Tat is an optimal target for vaccine development aimed at controlling virus replication and blocking disease onset. Here are reviewed the results of our studies including the effects of the Tat protein on monocyte-derived dendritic cells (MDDCs) that are key antigen-presenting cells (APCs), and the results from vaccination trials with both the Tat protein or tat DNA in monkeys. We provide evidence that the HIV-1 Tat protein is very efficiently taken up by MDDCs and promotes T helper (Th)-1 type immune responses against itself as well as other Ag. In addition, a Tat-based vaccine elicits an immune response capable of controlling primary infection of monkeys with the pathogenic SHIV89.6P at its early stages allowing the containment of virus spread. Based on these results and on data of Tat conservation and immune cross-recognition in field isolates from different clades, phase I clinical trials are being initiated in Italy for both preventive and therapeutic vaccination.

Responses evoked by a vestibular implant providing chronic stimulation.

PubMed

Thompson, Lara A; Haburcakova, Csilla; Gong, Wangsong; Lee, Daniel J; Wall, Conrad; Merfeld, Daniel M; Lewis, Richard F

2012-01-01

Patients with bilateral vestibular loss experience dehabilitating visual, perceptual, and postural difficulties, and an implantable vestibular prosthesis that could improve these symptoms would be of great benefit to these patients. In previous work, we have shown that a one-dimensional, unilateral canal prosthesis can improve the vestibulooccular reflex (VOR) in canal-plugged squirrel monkeys. In addition to the VOR, the potential effects of a vestibular prosthesis on more complex, highly integrative behaviors, such as the perception of head orientation and posture have remained unclear. We tested a one-dimensional, unilateral prosthesis in a rhesus monkey with bilateral vestibular loss and found that chronic electrical stimulation partially restored the compensatory VOR and also that percepts of head orientation relative to gravity were improved. However, the one-dimensional prosthetic stimulation had no clear effect on postural stability during quiet stance, but sway evoked by head-turns was modestly reduced. These results suggest that not only can the implementation of a vestibular prosthesis provide partial restitution of VOR but may also improve perception and posture in the presence of bilateral vestibular hypofunction (BVH). In this review, we provide an overview of our previous and current work directed towards the eventual clinical implementation of an implantable vestibular prosthesis.

[Comparative analysis of virulence of the Siberian and Far-East subtypes of the tick-born encephalitis virus].

PubMed

Pogodina, V V; Bochkova, N G; Karan', L S; Frolova, M P; Trukhina, A G; Malenko, G V; Levina, L S; Platonov, A E

2004-01-01

The Siberian subtype of the tick-borne encephalitis virus (TEV) is different from the Far-East subtype by a moderate virulence observed in Siberian hamsters and by a low infection development rate (100 strains were compared). No differences were found in neuro-invasiveness. Clinical findings and experiments with monkeys denote the ability of the Siberian subtype to provoke severe forms of tick-borne encephalitis (TBE). The inflammation-and-degenerative changes were localized in the brain cortex, subcortical ganglions, nuclei of medulla oblongata, in the cortex and nuclei of the cerebellum as well as in the anterior horns of the spinal cord. 18 disease cases triggered by the Siberian TEV subtypes in residents of the Western and Eastern Siberia and of Central Russia (Yaroslavl Region), including 7 acute TBE cases (5 lethal outcomes), as well as 11 chronic TBE cases are analyzed. The viral RNA was found in the cortex, medulla oblongata, horn and in the cervical part of the spinal cord of those diseased of acute TBE. Sequences of genotyped strains were presented to Gen Bank, NCBI (AY363846-AY363865).

New Animal Model Could Boost Research on AIDS Drugs and Vaccines | Poster

Cancer.gov

By Frank Blanchard, Staff Writer, and Jeff Lifson, Guest Writer In a research milestone reported in the June 20 issue of the journal Science, scientists have developed a minimally modified version of HIV-1, the virus that causes AIDS in infected humans, that is capable of causing progressive infection and AIDS in monkeys. The advance should help create more authentic animal models of the disease and provide a potentially invaluable approach for faster and better preclinical evaluation of new drugs and vaccines.

Treatment of Ebola Virus Infection With a Recombinant Inhibitor of Factor Vlla/Tissue Factor: A Study in Rhesus Monkeys

DTIC Science & Technology

2003-12-13

ameliorate the effects of Ebola haemorrhagic fever . Here, we tested the notion that blockade of fVIIa/tissue factor is beneficial after infection with...Ebola virus. Methods We used a rhesus macaque model of Ebola haemorrhagic fever , which produces near 100% mortality. We administered recombinant...severe haemorrhagic fever in primates.1,2 Acute mortality caused by the Zaire species of Ebola virus has been about 80% in outbreaks in human beings1

Natural Gastric Infection with Helicobacter pylori in Monkeys: A Model for Spiral Bacteria Infection in Humans

DTIC Science & Technology

1994-01-01

ANDRZEJ TARNAWSKI,11 WILLIAM N. FISHBEIN,1 GUILLERMO I. PEREZ-PEREZV and MARTIN J . BLASER# *Laboratory of Gastrointestinal and Uver Studies...from 38. Fox JG, Blanco MC, Yan L, Shames B, Polidoro D, Dewhirst FE, cheetahs with gastritis. Int J Syst Bacteriol 1993;43:99-106. Paster BJ. Role of...For NTIS CRA& J 13. ABSTRACT (Maximuom 200 wardaW Unnnuce C ~Justification_ - DrfG Aj 0-11994 DistributionI 0 Availability CodesGit Avail and/orDist

A novel highly reproducible and lethal nonhuman primate model for orthopox virus infection.

PubMed

Kramski, Marit; Mätz-Rensing, Kerstin; Stahl-Hennig, Christiane; Kaup, Franz-Josef; Nitsche, Andreas; Pauli, Georg; Ellerbrok, Heinz

2010-04-29

The intentional re-introduction of Variola virus (VARV), the agent of smallpox, into the human population is of great concern due its bio-terroristic potential. Moreover, zoonotic infections with Cowpox (CPXV) and Monkeypox virus (MPXV) cause severe diseases in humans. Smallpox vaccines presently available can have severe adverse effects that are no longer acceptable. The efficacy and safety of new vaccines and antiviral drugs for use in humans can only be demonstrated in animal models. The existing nonhuman primate models, using VARV and MPXV, need very high viral doses that have to be applied intravenously or intratracheally to induce a lethal infection in macaques. To overcome these drawbacks, the infectivity and pathogenicity of a particular CPXV was evaluated in the common marmoset (Callithrix jacchus).A CPXV named calpox virus was isolated from a lethal orthopox virus (OPV) outbreak in New World monkeys. We demonstrated that marmosets infected with calpox virus, not only via the intravenous but also the intranasal route, reproducibly develop symptoms resembling smallpox in humans. Infected animals died within 1-3 days after onset of symptoms, even when very low infectious viral doses of 5x10(2) pfu were applied intranasally. Infectious virus was demonstrated in blood, saliva and all organs analyzed.We present the first characterization of a new OPV infection model inducing a disease in common marmosets comparable to smallpox in humans. Intranasal virus inoculation mimicking the natural route of smallpox infection led to reproducible infection. In vivo titration resulted in an MID(50) (minimal monkey infectious dose 50%) of 8.3x10(2) pfu of calpox virus which is approximately 10,000-fold lower than MPXV and VARV doses applied in the macaque models. Therefore, the calpox virus/marmoset model is a suitable nonhuman primate model for the validation of vaccines and antiviral drugs. Furthermore, this model can help study mechanisms of OPV pathogenesis.

A Novel Highly Reproducible and Lethal Nonhuman Primate Model for Orthopox Virus Infection

PubMed Central

Kramski, Marit; Mätz-Rensing, Kerstin; Stahl-Hennig, Christiane; Kaup, Franz-Josef; Nitsche, Andreas; Pauli, Georg; Ellerbrok, Heinz

2010-01-01

The intentional re-introduction of Variola virus (VARV), the agent of smallpox, into the human population is of great concern due its bio-terroristic potential. Moreover, zoonotic infections with Cowpox (CPXV) and Monkeypox virus (MPXV) cause severe diseases in humans. Smallpox vaccines presently available can have severe adverse effects that are no longer acceptable. The efficacy and safety of new vaccines and antiviral drugs for use in humans can only be demonstrated in animal models. The existing nonhuman primate models, using VARV and MPXV, need very high viral doses that have to be applied intravenously or intratracheally to induce a lethal infection in macaques. To overcome these drawbacks, the infectivity and pathogenicity of a particular CPXV was evaluated in the common marmoset (Callithrix jacchus). A CPXV named calpox virus was isolated from a lethal orthopox virus (OPV) outbreak in New World monkeys. We demonstrated that marmosets infected with calpox virus, not only via the intravenous but also the intranasal route, reproducibly develop symptoms resembling smallpox in humans. Infected animals died within 1–3 days after onset of symptoms, even when very low infectious viral doses of 5×102 pfu were applied intranasally. Infectious virus was demonstrated in blood, saliva and all organs analyzed. We present the first characterization of a new OPV infection model inducing a disease in common marmosets comparable to smallpox in humans. Intranasal virus inoculation mimicking the natural route of smallpox infection led to reproducible infection. In vivo titration resulted in an MID50 (minimal monkey infectious dose 50%) of 8.3×102 pfu of calpox virus which is approximately 10,000-fold lower than MPXV and VARV doses applied in the macaque models. Therefore, the calpox virus/marmoset model is a suitable nonhuman primate model for the validation of vaccines and antiviral drugs. Furthermore, this model can help study mechanisms of OPV pathogenesis. PMID:20454688

Left ventricular, systemic arterial, and baroreflex responses to ketamine and TEE in chronically instrumented monkeys

NASA Technical Reports Server (NTRS)

Koenig, S. C.; Ludwig, D. A.; Reister, C.; Fanton, J. W.; Ewert, D.; Convertino, V. A.

2001-01-01

Effects of prescribed doses of ketamine five minutes after application and influences of transesophageal echocardiography (TEE) on left ventricular, systemic arterial, and baroreflex responses were investigated to test the hypothesis that ketamine and/or TEE probe insertion alter cardiovascular function. Seven rhesus monkeys were tested under each of four randomly selected experimental conditions: (1) intravenous bolus dose of ketamine (0.5 ml), (2) continuous infusion of ketamine (500 mg/kg/min), (3) continuous infusion of ketamine (500 mg/kg/min) with TEE, and (4) control (no ketamine or TEE). Monkeys were chronically instrumented with a high fidelity, dual-sensor micromanometer to measure left ventricular and aortic pressure and a transit-time ultrasound probe to measure aortic flow. These measures were used to calculate left ventricular function. A 4-element Windkessel lumped-parameter model was used to estimate total peripheral resistance and systemic arterial compliance. Baroreflex response was calculated as the change in R-R interval divided by the change in mean aortic pressure measured during administration of graded concentrations of nitroprusside. The results indicated that five minutes after ketamine application heart rate and left ventricular diastolic compliance decreased while TEE increased aortic systolic and diastolic pressure. We conclude that ketamine may be administered as either a bolus or continuous infusion without affecting cardiovascular function 5 minutes after application while the insertion of a TEE probe will increase aortic pressure. The results for both ketamine and TEE illustrate the classic "Hawthorne Effect," where the observed values are partly a function of the measurement process. Measures of aortic pressure, heart rate, and left ventricular diastolic pressure should be viewed as relative, as opposed to absolute, when organisms are sedated with ketamine or instrumented with a TEE probe.

[Role of infection in the pathogenesis of obesity].

PubMed

Hainer, Vojtěch; Hainerová, Irena Aldhoon; Zamrazilová, Hana

2012-01-01

Current global epidemic of obesity is mainly related to increased consumption of high energy density foods and sedentary lifestyle that leads to a positive energy balance with subsequent accumulation of fat stores, primarily in genetically predisposed individuals. However, additional pathogenetic factors should be considered, including an infection. Several viruses causing obesity have been described in mice, chicken, rats, hamsters and monkeys. In humans, a significant positive association between being overweight and IgG antibodies was found for Helicobacter pylori and Chlamydia pneumoniae. This association of bacterial infections with increased BMI might not represent a causal relationship but could be a marker for greater susceptibility of obese individuals to infection. Crucial role in the development of "infectious obesity" in humans may be played by adenovirus infection, particularly AD-36 type that is also capable of inducing obesity in experimental animals as chicken, mice and monkeys. AD-36-induced obesity is paradoxically associated with lower levels of serum cholesterol and triglycerides both in humans and in experimental animals. Moreover, AD-36 enhances insulin sensitivity and improves hepatic steatosis. AD-36 effects in target organs as adipose tissue, liver and skeletal muscle are mediated through the viral protein E4orf1. This way AD-36 improves metabolic profile, as indicated by a greater glucose uptake by adipose tissue and skeletal muscle, reduced glucose output by hepatocytes, increased adiponectin levels and increased expression of adipogenic genes as peroxisome proliferator-activated receptor gamma. If E4orf1 improves glycemic control without reducing dietary fat intake and body fat stores, this viral protein would be highly valuable to develop novel anti-diabetic agents that mimic its effects.Key words: obesity, infection, adenovirus AD-36, diabetes mellitus, lipid profile, insulin sensitivity.

Role of Plasmodium vivax Duffy-binding protein 1 in invasion of Duffy-null Africans

PubMed Central

Gunalan, Karthigayan; Lo, Eugenia; Hostetler, Jessica B.; Yewhalaw, Delenasaw; Mu, Jianbing; Neafsey, Daniel E.; Yan, Guiyun; Miller, Louis H.

2016-01-01

The ability of the malaria parasite Plasmodium vivax to invade erythrocytes is dependent on the expression of the Duffy blood group antigen on erythrocytes. Consequently, Africans who are null for the Duffy antigen are not susceptible to P. vivax infections. Recently, P. vivax infections in Duffy-null Africans have been documented, raising the possibility that P. vivax, a virulent pathogen in other parts of the world, may expand malarial disease in Africa. P. vivax binds the Duffy blood group antigen through its Duffy-binding protein 1 (DBP1). To determine if mutations in DBP1 resulted in the ability of P. vivax to bind Duffy-null erythrocytes, we analyzed P. vivax parasites obtained from two Duffy-null individuals living in Ethiopia where Duffy-null and -positive Africans live side-by-side. We determined that, although the DBP1s from these parasites contained unique sequences, they failed to bind Duffy-null erythrocytes, indicating that mutations in DBP1 did not account for the ability of P. vivax to infect Duffy-null Africans. However, an unusual DNA expansion of DBP1 (three and eight copies) in the two Duffy-null P. vivax infections suggests that an expansion of DBP1 may have been selected to allow low-affinity binding to another receptor on Duffy-null erythrocytes. Indeed, we show that Salvador (Sal) I P. vivax infects Squirrel monkeys independently of DBP1 binding to Squirrel monkey erythrocytes. We conclude that P. vivax Sal I and perhaps P. vivax in Duffy-null patients may have adapted to use new ligand–receptor pairs for invasion. PMID:27190089

Antiviral treatment is more effective than smallpox vaccination upon lethal monkeypox virus infection.

PubMed

Stittelaar, Koert J; Neyts, Johan; Naesens, Lieve; van Amerongen, Geert; van Lavieren, Rob F; Holý, Antonin; De Clercq, Erik; Niesters, Hubert G M; Fries, Edwin; Maas, Chantal; Mulder, Paul G H; van der Zeijst, Ben A M; Osterhaus, Albert D M E

2006-02-09

There is concern that variola virus, the aetiological agent of smallpox, may be used as a biological weapon. For this reason several countries are now stockpiling (vaccinia virus-based) smallpox vaccine. Although the preventive use of smallpox vaccination has been well documented, little is known about its efficacy when used after exposure to the virus. Here we compare the effectiveness of (1) post-exposure smallpox vaccination and (2) antiviral treatment with either cidofovir (also called HPMPC or Vistide) or with a related acyclic nucleoside phosphonate analogue (HPMPO-DAPy) after lethal intratracheal infection of cynomolgus monkeys (Macaca fascicularis) with monkeypox virus (MPXV). MPXV causes a disease similar to human smallpox and this animal model can be used to measure differences in the protective efficacies of classical and new-generation candidate smallpox vaccines. We show that initiation of antiviral treatment 24 h after lethal intratracheal MPXV infection, using either of the antiviral agents and applying various systemic treatment regimens, resulted in significantly reduced mortality and reduced numbers of cutaneous monkeypox lesions. In contrast, when monkeys were vaccinated 24 h after MPXV infection, using a standard human dose of a currently recommended smallpox vaccine (Elstree-RIVM), no significant reduction in mortality was observed. When antiviral therapy was terminated 13 days after infection, all surviving animals had virus-specific serum antibodies and antiviral T lymphocytes. These data show that adequate preparedness for a biological threat involving smallpox should include the possibility of treating exposed individuals with antiviral compounds such as cidofovir or other selective anti-poxvirus drugs.

Chronic Pseudomonas aeruginosa infection and respiratory muscle impairment in cystic fibrosis.

PubMed

Dassios, Theodore G; Katelari, Anna; Doudounakis, Stavros; Dimitriou, Gabriel

2014-03-01

Chronic infection with Pseudomonas aeruginosa in patients with cystic fibrosis (CF) is associated with increased morbidity. Chronic infection can cause limb and respiratory muscle compromise. Respiratory muscle function can be assessed via maximal inspiratory pressure (PImax), maximal expiratory pressure (PEmax), and the pressure-time index of the respiratory muscles (PTImus). We studied the effect of chronic P. aeruginosa infection on respiratory muscle function in patients with CF. This cross-sectional study assessed PImax, PEmax, PTImus, FEV1, FVC, maximum expiratory flow during the middle half of the FVC maneuver, body mass index, and upper arm muscle area in 122 subjects with CF, in 4 subgroups matched for age and sex at different stages of P. aeruginosa infection, according to the Leeds criteria. We compared respiratory muscle function in the subgroups according to P. aeruginosa infection state. Median PImax was significantly lower in CF subjects with chronic P. aeruginosa infection (PImax = 62 cm H2O), compared to subjects who were never infected (PImax = 86 cm H2O, P = .02), free of infection (PImax = 74 cm H2O, P = .01), or intermittently infected (PImax = 72 cm H2O, P = .02). Median PTImus was significantly increased in CF subjects with chronic P. aeruginosa infection (PTImus = .142), compared to subjects who were free of infection (PTImus = .102, P = .006). Median upper-arm muscle area was significantly lower in CF subjects with chronic P. aeruginosa infection (upper-arm muscle area = 2,219 mm(2)), compared to subjects who were never infected (2,754 mm(2), P = .03), free of infection (2,678 mm(2), P = .01), or intermittently infected (2,603 mm(2), P = .04). Multivariate logistic regression revealed P. aeruginosa state of infection as a significant determinant of PTImus (P = .03) independently of sex, upper-arm muscle area, and FEV1. CF subjects with chronic P. aeruginosa infection exhibited impaired respiratory muscle function and decreased inspiratory muscle strength, and chronic P. aeruginosa infection independently impacts respiratory muscle function in subjects with CF.

Sex and menstrual cycle effects on chronic oral cocaine self-administration in rhesus monkeys: Effects of a nondrug alternative reward.

PubMed

Carroll, Marilyn E; Collins, Molly; Kohl, Emily A; Johnson, Seth; Dougen, Ben

2016-08-01

In previous studies, female monkeys self-administered more oral phencyclidine (PCP) than males, and PCP intake differed by phase of menstrual cycle. The purpose of this study was to examine sex and hormonal influences on oral cocaine self-administration in male and female rhesus monkeys in the follicular vs. luteal phases of the menstrual cycle, with concurrent access to an alternative nondrug reward, saccharin (SACC) vs. water. Concurrent access to cocaine (0.2, 0.4, and 0.8 mg/ml) and SACC or water was available from two drinking spouts under concurrent fixed-ratio (FR) 2, 4, and 8 schedules during daily 3-h sessions. Cocaine deliveries were similar in males and females in the females' luteal phase, but cocaine deliveries were higher in females during the follicular phase than the luteal phase and compared to males. When SACC was available, cocaine deliveries were reduced in females in the follicular phase of the cycle, and cocaine intake (mg/kg) was reduced in males and in females' follicular and luteal phases. Access to concurrent SACC (vs. water) reduced cocaine intake (mg/kg) in males and in females during both menstrual phases, and the magnitude of the reduction in cocaine intake was greatest during the females' follicular phase. Thus, a nondrug alternative reward, SACC, is a viable alternative treatment for reducing cocaine's rewarding effects on male and female monkeys, and reductions in cocaine seeking were optimal in the females' luteal phase.

Radical curative efficacy of tafenoquine combination regimens in Plasmodium cynomolgi-infected Rhesus monkeys (Macaca mulatta).

PubMed

Dow, Geoffrey S; Gettayacamin, Montip; Hansukjariya, Pranee; Imerbsin, Rawiwan; Komcharoen, Srawuth; Sattabongkot, Jetsumon; Kyle, Dennis; Milhous, Wilbur; Cozens, Simon; Kenworthy, David; Miller, Anne; Veazey, Jim; Ohrt, Colin

2011-07-29

Tafenoquine is an 8-aminoquinoline being developed for radical cure (blood and liver stage elimination) of Plasmodium vivax. During monotherapy treatment, the compound exhibits slow parasite and fever clearance times, and toxicity in glucose-6-phosphate dehydrogenase (G6PD) deficiency is a concern. Combination with other antimalarials may mitigate these concerns. In 2005, the radical curative efficacy of tafenoquine combinations was investigated in Plasmodium cynomolgi-infected naïve Indian-origin Rhesus monkeys. In the first cohort, groups of two monkeys were treated with a three-day regimen of tafenoquine at different doses alone and in combination with a three-day chloroquine regimen to determine the minimum curative dose (MCD). In the second cohort, the radical curative efficacy of a single-day regimen of tafenoquine-mefloquine was compared to that of two three-day regimens comprising tafenoquine at its MCD with chloroquine or artemether-lumefantrine in groups of six monkeys. In a final cohort, the efficacy of the MCD of tafenoquine against hypnozoites alone and in combination with chloroquine was investigated in groups of six monkeys after quinine pre-treatment to eliminate asexual parasites. Plasma tafenoquine, chloroquine and desethylchloroquine concentrations were determined by LC-MS in order to compare doses of the drugs to those used clinically in humans. The total MCD of tafenoquine required in combination regimens for radical cure was ten-fold lower (1.8 mg/kg versus 18 mg/kg) than for monotherapy. This regimen (1.8 mg/kg) was equally efficacious as monotherapy or in combination with chloroquine after quinine pre-treatment to eliminate asexual stages. The same dose of (1.8 mg/kg) was radically curative in combination with artemether-lumefantrine. Tafenoquine was also radically curative when combined with mefloquine. The MCD of tafenoquine monotherapy for radical cure (18 mg/kg) appears to be biologically equivalent to a 600-1200 mg dose in humans. At its MCD in combination with blood schizonticidal drugs (1.8 mg/kg), the maximum observed plasma concentrations were substantially lower than (20-84 versus 550-1,100 ng/ml) after administration of 1, 200 mg in clinical studies. Ten-fold lower clinical doses of tafenoquine than used in prior studies may be effective against P. vivax hypnozoites if the drug is deployed in combination with effective blood-schizonticidal drugs.

Radical curative efficacy of tafenoquine combination regimens in Plasmodium cynomolgi-infected Rhesus monkeys (Macaca mulatta)

PubMed Central

2011-01-01

Background Tafenoquine is an 8-aminoquinoline being developed for radical cure (blood and liver stage elimination) of Plasmodium vivax. During monotherapy treatment, the compound exhibits slow parasite and fever clearance times, and toxicity in glucose-6-phosphate dehydrogenase (G6PD) deficiency is a concern. Combination with other antimalarials may mitigate these concerns. Methods In 2005, the radical curative efficacy of tafenoquine combinations was investigated in Plasmodium cynomolgi-infected naïve Indian-origin Rhesus monkeys. In the first cohort, groups of two monkeys were treated with a three-day regimen of tafenoquine at different doses alone and in combination with a three-day chloroquine regimen to determine the minimum curative dose (MCD). In the second cohort, the radical curative efficacy of a single-day regimen of tafenoquine-mefloquine was compared to that of two three-day regimens comprising tafenoquine at its MCD with chloroquine or artemether-lumefantrine in groups of six monkeys. In a final cohort, the efficacy of the MCD of tafenoquine against hypnozoites alone and in combination with chloroquine was investigated in groups of six monkeys after quinine pre-treatment to eliminate asexual parasites. Plasma tafenoquine, chloroquine and desethylchloroquine concentrations were determined by LC-MS in order to compare doses of the drugs to those used clinically in humans. Results The total MCD of tafenoquine required in combination regimens for radical cure was ten-fold lower (1.8 mg/kg versus 18 mg/kg) than for monotherapy. This regimen (1.8 mg/kg) was equally efficacious as monotherapy or in combination with chloroquine after quinine pre-treatment to eliminate asexual stages. The same dose of (1.8 mg/kg) was radically curative in combination with artemether-lumefantrine. Tafenoquine was also radically curative when combined with mefloquine. The MCD of tafenoquine monotherapy for radical cure (18 mg/kg) appears to be biologically equivalent to a 600-1200 mg dose in humans. At its MCD in combination with blood schizonticidal drugs (1.8 mg/kg), the maximum observed plasma concentrations were substantially lower than (20-84 versus 550-1,100 ng/ml) after administration of 1, 200 mg in clinical studies. Conclusions Ten-fold lower clinical doses of tafenoquine than used in prior studies may be effective against P. vivax hypnozoites if the drug is deployed in combination with effective blood-schizonticidal drugs. PMID:21801400

Early-life stress and the development of obesity and insulin resistance in juvenile bonnet macaques.

PubMed

Kaufman, Daniel; Banerji, Mary Ann; Shorman, Igor; Smith, Eric L P; Coplan, Jeremy D; Rosenblum, Leonard A; Kral, John G

2007-05-01

Stress is a risk factor for chronic illnesses such as obesity, type 2 diabetes, and hypertension and has been postulated to cause the metabolic syndrome via perturbation of the hypothalamo-pituitary-adrenal (HPA) axis. In our model of early-life stress (variable foraging demand [VFD]), food insecurity is imposed on monkey mothers for 16 weeks beginning when their nursing offspring are 3-5 months of age. Under VFD, food availability is never restricted, and the infant's growth is unaffected. VFD rearing does, however, cause a range of neurobiological abnormalities, including dysregulation of the HPA axis, manifested in abnormal cerebrospinal fluid cortisol and corticotropin-releasing factor levels. We previously reported spontaneous occurrence of metabolic syndrome in 14% of normally reared peripubertal bonnet macaques given ad libitum access to standard monkey chow. Here, we show that compared with normally reared monkeys, peripubertal VFD juveniles exhibit greater weight, BMI, abdominal circumference, and glucagon-like peptide-1 and decreased glucose disposal rates during hyperinsulinemic-euglycemic clamps. Our data suggest that early-life stress during a critical period of neuro development can result in the peripubertal emergence of obesity and insulin resistance.

A Fully Implanted Drug Delivery System for Peripheral Nerve Blocks in Behaving Animals

PubMed Central

Pohlmeyer, Eric A.; Jordon, Luke R.; Kim, Peter; Miller, Lee E.

2009-01-01

Inhibiting peripheral nerve function can be useful for many studies of the nervous system or motor control. Accomplishing this in a temporary fashion in animal models by using peripheral nerve blocks permits studies of the immediate effects of the loss, and/or any resulting short-term changes and adaptations in behavior or motor control, while avoiding the complications commonly associated with permanent lesions, such as sores or self-mutilation. We have developed a method of quickly and repeatedly inducing temporary, controlled motor deficits in rhesus macaque monkeys via a chronically implanted drug delivery system. This assembly consists of a nerve cuff and a subdermal injection dome, and has proved effective for delivering local anesthetics directly to peripheral nerves for many months. Using this assembly for median and ulnar nerve blocks routinely resulted in over 80% losses in hand and wrist strength for rhesus monkeys. The assembly was also effective for inducing ambulatory motor deficits in rabbits through blocks of the sciatic nerve. Interestingly, while standard anesthetics were sufficient for the rabbit nerve blocks, the inclusion of epinephrine was essential for achieving significant motor blockade in the monkeys. PMID:19524613

Continuous intraputamenal convection-enhanced delivery in adult rhesus macaques.

PubMed

Fan, Xiaotong; Nelson, Brian D; Ai, Yi; Stiles, David K; Gash, Don M; Hardy, Peter A; Zhang, Zhiming

2015-12-01

Assessing the safety and feasibility of chronic delivery of compounds to the brain using convection-enhanced delivery (CED) is important for the further development of this important therapeutic technology. The objective of this study was to follow and model the distribution of a compound delivered by CED into the putamen of rhesus monkeys. The authors sequentially implanted catheters into 4 sites spanning the left and right putamen in each of 6 rhesus monkeys. The catheters were connected to implanted pumps, which were programmed to deliver a 5-mM solution of the MRI contrast agent Gd-DTPA at 0.1 μl/minute for 7 days and 0.3 μl/minute for an additional 7 days. The animals were followed for 28 days per implant cycle during which they were periodically examined with MRI. All animals survived the 4 surgeries with no deficits in behavior. Compared with acute infusion, the volume of distribution (Vd) increased 2-fold with 7 days of chronic infusion. Increasing the flow rate 3-fold over the next week increased the Vd an additional 3-fold. Following withdrawal of the compound, the half-life of Gd-DTPA in the brain was estimated as 3.1 days based on first-order pharmacokinetics. Histological assessment of the brain showed minimal tissue damage limited to the insertion site. These results demonstrate several important features in the development of a chronically implanted pump and catheter system: 1) the ability to place catheters accurately in a predetermined target; 2) the ability to deliver compounds in a chronic fashion to the putamen; and 3) the use of MRI and MR visible tracers to follow the evolution of the infusion volume over time.

Human factors with nonhumans - Factors that affect computer-task performance

NASA Technical Reports Server (NTRS)

Washburn, David A.

1992-01-01

There are two general strategies that may be employed for 'doing human factors research with nonhuman animals'. First, one may use the methods of traditional human factors investigations to examine the nonhuman animal-to-machine interface. Alternatively, one might use performance by nonhuman animals as a surrogate for or model of performance by a human operator. Each of these approaches is illustrated with data in the present review. Chronic ambient noise was found to have a significant but inconsequential effect on computer-task performance by rhesus monkeys (Macaca mulatta). Additional data supported the generality of findings such as these to humans, showing that rhesus monkeys are appropriate models of human psychomotor performance. It is argued that ultimately the interface between comparative psychology and technology will depend on the coordinated use of both strategies of investigation.

Facts about Ebola

MedlinePlus

... legally purchased in the U.S. You can only get Ebola from • The body fluids of a person who is sick with or has died from Ebola. • Objects contaminated with body fluids of a person sick with Ebola or who has died of Ebola. • Infected fruit bats and primates (apes and monkeys). • And, possibly from ...

Aptamer Against Mannose-capped Lipoarabinomannan Inhibits Virulent Mycobacterium tuberculosis Infection in Mice and Rhesus Monkeys

PubMed Central

Pan, Qin; Wang, Qilong; Sun, Xiaoming; Xia, Xianru; Wu, Shimin; Luo, Fengling; Zhang, Xiao-Lian

2014-01-01

The major surface lipoglycan of Mycobacterium tuberculosis (M. tb), mannose-capped lipoarabinomannan (ManLAM), is an immunosuppressive epitope of M. tb. We used systematic evolution of ligands by exponential enrichment (SELEX) to generate an aptamer (ZXL1) that specifically bound to ManLAM from the virulent M. tb strain H37Rv. Aptamer ZXL1 had the highest binding affinity, with an equilibrium dissociation constant (Kd) of 436.3 ± 37.84 nmol/l, and competed with the mannose receptor for binding to ManLAM and M. tb H37Rv. ZXL1 significantly inhibited the ManLAM-induced immunosuppression of CD11c+ dendritic cells (DCs) and enhanced the M. tb antigen–presenting activity of DCs for naive CD4+ Th1 cell activation. More importantly, we demonstrated that injection of aptamer ZXL1 significantly reduced the progression of M. tb H37Rv infections and bacterial loads in lungs of mice and rhesus monkeys. These results suggest that the aptamer ZXL1 is a new potential antimycobacterial agent and tuberculosis vaccine immune adjuvant. PMID:24572295

ELECTROPHORESIS EXPERIMENTS WITH THE VIRUS AND PROTECTIVE BODIES OF YELLOW FEVER

PubMed Central

Frobisher, Martin

1931-01-01

1. When suspended in slightly alkaline (pH 7.4 to 7.8) saline dilutions of clear, hemoglobin-free normal monkey serum, the virus of yellow fever from infected monkeys and from infected, but blood-free, mosquitoes, usually acts as if it were possessed of a positive electrical charge. 2. The virus tends to assume a negative charge in fluids having a slightly acid reaction. 3. The isoelectric point of the virus seems to be in the neighborhood of pH 7.0, possibly ranging from pH 7.3 to pH 6.9. 4. Exposure to fluid having a reaction of pH 5.0 for 3 hours appeared to inactivate the virus. 5. In experiments in which the suspending fluid was prepared with normal serum diluted with distilled water and containing a good quantity of partly hemolyzed erythrocytes, the virus tended to migrate to the anode. 6. The protective bodies in yellow fever immune serum appear to carry a negative charge in slightly alkaline saline dilutions of serum. PMID:19869954

Development of a new live attenuated mumps virus vaccine in human diploid cells.

PubMed

Sassani, A; Mirchamsy, H; Shafyi, A; Ahourai, P; Razavi, J; Gholami, M R; Mohammadi, A; Ezzi, A; Rahmani, M; Fateh, G

1991-07-01

A new live attenuated mumps vaccine was developed in human diploid cells. The S-12 virus was isolated from a 10-year-old girl showing typical symptoms of mumps infection, the diagnosis was confirmed by a pediatrician. The virus was isolated in green monkey kidney cells, without passage in chick embryo cavity or chick embryo fibroblasts. Attenuation of the wild virus was performed by serial passages in human diploid cells (MRC-5). The attenuated virus was characterized by identity tests, as well as by a reduction in plaque size, as marker tests. The virus was free from adventitious agents and safe for laboratory animals as well as for monkeys. The reactogenicity and immunogenicity of the S-12 virus for man was investigated by administration of a monovalent vaccine to 20 seronegative adult male volunteers and 30 children aged 1 to 5 years without history of mumps infection or vaccination. Seroconversion was obtained in 95% of the vaccinees. The new vaccine has the advantage of not requiring specific pathogen-free eggs, and being free from avian proteins and therefore can be used in sensitized patients.

Reston ebolavirus in humans and animals in the Philippines: a review.

PubMed

Miranda, Mary Elizabeth G; Miranda, Noel Lee J

2011-11-01

The 2008 Reston ebolavirus infection event in domestic pigs has triggered continuing epidemiologic investigations among Philippine health and veterinary agencies in collaboration with international filovirus experts. Prior to this, there were only 3 known and documented Reston ebolavirus outbreaks in nonhuman primates in the world, all traced back to a single geographic source in the Philippines in a monkey breeding/export facility. The first one in 1989 was the first-ever Ebola virus that emerged outside of Africa and was also the first known natural infection of Ebola virus in nonhuman primates. When it was first discovered among laboratory monkeys in the United States, the source was immediately traced back to the farm located in the Philippines. The second outbreak was in 1992-93. The third episode in 1996 was the last known outbreak before Reston ebolavirus reemerged in pigs in 2008. The isolated outbreaks involving 2 animal species bring forth issues requiring further investigations, and highlight the significance of intersectoral collaboration to effectively address zoonoses prevention and control/response in the interest of minimizing public health risk.

Prevalence of chronic infections and susceptibility to measles and varicella-zoster virus in Latin American immigrants.

PubMed

Jackson, Yves; Santos, Lilian; Arm-Vernez, Isabelle; Mauris, Anne; Wolff, Hans; Chappuis, François; Getaz, Laurent

2016-05-11

Large numbers of Latin American immigrants recently arrived in Western Europe. Curative and preventive programmes need to take account of their risk of suffering and transmitting imported chronic infections and of their susceptibility to cosmopolitan infections. We aimed to assess the prevalence and co-occurrence of imported chronic infections among Latin American immigrants, and their susceptibility to highly prevalent cosmopolitan infections. Adult participants were recruited in the community and in a primary health centre in Geneva in 2008. Serological tests were performed on stored sera for HIV, HBV, syphilis, Strongyloides stercoralis, Trypanosoma cruzi, varicella and measles. We considered only chronic active infections in the analysis. The 1 012 participants, aged 37.2 (SD 11.3) years, were mostly female (82.5 %) and Bolivians (48 %). Overall, 209 (20.7 %) had at least one and 27 (2.7 %) two or more chronic infections. T. cruzi (12.8 %) and S. stercoralis (8.4 %) were the most prevalent chronic active infections compared to syphilis (0.4 %), HBV (0.4 %) and HIV (1.4 %). Concomitant infections affected 28.2 and 18.5 % of T. cruzi and S. stercoralis infected cases. Bolivian origin (aOR: 13.6; 95 % CI: 3.2-57.9) was associated with risk of multiple infections. Susceptibilities for VZV and measles were 0.7 and 1.4 %, respectively. Latin American immigrants are at risk of complications and possible reactivation of chronic parasitic infections but have overall low risks of chronic viral and syphilitic active infections. Systematic screening for chronic active parasitic infections is therefore necessary especially among Bolivians. The high protection rate against measles and VZV doesn't require specific preventive interventions.

U. S. Army Medical Research and Development Technical Report

DTIC Science & Technology

1978-09-30

skin preparation prior to cathe- ter insertion, thi- type of catheter care following insertion, and the duration of central venous catheterization . An...NO. 3 A study is now underway to determine the optimal techniques for central venous catheter dressing care. A specially designed dress- ing tray that...chronically maintained male rhesus monkeys with indwelling central venous catheters. Two specific problems were en- countered. (1) Available data

Middle Ear Infection (Chronic Otitis Media) and Hearing Loss

MedlinePlus

... You Middle Ear Infection (Chronic Otitis Media) and Hearing Loss Middle Ear Infection (Chronic Otitis Media) and ... loss. How does otitis media affect a child’s hearing? All children with middle ear infection or fluid ...

Occupational exposure of cashew nut workers to Kyasanur Forest disease in Goa, India.

PubMed

Patil, D Y; Yadav, P D; Shete, A M; Nuchina, J; Meti, R; Bhattad, D; Someshwar, S; Mourya, D T

2017-08-01

A series of suspected cases of Kyasanur Forest disease (KFD) in subjects returning to Belgaum in Karnataka State from Goa, India, is reported herein. KFD was confirmed in 13 out of 76 cases, either by real time RT-PCR or IgM ELISA. No case fatality was recorded. KFD virus positivity was also recorded among humans and monkeys from Sattari taluk in Goa during the same period. The envelope gene sequence of positive human samples from Belgaum showed highest identity of 99.98% to 99.99% with sequences of KFD virus isolated from human cases and monkeys from Goa. KFD activity has been reported from Goa among humans and monkeys since 2015. However, it has not been reported from Belgaum to date. These findings suggest that the cases (migrant laborers) contracted infection during cashew nut harvesting from KFD-affected Keri village, Sattari taluk, Goa and became ill after or during migration from the affected area to their native residence. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Effect of animal sera on Bacillus anthracis Sterne spore germination and vegetative cell growth.

PubMed

Bensman, M D; Mackie, R S; Minter, Z A; Gutting, B W

2012-08-01

 The aims of this work were to investigate the effects of sera on B. anthracis Sterne germination and growth. Sera examined included human, monkey and rabbit sera, as well as sera from eight other species.  Standard dilution plate assay (with and without heat kill) was used as a measure of germination, and spectroscopy was used to measure growth. In addition, a Coulter Counter particle counter was used to monitor germination and growth based on bacterial size. Spores germinated best in foetal bovine and monkey sera, moderately with human sera and showed limited germination in the presence of rabbit or rat sera. Vegetative bacteria grew best in foetal bovine sera and moderately in rabbit sera. Human and monkey sera supported little growth of vegetative bacteria.  The data suggested sera can have a significant impact on germination and growth of Sterne bacteria.  These data should be considered when conducting in vitro cell culture studies and may aid in interpreting in vivo infection studies. © 2012 The Authors Journal of Applied Microbiology © 2012 The Society for Applied Microbiology.

Plasmid profile in oral Fusobacterium nucleatum from humans and Cebus apella monkeys.

PubMed

Paula, Marcia O; Gaetti-Jardim Júnior, Elerson; Avila-Campos, Mario J

2003-01-01

Fusobacterium nucleatum is a strict anaerobe and is indigenous of the human oral cavity. This organism is commonly recovered from different monomicrobial and mixed infections in humans and animals. In this study, the plasmid profile, the plasmid stability and the penicillin-resistance association in oral F. nucleatum isolated from periodontal patients, healthy subjects and Cebus apella monkeys were evaluated. Forty-five F. nucleatum strains from patients, 38 from healthy subjects and seven from C. apella were identified and analyzed. Plasmid extraction was performed in all the isolated strains. These elements were found in 26.7% strains from patients and one strain from C. apella. Strains from healthy subjects did not show any plasmid. Most of strains showed two plasmid bands ranging from 4 to 16 Kb, but digestions with endonucleases showed that they belonged to a single plasmid. The plasmid profile was similar and stable in human and monkey strains. Also, plasmids were classified into three groups according to size. Two strains were positive to beta-lactamase production and no plasmid DNA-hybridization with a beta-lactamase gene probe was observed, suggesting a chromosomal resistance.

Antiretroviral Therapy in Simian Immunodeficiency Virus-Infected Sooty Mangabeys: Implications for AIDS Pathogenesis

PubMed Central

Calascibetta, Francesca; Micci, Luca; Carnathan, Diane; Lawson, Benton; Vanderford, Thomas H.; Bosinger, Steven E.; Easley, Kirk; Chahroudi, Ann; Mackel, Joseph; Keele, Brandon F.; Long, Samuel; Lifson, Jeffrey; Paiardini, Mirko

2016-01-01

ABSTRACT Simian immunodeficiency virus (SIV)-infected sooty mangabeys (SMs) do not develop AIDS despite high levels of viremia. Key factors involved in the benign course of SIV infection in SMs are the absence of chronic immune activation and low levels of infection of CD4+ central memory (TCM) and stem cell memory (TSCM) T cells. To better understand the role of virus replication in determining the main features of SIV infection in SMs, we treated 12 SMs with a potent antiretroviral therapy (ART) regimen for 2 to 12 months. We observed that ART suppressed viremia to <60 copies/ml of plasma in 10 of 12 animals and induced a variable decrease in the level of cell-associated SIV DNA in peripheral blood (average changes of 0.9-, 1.1-, 1.5-, and 3.7-fold for CD4+ transitional memory [TTM], TCM, effector memory [TEM], and TSCM cells, respectively). ART-treated SIV-infected SMs showed (i) increased percentages of circulating CD4+ TCM cells, (ii) increased levels of CD4+ T cells in the rectal mucosa, and (iii) significant declines in the frequencies of HLA-DR+ CD8+ T cells in the blood and rectal mucosa. In addition, we observed that ART interruption resulted in rapid viral rebound in all SIV-infected SMs, indicating that the virus reservoir persists for at least a year under ART despite lower infection levels of CD4+ TCM and TSCM cells than those seen in pathogenic SIV infections of macaques. Overall, these data indicate that ART induces specific immunological changes in SIV-infected SMs, thus suggesting that virus replication affects immune function even in the context of this clinically benign infection. IMPORTANCE Studies of natural, nonpathogenic simian immunodeficiency virus (SIV) infection of African monkeys have provided important insights into the mechanisms responsible for the progression to AIDS during pathogenic human immunodeficiency virus (HIV) infection of humans and SIV infection of Asian macaques. In this study, for the first time, we treated SIV-infected sooty mangabeys, a natural host for the infection, with a potent antiretroviral therapy (ART) regimen for periods ranging from 2 to 12 months and monitored in detail how suppression of virus replication affected the main virological and immunological features of this nonpathogenic infection. The observed findings provide novel information on both the pathogenesis of residual immunological disease under ART during pathogenic infection and the mechanisms involved in virus persistence during primate lentiviral infections. PMID:27279614

Recognition of three epitopic regions on invasion plasmid antigen C by immune sera of rhesus monkeys infected with Shigella flexneri 2a.

PubMed Central

Turbyfill, K R; Joseph, S W; Oaks, E V

1995-01-01

The invasive ability of Shigella spp. is correlated with the expression of several plasmid-encoded proteins, including invasion plasmid antigen C (IpaC). By characterizing the antigenic structure of IpaC with monoclonal antibodies and convalescent-phase sera, it may be possible to determine the physical location of specific epitopes as well as the involvement of epitopes in a protective immune response or the host's susceptibility to disease. By using overlapping octameric synthetic peptides, which together represent the entire IpaC protein, the precise linear sequence of four surface-exposed epitopes was defined for four IpaC monoclonal antibodies. Furthermore, 17 unique peptide epitopes of IpaC were mapped by using 9-day-postinfection serum samples from 13 rhesus monkeys challenged with Shigella flexneri 2a. Each individual recognized a somewhat different array of IpaC peptide epitopes after infection with shigellae. However, the epitopes were clustered within three regions of the protein: region I (between amino acid residues 1 and 61), region II (between amino acid residues 177 and 258), and region III (between amino acid residues 298 and 307). Region II was recognized by 92% of S. flexneri-infected individuals and was considered to be a highly immunogenic region. Animals asymptomatic for shigellosis after challenge with S. flexneri recognized peptide epitopes within all three epitopic regions of IpaC, whereas symptomatic animals recognized peptides in only one or two of the epitopic regions. Antibody from monkeys challenged with S. sonnei recognized IpaC peptide epitopes which fell within and outside the three S. flexneri epitopic regions. While numerous potential epitopes exist on the IpaC protein, the identification of three regions in which epitopes are clustered suggests that these regions are significant with respect to the immune response and to subsequent pathogenesis postinfection. PMID:7558301

Rotavirus Activates Lymphocytes from Non-Obese Diabetic Mice by Triggering Toll-Like Receptor 7 Signaling and Interferon Production in Plasmacytoid Dendritic Cells

PubMed Central

Pane, Jessica A.; Webster, Nicole L.; Coulson, Barbara S.

2014-01-01

It has been proposed that rotavirus infection promotes the progression of genetically-predisposed children to type 1 diabetes, a chronic autoimmune disease marked by infiltration of activated lymphocytes into pancreatic islets. Non-obese diabetic (NOD) mice provide a model for the human disease. Infection of adult NOD mice with rhesus monkey rotavirus (RRV) accelerates diabetes onset, without evidence of pancreatic infection. Rather, RRV spreads to the pancreatic and mesenteric lymph nodes where its association with antigen-presenting cells, including dendritic cells, induces cellular maturation. RRV infection increases levels of the class I major histocompatibility complex on B cells and proinflammatory cytokine expression by T cells at these sites. In autoimmunity-resistant mice and human mononuclear cells from blood, rotavirus-exposed plasmacytoid dendritic cells contribute to bystander polyclonal B cell activation through type I interferon expression. Here we tested the hypothesis that rotavirus induces bystander activation of lymphocytes from NOD mice by provoking dendritic cell activation and proinflammatory cytokine secretion. NOD mouse splenocytes were stimulated with rotavirus and assessed for activation by flow cytometry. This stimulation activated antigen-presenting cells and B cells independently of virus strain and replicative ability. Instead, activation depended on virus dose and was prevented by blockade of virus decapsidation, inhibition of endosomal acidification and interference with signaling through Toll-like receptor 7 and the type I interferon receptor. Plasmacytoid dendritic cells were more efficiently activated than conventional dendritic cells by RRV, and contributed to the activation of B and T cells, including islet-autoreactive CD8+ T cells. Thus, a double-stranded RNA virus can induce Toll-like receptor 7 signaling, resulting in lymphocyte activation. Our findings suggest that bystander activation mediated by type I interferon contributes to the lymphocyte activation observed following RRV infection of NOD mice, and may play a role in diabetes acceleration by rotavirus. PMID:24676425

Versatile, modular 3D microelectrode arrays for neuronal ensemble recordings: from design to fabrication, assembly, and functional validation in non-human primates.

PubMed

Barz, F; Livi, A; Lanzilotto, M; Maranesi, M; Bonini, L; Paul, O; Ruther, P

2017-06-01

Application-specific designs of electrode arrays offer an improved effectiveness for providing access to targeted brain regions in neuroscientific research and brain machine interfaces. The simultaneous and stable recording of neuronal ensembles is the main goal in the design of advanced neural interfaces. Here, we describe the development and assembly of highly customizable 3D microelectrode arrays and demonstrate their recording performance in chronic applications in non-human primates. System assembly relies on a microfabricated stacking component that is combined with Michigan-style silicon-based electrode arrays interfacing highly flexible polyimide cables. Based on the novel stacking component, the lead time for implementing prototypes with altered electrode pitches is minimal. Once the fabrication and assembly accuracy of the stacked probes have been characterized, their recording performance is assessed during in vivo chronic experiments in awake rhesus macaques (Macaca mulatta) trained to execute reaching-grasping motor tasks. Using a single set of fabrication tools, we implemented three variants of the stacking component for electrode distances of 250, 300 and 350 µm in the stacking direction. We assembled neural probes with up to 96 channels and an electrode density of 98 electrodes mm -2 . Furthermore, we demonstrate that the shank alignment is accurate to a few µm at an angular alignment better than 1°. Three 64-channel probes were chronically implanted in two monkeys providing single-unit activity on more than 60% of all channels and excellent recording stability. Histological tissue sections, obtained 52 d after implantation from one of the monkeys, showed minimal tissue damage, in accordance with the high quality and stability of the recorded neural activity. The versatility of our fabrication and assembly approach should significantly support the development of ideal interface geometries for a broad spectrum of applications. With the demonstrated performance, these probes are suitable for both semi-chronic and chronic applications.

Versatile, modular 3D microelectrode arrays for neuronal ensemble recordings: from design to fabrication, assembly, and functional validation in non-human primates

NASA Astrophysics Data System (ADS)

Barz, F.; Livi, A.; Lanzilotto, M.; Maranesi, M.; Bonini, L.; Paul, O.; Ruther, P.

2017-06-01

Objective. Application-specific designs of electrode arrays offer an improved effectiveness for providing access to targeted brain regions in neuroscientific research and brain machine interfaces. The simultaneous and stable recording of neuronal ensembles is the main goal in the design of advanced neural interfaces. Here, we describe the development and assembly of highly customizable 3D microelectrode arrays and demonstrate their recording performance in chronic applications in non-human primates. Approach. System assembly relies on a microfabricated stacking component that is combined with Michigan-style silicon-based electrode arrays interfacing highly flexible polyimide cables. Based on the novel stacking component, the lead time for implementing prototypes with altered electrode pitches is minimal. Once the fabrication and assembly accuracy of the stacked probes have been characterized, their recording performance is assessed during in vivo chronic experiments in awake rhesus macaques (Macaca mulatta) trained to execute reaching-grasping motor tasks. Main results. Using a single set of fabrication tools, we implemented three variants of the stacking component for electrode distances of 250, 300 and 350 µm in the stacking direction. We assembled neural probes with up to 96 channels and an electrode density of 98 electrodes mm-2. Furthermore, we demonstrate that the shank alignment is accurate to a few µm at an angular alignment better than 1°. Three 64-channel probes were chronically implanted in two monkeys providing single-unit activity on more than 60% of all channels and excellent recording stability. Histological tissue sections, obtained 52 d after implantation from one of the monkeys, showed minimal tissue damage, in accordance with the high quality and stability of the recorded neural activity. Significance. The versatility of our fabrication and assembly approach should significantly support the development of ideal interface geometries for a broad spectrum of applications. With the demonstrated performance, these probes are suitable for both semi-chronic and chronic applications.

An unusual renal manifestation of chronic HBV infection.

PubMed

Aravindan, Ananthakrishnapuram; Yong, Jim; Killingsworth, Murray; Strasser, Simone; Suranyi, Michael

2010-08-01

Hepatitis B viral infection is usually a self-limiting disease in immunocompetent individuals. Chronic infection can be seen in up to 5% of infected patients. Renal manifestations of chronic HBV infection are usually glomerular. We describe here an uncommon presentation of a patient with chronic HBV infection with very high viral load and rapidly progressive renal failure. Renal biopsy showed features of tubulointerstitial nephritis and tubular epithelial inclusion bodies suggestive of HBV infection. Entecavir treatment slowed down the progression of his renal disease. Tubulointerstitial nephritis should be considered as a part of the differential diagnosis in patients with HBV infection. Early antiviral treatment may halt the progression of renal disease.

The full genome sequence of three strains of Jamestown Canyon virus and their pathogenesis in mice or monkeys

PubMed Central

2011-01-01

Background Jamestown Canyon virus (JCV), family Bunyaviridae, is a mosquito-borne pathogen endemic in the United States and Canada that can cause encephalitis in humans and is considered an emerging threat to public health. The virus is genetically similar to Inkoo virus circulating in Europe, suggesting that much of the northern hemisphere contains JCV or similar variants. Results We have completed the sequence of three isolates of JCV collected in geographically diverse locations over a 57 year time span. The nucleotide identity for the three strains is 90, 83, and 85% for the S, M, and L segments respectively whereas the percent identify for the predicted amino acid sequences of the N, NSS, M poly, GN, NSM, GC, and L proteins was 97, 91, 94, 98, 91, 94, and 97%, respectively. In Swiss Webster mice, each JCV isolate exhibits low neuroinvasiveness but high infectivity. Two of the three JCV isolates were highly neurovirulent after IC inoculation whereas one isolate, JCV/03/CT, exhibited low neurovirulence. In rhesus monkeys, JCV infection is accompanied by a low-titered viremia, lack of clinical disease, but a robust neutralizing antibody response. Conclusions The first complete sequence of JCV is reported for three separate isolates, and a relatively high level of amino acid sequence conservation was observed even for viruses isolated 57 years apart indicating that the virus is in relative evolutionary stasis. JCV is highly infectious for mice and monkeys, and these animals, especially mice, represent useful experimental hosts for further study. PMID:21435230

Natural Killer Cell Function and Dysfunction in Hepatitis C Virus Infection

PubMed Central

Holder, Kayla A.; Russell, Rodney S.; Grant, Michael D.

2014-01-01

Viruses must continually adapt against dynamic innate and adaptive responses of the host immune system to establish chronic infection. Only a small minority (~20%) of those exposed to hepatitis C virus (HCV) spontaneously clear infection, leaving approximately 200 million people worldwide chronically infected with HCV. A number of recent research studies suggest that establishment and maintenance of chronic HCV infection involve natural killer (NK) cell dysfunction. This relationship is illustrated in vitro by disruption of typical NK cell responses including both cell-mediated cytotoxicity and cytokine production. Expression of a number of activating NK cell receptors in vivo is also affected in chronic HCV infection. Thus, direct in vivo and in vitro evidence of compromised NK function in chronic HCV infection in conjunction with significant epidemiological associations between the outcome of HCV infection and certain combinations of NK cell regulatory receptor and class I human histocompatibility linked antigen (HLA) genotypes indicate that NK cells are important in the immune response against HCV infection. In this review, we highlight evidence suggesting that selective impairment of NK cell activity is related to establishment of chronic HCV infection. PMID:25057504

Swim stress reduces chronic pain in mice through an opioid mechanism.

PubMed

Carmody, J; Cooper, K

1987-03-09

Chronic nociception has been studied in male mice by means of the formalin test in which forelimb motor behaviour is scored after subcutaneous formalin injection. The rating remained above 2.0 for 30 min after the injection (scale range 0-3). The magnitude of the nociception has been compared with that reported in other animal types. Mice are more sensitive than rats, cats and monkeys. The stress of a swim of 3 min has been found to reduce nociception by up to 25%. This analgesia is wholly opioid in nature, being abolished by a moderate dose of naloxone (1 mg/kg).

[Effect of the Epstein-Barr virus on the nervous system].

PubMed

Kononenko, V V

2001-01-01

On the basis of a comprehensive examination of 12 patients with verified Epstein-Barr virus (EBV) infection it has been shown that this infection can be accompanied by acute and chronic affections of the central and peripheral nervous system. The pathogenesis of chronic EBV-infection involves autoimmune disorders, neurosensitization, a hazard of an injury to the muscular tissue. Chronic EBV-infection calls for differential diagnosis with other slow virus infections, systemic tumor afflictions, systemic diseases of the connective tissue. Acyclovir or valacyclovir can be recommended as treatment of acute and chronic EBV-infection.

Black and gold howler monkeys (Alouatta caraya) as sentinels of ecosystem health: patterns of zoonotic protozoa infection relative to degree of human-primate contact.

PubMed

Kowalewski, Martin M; Salzer, Johanna S; Deutsch, Joseph C; Raño, Mariana; Kuhlenschmidt, Mark S; Gillespie, Thomas R

2011-01-01

Exponential expansion of human populations and human activities within primate habitats has resulted in high potential for pathogen exchange creating challenges for biodiversity conservation and global health. Under such conditions, resilient habitat generalists such as black and gold howler monkeys (Alouatta caraya) may act as effective sentinels to overall ecosystem health and alert us to impending epidemics in the human population. To better understand this potential, we examined noninvasively collected fecal samples from black and gold howler monkeys from remote, rural, and village populations in Northern Argentina. We examined all samples (n=90) for the zoonotic protozoa Cryptosporidium sp. and Giardia sp. via immunofluorescent antibody (IFA) detection. All samples were negative for Cryptosporidium sp. The prevalence of Giardia sp. was significantly higher at the rural site (67%) compared with the remote forest (57%) and village (40%) sites. A lack of Cryptosporidium sp. in all samples examined suggests that this pathogen is not a natural component of the howler parasite communities at these sites and that current land-use patterns and livestock contact are not exposing Argentine howler monkeys to this pathogen. High prevalence of Giardia sp. at all sites suggests that howler monkeys may serve as a viable reservoir for Giardia. Significantly higher prevalence of Giardia sp. at the rural site, where primate-livestock contact is highest, suggests the presence of multiple Giardia clades or increased exposure to Giardia through repeated zoonotic transmission among nonhuman primates, livestock, and/or people. These results highlight the need for future research into the epidemiology, cross-species transmission ecology, and clinical consequences of Giardia and other infectious agents not only in humans and livestock, but also in the wild animals that share their environments. © 2010 Wiley-Liss, Inc.

Sub-chronic inhalation of high concentrations of manganese sulfate induces lower airway pathology in rhesus monkeys

PubMed Central

Dorman, David C; Struve, Melanie F; Gross, Elizabeth A; Wong, Brian A; Howroyd, Paul C

2005-01-01

Background Neurotoxicity and pulmonary dysfunction are well-recognized problems associated with prolonged human exposure to high concentrations of airborne manganese. Surprisingly, histological characterization of pulmonary responses induced by manganese remains incomplete. The primary objective of this study was to characterize histologic changes in the monkey respiratory tract following manganese inhalation. Methods Subchronic (6 hr/day, 5 days/week) inhalation exposure of young male rhesus monkeys to manganese sulfate was performed. One cohort of monkeys (n = 4–6 animals/exposure concentration) was exposed to air or manganese sulfate at 0.06, 0.3, or 1.5 mg Mn/m3 for 65 exposure days. Another eight monkeys were exposed to manganese sulfate at 1.5 mg Mn/m3 for 65 exposure days and held for 45 or 90 days before evaluation. A second cohort (n = 4 monkeys per time point) was exposed to manganese sulfate at 1.5 mg Mn/m3 and evaluated after 15 or 33 exposure days. Evaluations included measurement of lung manganese concentrations and evaluation of respiratory histologic changes. Tissue manganese concentrations were compared for the exposure and control groups by tests for homogeneity of variance, analysis of variance, followed by Dunnett's multiple comparison. Histopathological findings were evaluated using a Pearson's Chi-Square test. Results Animals exposed to manganese sulfate at ≥0.3 mg Mn/m3 for 65 days had increased lung manganese concentrations. Exposure to manganese sulfate at 1.5 mg Mn/m3 for ≥15 exposure days resulted in increased lung manganese concentrations, mild subacute bronchiolitis, alveolar duct inflammation, and proliferation of bronchus-associated lymphoid tissue. Bronchiolitis and alveolar duct inflammatory changes were absent 45 days post-exposure, suggesting that these lesions are reversible upon cessation of subchronic high-dose manganese exposure. Conclusion High-dose subchronic manganese sulfate inhalation is associated with increased lung manganese concentrations and small airway inflammatory changes in the absence of observable clinical signs. Subchronic exposure to manganese sulfate at exposure concentrations (≤0.3 mg Mn/m3) similar to the current 8-hr occupational threshold limit value established for inhaled manganese was not associated with pulmonary pathology. PMID:16242036

Bacillus Anthracis Spore Interactions with Mammalian Cells: Relationship Between Germination State and the Outcome of in Vitro Infections

DTIC Science & Technology

2011-02-28

unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Report Documentation Page Form ApprovedOMB... Peacock S, Belton FC: Observations on the prophylaxis of experimental pulmonary anthrax in the monkey. J Hyg (Lond) 1956, 54(1):28-36. 8. Cleret A

Induction of Type I Interferons by Therapeutic Nanoparticle-Based Vaccination Is Indispensable to Reinforce Cytotoxic CD8+ T Cell Responses During Chronic Retroviral Infection

PubMed Central

Knuschke, Torben; Rotan, Olga; Bayer, Wibke; Kollenda, Sebastian; Dickow, Julia; Sutter, Kathrin; Hansen, Wiebke; Dittmer, Ulf; Lang, Karl S.; Epple, Matthias; Buer, Jan; Westendorf, Astrid M.

2018-01-01

T cell dysfunction and immunosuppression are characteristic for chronic viral infections and contribute to viral persistence. Overcoming these burdens is the goal of new therapeutic strategies to cure chronic infectious diseases. We recently described that therapeutic vaccination of chronic retrovirus infected mice with a calcium phosphate (CaP) nanoparticle (NP)-based vaccine carrier, functionalized with CpG and viral peptides is able to efficiently reactivate the CD8+ T cell response and improve the eradication of virus infected cells. However, the mechanisms underlying this effect were largely unclear. While type I interferons (IFNs I) are considered to drive T cell exhaustion by persistent immune activation during chronic viral infection, we here describe an indispensable role of IFN I induced by therapeutic vaccination to efficiently reinforce cytotoxic CD8+ T cells (CTL) and improve control of chronic retroviral infection. The induction of IFN I is CpG dependent and leads to significant IFN signaling indicated by upregulation of IFN stimulated genes. By vaccinating chronically retrovirus-infected mice lacking the IFN I receptor (IFNAR−/−) or by blocking IFN I signaling in vivo during therapeutic vaccination, we demonstrate that IFN I signaling is necessary to drive full reactivation of CTLs. Surprisingly, we also identified an impaired suppressive capability of regulatory T cells in the presence of IFNα, which implicates an important role for vaccine-induced IFNα in the regulation of the T cell response during chronic retroviral infection. Our data suggest that inducing IFN I signaling in conjunction with the presentation of viral antigens can reactivate immune functions and reduce viral loads in chronic infections. Therefore, we propose CaP NPs as potential therapeutic tool to treat chronic infections. PMID:29740425

Viral FGARAT Homolog ORF75 of Rhesus Monkey Rhadinovirus Effects Proteasomal Degradation of the ND10 Components SP100 and PML.

PubMed

Hahn, Alexander S; Großkopf, Anna K; Jungnickl, Doris; Scholz, Brigitte; Ensser, Armin

2016-09-01

Nuclear domain 10 (ND10) components restrict herpesviral infection, and herpesviruses antagonize this restriction by a variety of strategies, including degradation or relocalization of ND10 proteins. The rhesus monkey rhadinovirus (RRV) shares many key biological features with the closely related Kaposi's sarcoma-associated herpesvirus (KSHV; human herpesvirus 8) and readily infects cells of both human and rhesus monkey origin. We used the clustered regularly interspaced short palindromic repeat-Cas9 (CRISPR-Cas9) technique to generate knockout (ko) cells for each of the four ND10 components, PML, SP100, DAXX, and ATRX. These ko cells were analyzed with regard to permissiveness for RRV infection. In addition, we analyzed the fate of the individual ND10 components in infected cells by immunofluorescence and Western blotting. Knockout of the ND10 component DAXX markedly increased RRV infection, while knockout of PML or SP100 had a less pronounced effect. In line with these observations, RRV infection resulted in rapid degradation of SP100, followed by degradation of PML and the loss of ND10 structures, whereas the protein levels of ATRX and DAXX remained constant. Notably, inhibition of the proteasome but not inhibition of de novo gene expression prevented the loss of SP100 and PML in cells that did not support lytic replication, compatible with proteasomal degradation of these ND10 components through the action of a viral tegument protein. Expression of the RRV FGARAT homolog ORF75 was sufficient to effect the loss of SP100 and PML in transfected or transduced cells, implicating ORF75 as the viral effector protein. Our findings highlight the antiviral role of ND10 and its individual components and further establish the viral FGARAT homologs of the gammaherpesviruses to be important viral effectors that counteract ND10-instituted intrinsic immunity. Surprisingly, even closely related viruses like KSHV and RRV evolved to use different strategies to evade ND10-mediated restriction. RRV first targets SP100 for degradation and then targets PML with a delayed kinetic, a strategy which clearly differs from that of other gammaherpesviruses. Despite efficient degradation of these two major ND10 components, RRV is still restricted by DAXX, another abundant ND10 component, as evidenced by a marked increase in RRV infection and replication upon knockout of DAXX. Taken together, our findings substantiate PML, SP100, and DAXX as key antiviral proteins, in that the first two are targeted for degradation by RRV and the last one still potently restricts replication of RRV. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

78 FR 63218 - Draft Guidance for Industry on Chronic Hepatitis C Virus Infection: Developing Direct-Acting...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-10-23

...] Draft Guidance for Industry on Chronic Hepatitis C Virus Infection: Developing Direct-Acting Antiviral... entitled ``Chronic Hepatitis C Virus Infection: Developing Direct-Acting Antiviral Drugs for Treatment... antiviral (DAA) drugs for the treatment of chronic hepatitis C. This guidance revises and replaces a...

TRPV1 and the MCP-1/CCR2 Axis Modulate Post-UTI Chronic Pain.

PubMed

Rosen, John M; Yaggie, Ryan E; Woida, Patrick J; Miller, Richard J; Schaeffer, Anthony J; Klumpp, David J

2018-05-08

The etiology of chronic pelvic pain syndromes remains unknown. In a murine urinary tract infection (UTI) model, lipopolysaccharide of uropathogenic E. coli and its receptor TLR4 are required for post-UTI chronic pain development. However, downstream mechanisms of post-UTI chronic pelvic pain remain unclear. Because the TRPV1 and MCP-1/CCR2 pathways are implicated in chronic neuropathic pain, we explored their role in post-UTI chronic pain. Mice were infected with the E. coli strain SΦ874, known to produce chronic allodynia, and treated with the TRPV1 antagonist capsazepine. Mice treated with capsazepine at the time of SΦ874 infection failed to develop chronic allodynia, whereas capsazepine treatment of mice at two weeks following SΦ874 infection did not reduce chronic allodynia. TRPV1-deficient mice did not develop chronic allodynia either. Similar results were found using novelty-suppressed feeding (NSF) to assess depressive behavior associated with neuropathic pain. Imaging of reporter mice also revealed induction of MCP-1 and CCR2 expression in sacral dorsal root ganglia following SΦ874 infection. Treatment with a CCR2 receptor antagonist at two weeks post-infection reduced chronic allodynia. Taken together, these results suggest that TRPV1 has a role in the establishment of post-UTI chronic pain, and CCR2 has a role in maintenance of post-UTI chronic pain.

Studies on Infectious Mononucleosis

PubMed Central

Joncas, J.; Lussier, G.; Pavilanis, V.

1966-01-01

Heparinized blood specimens obtained from two patients in the acute phase of infectious mononucleosis and from a healthy technician were injected intravenously into rhesus monkeys (Macaca mulatta) and the animals were observed for three weeks to one month for clinical, hematological and serological signs of infectious mononucleosis. Splenomegaly was the only definite clinical finding after 12 and 16 days, respectively. There were no definite hematological changes. At autopsy, hyperplasia of the germinal centres of lymphoid follicles, occasional foci of lymphocytic infiltration in the red pulp, and abnormal lymphoid cells in venules or arteries of the spleen were noted. The lesions in the spleen suggest that asymptomatic, presumably viral, infections occur in rhesus monkeys after inoculation with material from patients with infectious mononucleosis. ImagesFig. 1Fig. 2Fig. 3Fig. 4Fig. 5Fig. 6Fig. 7 PMID:4957314

Primate-to-Human Retroviral Transmission in Asia

PubMed Central

Engel, Gregory A.; Schillaci, Michael A.; Rompis, Aida; Putra, Artha; Suaryana, Komang Gde; Fuentes, Agustin; Beer, Brigitte; Hicks, Sarah; White, Robert; Wilson, Brenda; Allan, Jonathan S.

2005-01-01

We describe the first reported transmission to a human of simian foamy virus (SFV) from a free-ranging population of nonhuman primates in Asia. The transmission of an exogenous retrovirus, SFV, from macaques (Macaca fascicularis) to a human at a monkey temple in Bali, Indonesia, was investigated with molecular and serologic techniques. Antibodies to SFV were detected by Western blotting of serum from 1 of 82 humans tested. SFV DNA was detected by nested polymerase chain reaction (PCR) from the blood of the same person. Cloning and sequencing of PCR products confirmed the virus's close phylogenetic relationship to SFV isolated from macaques at the same temple. This study raises concerns that persons who work at or live around monkey temples are at risk for infection with SFV. PMID:16022776

Perinatal exposure of patas monkeys to antiretroviral nucleoside reverse-transcriptase inhibitors induces genotoxicity persistent for up to 3 years of age.

PubMed

Olivero, Ofelia A; Torres, Lorangelly Rivera; Gorjifard, Sayeh; Momot, Dariya; Marrogi, Eryney; Divi, Rao L; Liu, Yongmin; Woodward, Ruth A; Sowers, Marsha J; Poirier, Miriam C

2013-07-15

Erythrocebus patas (patas) monkeys were used to model antiretroviral (ARV) drug in human immunodeficiency virus type 1-infected pregnant women. Pregnant patas dams were given human-equivalent doses of ARVs daily during 50% of gestation. Mesenchymal cells, cultured from bone marrow of patas offspring obtained at birth and at 1 and 3 years of age, were examined for genotoxicity, including centrosomal amplification, micronuclei, and micronuclei containing whole chromosomes. Compared with controls, statistically significant increases (P < .05) in centrosomal amplification, micronuclei, and micronuclei containing whole chromosomes were found in mesenchymal cells from most groups of offspring at the 3 time points. Transplacental nucleoside reverse-transcriptase inhibitor exposures induced fetal genotoxicity that was persistent for 3 years.

Cardiovascular results from a rhesus monkey flown aboard the Cosmos 1514 spaceflight

NASA Technical Reports Server (NTRS)

Sandler, H.; Hines, J.; Benjamin, B. A.; Halpryn, B. M.; Krotov, V. P.

1987-01-01

The results of the Cosmos 1514 cardiovascular experiment, in which the blood flow to the head and the carotid pressure of a rhesus monkey were measured during the 5-d spaceflight, are reported. A single cylindrical probe containing both pressure and flow transducers was chronically implanted as a cuff around the left common carotid artery; measurements were obtained for 4 min every 2 h and compared to identical recordings obtained during a preflight control period and during 12 h on a launch pad. Immediately on its insertion into orbit, mean arterial pressure increased by 10 percent and has maintained a 16-27 percent increase over the first few hours of flight before returning to baseline level. Blood flow showed reciprocal changes to pressure on orbital insertion. Cardiovascular system changes persisted into the second day of flight, with the signs of adaptation appearing on days 3-5.

Characterization of the pH and Temperature in the Rabbit, Pig, and Monkey Eye: Key Parameters for the Development of Long-Acting Delivery Ocular Strategies.

PubMed

Lorget, Florence; Parenteau, Audrey; Carrier, Michel; Lambert, Daniel; Gueorguieva, Ana; Schuetz, Chris; Bantseev, Vlad; Thackaberry, Evan

2016-09-06

Many long-acting delivery strategies for ocular indications rely on pH- and/or temperature-driven release of the therapeutic agent and degradation of the drug carrier. Yet, these physiological parameters are poorly characterized in ocular animal models. These strategies aim at reducing the frequency of dosing, which is of particular interest for the treatment of chronic disorders affecting the posterior segment of the eye, such as macular degeneration that warrants monthly or every other month intravitreal injections. We used anesthetized white New Zealand rabbits, Yucatan mini pigs, and cynomolgus monkeys to characterize pH and temperature in several vitreous locations and the central aqueous location. We also established post mortem pH changes in the vitreous. Our data showed regional and species differences, which need to be factored into strategies for developing biodegradable long-acting delivery systems.

Decoding grating orientation from microelectrode array recordings in monkey cortical area V4.

PubMed

Manyakov, Nikolay V; Van Hulle, Marc M

2010-04-01

We propose an invasive brain-machine interface (BMI) that decodes the orientation of a visual grating from spike train recordings made with a 96 microelectrodes array chronically implanted into the prelunate gyrus (area V4) of a rhesus monkey. The orientation is decoded irrespective of the grating's spatial frequency. Since pyramidal cells are less prominent in visual areas, compared to (pre)motor areas, the recordings contain spikes with smaller amplitudes, compared to the noise level. Hence, rather than performing spike decoding, feature selection algorithms are applied to extract the required information for the decoder. Two types of feature selection procedures are compared, filter and wrapper. The wrapper is combined with a linear discriminant analysis classifier, and the filter is followed by a radial-basis function support vector machine classifier. In addition, since we have a multiclass classification problen, different methods for combining pairwise classifiers are compared.

Sex and menstrual cycle effects on chronic oral cocaine self-administration in rhesus monkeys: Effects of a nondrug alternative reward

PubMed Central

Carroll, Marilyn E.; Collins, Molly; Kohl, Emily A.; Johnson, Seth; Dougen, Ben

2016-01-01

Background In previous studies female monkeys self-administered more oral phencyclidine (PCP) than males, and PCP intake differed by phase of menstrual cycle. Objectives The purpose of this study was to examine sex and hormonal influences on oral cocaine self-administration in male and female rhesus monkeys in the follicular vs. luteal phases of the menstrual cycle, with concurrent access to an alternative nondrug reward, saccharin (SACC) vs. water. Materials and methods Concurrent access to cocaine (0.2, 0.4 and 0.8 mg/ml) and SACC or water was available from two drinking spouts under concurrent fixed-ratio (FR) 2, 4, and 8 schedules during daily 3-h sessions. Results Cocaine deliveries were similar in males and females in the females’ luteal phase, but cocaine deliveries were higher in females during the follicular phase than the luteal phase and compared to males. When SACC was available cocaine deliveries were reduced in females in the follicular phase of the cycle, and cocaine intake (mg/kg) was reduced in males and in females’ follicular and luteal phases. Conclusions Access to concurrent SACC (vs. water) reduced cocaine intake (mg/kg) in males and in females during both menstrual phases, and the magnitude of the reduction in cocaine intake was greatest during the females’ follicular phase. Thus, a nondrug alternative reward, SACC, is a viable alternative treatment for reducing cocaine’s rewarding effects on male and female monkeys, and reductions in cocaine-seeking were optimal in the females’ luteal phase. PMID:27318989

Behavioral and physiological responses to fruit availability of spider monkeys ranging in a small forest fragment

PubMed Central

Rimbach, Rebecca; Link, Andrés; Montes-Rojas, Andrés; Di Fiore, Anthony; Heistermann, Michael; Heymann, Eckhard W

2014-01-01

Numerous animal species currently experience habitat loss and fragmentation. This might result in behavioral and dietary adjustments, especially because fruit availability is frequently reduced in fragments. Food scarcity can result in elevated physiological stress levels, and chronic stress often has detrimental effects on individuals. Some animal species exhibit a high degree of fission–fusion dynamics, and theory predicts that these species reduce intragroup feeding competition by modifying their subgroup size according to resource availability. Until now, however, there have been few studies on how species with such fission–fission dynamics adjust their grouping patterns and social behavior in small fragments or on how food availability influences their stress levels. We collected data on fruit availability, feeding behavior, stress hormone levels (measured through fecal glucocorticoid metabolites (FGCM)), subgroup size, and aggression for two groups of brown spider monkeys (Ateles hybridus) in a small forest fragment in Colombia and examined whether fruit availability influences these variables. Contrary to our predictions, spider monkeys ranged in smaller subgroups, had higher FGCM levels and higher aggression rates when fruit availability was high compared to when it was low. The atypical grouping pattern of the study groups seems to be less effective at mitigating contest competition over food resources than more typical fission–fusion patterns. Overall, our findings illustrate that the relationship between resource availability, grouping patterns, aggression rates, and stress levels can be more complex than assumed thus far. Additional studies are needed to investigate the long-term consequences on the health and persistence of spider monkeys in fragmented habitats. PMID:24820229

Age-related alterations of plasma glutathione and oxidation of redox potentials in chimpanzee (Pan troglodytes) and rhesus monkey (Macaca mulatta).

PubMed

Paredes, Jamespaul; Jones, Dean P; Wilson, Mark E; Herndon, James G

2014-04-01

Chimpanzee (Pan troglodytes) and rhesus macaque (Macaca mulatta) and humans (Homo sapiens) share physiological and genetic characteristics, but have remarkably different life spans, with chimpanzees living 50-60 % and the rhesus living 35-40 % of maximum human survival. Since oxidative processes are associated with aging and longevity, we might expect to see species differences in age-related oxidative processes. Blood and extracellular fluid contain two major thiol redox nodes, glutathione (GSH)/glutathione-disulfide (GSSG) and cysteine (Cys)/cystine (CySS), which are subject to reversible oxidation-reduction reactions and are maintained in a dynamic non-equilibrium state. Disruption of these thiol redox nodes leads to oxidation of their redox potentials (EhGSSG and EhCySS) which affects cellular physiology and is associated with aging and the development of chronic diseases in humans. The purpose of this study was to measure age-related changes in these redox thiols and their corresponding redox potentials (Eh) in chimpanzees and rhesus monkeys. Our results show similar age-related decreases in the concentration of plasma GSH and Total GSH as well as oxidation of the EhGSSG in male and female chimpanzees. Female chimpanzees and female rhesus monkeys also were similar in several outcome measures. For example, similar age-related decreases in the concentration of plasma GSH and Total GSH, as well as age-related oxidation of the EhGSSG were observed. The data collected from chimpanzees and rhesus monkeys corroborates previous reports on oxidative changes in humans and confirms their value as a comparative reference for primate aging.

Rational design of a live attenuated dengue vaccine: 2'-o-methyltransferase mutants are highly attenuated and immunogenic in mice and macaques.

PubMed

Züst, Roland; Dong, Hongping; Li, Xiao-Feng; Chang, David C; Zhang, Bo; Balakrishnan, Thavamalar; Toh, Ying-Xiu; Jiang, Tao; Li, Shi-Hua; Deng, Yong-Qiang; Ellis, Brett R; Ellis, Esther M; Poidinger, Michael; Zolezzi, Francesca; Qin, Cheng-Feng; Shi, Pei-Yong; Fink, Katja

2013-01-01

Dengue virus is transmitted by Aedes mosquitoes and infects at least 100 million people every year. Progressive urbanization in Asia and South-Central America and the geographic expansion of Aedes mosquito habitats have accelerated the global spread of dengue, resulting in a continuously increasing number of cases. A cost-effective, safe vaccine conferring protection with ideally a single injection could stop dengue transmission. Current vaccine candidates require several booster injections or do not provide protection against all four serotypes. Here we demonstrate that dengue virus mutants lacking 2'-O-methyltransferase activity are highly sensitive to type I IFN inhibition. The mutant viruses are attenuated in mice and rhesus monkeys and elicit a strong adaptive immune response. Monkeys immunized with a single dose of 2'-O-methyltransferase mutant virus showed 100% sero-conversion even when a dose as low as 1,000 plaque forming units was administrated. Animals were fully protected against a homologous challenge. Furthermore, mosquitoes feeding on blood containing the mutant virus were not infected, whereas those feeding on blood containing wild-type virus were infected and thus able to transmit it. These results show the potential of 2'-O-methyltransferase mutant virus as a safe, rationally designed dengue vaccine that restrains itself due to the increased susceptibility to the host's innate immune response.

Rational Design of a Live Attenuated Dengue Vaccine: 2′-O-Methyltransferase Mutants Are Highly Attenuated and Immunogenic in Mice and Macaques

PubMed Central

Chang, David C.; Zhang, Bo; Balakrishnan, Thavamalar; Toh, Ying-Xiu; Jiang, Tao; Li, Shi-Hua; Deng, Yong-Qiang; Ellis, Brett R.; Ellis, Esther M.; Poidinger, Michael; Zolezzi, Francesca; Qin, Cheng-Feng; Shi, Pei-Yong; Fink, Katja

2013-01-01

Dengue virus is transmitted by Aedes mosquitoes and infects at least 100 million people every year. Progressive urbanization in Asia and South-Central America and the geographic expansion of Aedes mosquito habitats have accelerated the global spread of dengue, resulting in a continuously increasing number of cases. A cost-effective, safe vaccine conferring protection with ideally a single injection could stop dengue transmission. Current vaccine candidates require several booster injections or do not provide protection against all four serotypes. Here we demonstrate that dengue virus mutants lacking 2′-O-methyltransferase activity are highly sensitive to type I IFN inhibition. The mutant viruses are attenuated in mice and rhesus monkeys and elicit a strong adaptive immune response. Monkeys immunized with a single dose of 2′-O-methyltransferase mutant virus showed 100% sero-conversion even when a dose as low as 1,000 plaque forming units was administrated. Animals were fully protected against a homologous challenge. Furthermore, mosquitoes feeding on blood containing the mutant virus were not infected, whereas those feeding on blood containing wild-type virus were infected and thus able to transmit it. These results show the potential of 2′-O-methyltransferase mutant virus as a safe, rationally designed dengue vaccine that restrains itself due to the increased susceptibility to the host's innate immune response. PMID:23935499

Localizing chronic Q fever: a challenging query

PubMed Central

2013-01-01

Background Chronic Q fever usually presents as endocarditis or endovascular infection. We investigated whether 18F-FDG PET/CT and echocardiography were able to detect the localization of infection. Also, the utility of the modified Duke criteria was assessed. Methods Fifty-two patients, who had an IgG titre of ≥ 1024 against C. burnetii phase I ≥ 3 months after primary infection or a positive PCR ≥ 1 month after primary infection, were retrospectively included. Data on serology, the results of all imaging studies, possible risk factors for developing proven chronic Q fever and clinical outcome were recorded. Results According to the Dutch consensus on Q fever diagnostics, 18 patients had proven chronic Q fever, 14 probable chronic Q fever, and 20 possible chronic Q fever. Of the patients with proven chronic Q fever, 22% were diagnosed with endocarditis, 17% with an infected vascular prosthesis, and 39% with a mycotic aneurysm. 56% of patients with proven chronic Q fever did not recall an episode of acute Q fever. Ten out of 13 18F-FDG PET/CT-scans in patients with proven chronic Q fever localized the infection. TTE and TEE were helpful in only 6% and 50% of patients, respectively. Conclusions If chronic Q fever is diagnosed, 18F-FDG PET/CT is a helpful imaging technique for localization of vascular infections due to chronic Q fever. Patients with proven chronic Q fever were diagnosed significantly more often with mycotic aneurysms than in previous case series. Definite endocarditis due to chronic Q fever was less frequently diagnosed in the current study. Chronic Q fever often occurs in patients without a known episode of acute Q fever, so clinical suspicion should remain high, especially in endemic regions. PMID:24004470

Comparative Performance of Linear Multielectrode Probes and Single-Tip Electrodes for Intracortical Microstimulation and Single-Neuron Recording in Macaque Monkey

PubMed Central

Ferroni, Carolina G.; Maranesi, Monica; Livi, Alessandro; Lanzilotto, Marco; Bonini, Luca

2017-01-01

Intracortical microstimulation (ICMS) is one of the most widely employed techniques for providing causal evidence of the relationship between neuronal activity and specific motor, perceptual, or even cognitive functions. In recent years, several new types of linear multielectrode silicon probes have been developed, allowing researchers to sample neuronal activity at different depths along the same cortical site simultaneously and with high spatial precision. Nevertheless, silicon multielectrode probes have been rarely employed for ICMS studies and, more importantly, it is unknown whether and to what extent they can be used for combined recording and stimulation experiments. Here, we addressed these issues during both acute and chronic conditions. First, we compared the behavioral outcomes of ICMS delivered to the hand region of a monkey's motor cortex with multielectrode silicon probes, commercially available multisite stainless-steel probes and single-tip glass-coated tungsten microelectrodes. The results for all three of the probes were reliable and similar. Furthermore, we tested the impact of long-train ICMS delivered through chronically implanted silicon probes at different time intervals, from 1 to 198 days after ICMS sessions, showing that although the number of recorded neurons decreased over time, in line with previous studies, ICMS did not alter silicon probes' recording capabilities. These findings indicate that in ICMS experiments, the performance of linear multielectrode silicon probes is comparable to that of both single-tip and multielectrode stainless-steel probes, suggesting that the silicon probes can be successfully used for combined recording and stimulation studies in chronic conditions. PMID:29187815

Comparative Performance of Linear Multielectrode Probes and Single-Tip Electrodes for Intracortical Microstimulation and Single-Neuron Recording in Macaque Monkey.

PubMed

Ferroni, Carolina G; Maranesi, Monica; Livi, Alessandro; Lanzilotto, Marco; Bonini, Luca

2017-01-01

Intracortical microstimulation (ICMS) is one of the most widely employed techniques for providing causal evidence of the relationship between neuronal activity and specific motor, perceptual, or even cognitive functions. In recent years, several new types of linear multielectrode silicon probes have been developed, allowing researchers to sample neuronal activity at different depths along the same cortical site simultaneously and with high spatial precision. Nevertheless, silicon multielectrode probes have been rarely employed for ICMS studies and, more importantly, it is unknown whether and to what extent they can be used for combined recording and stimulation experiments. Here, we addressed these issues during both acute and chronic conditions. First, we compared the behavioral outcomes of ICMS delivered to the hand region of a monkey's motor cortex with multielectrode silicon probes, commercially available multisite stainless-steel probes and single-tip glass-coated tungsten microelectrodes. The results for all three of the probes were reliable and similar. Furthermore, we tested the impact of long-train ICMS delivered through chronically implanted silicon probes at different time intervals, from 1 to 198 days after ICMS sessions, showing that although the number of recorded neurons decreased over time, in line with previous studies, ICMS did not alter silicon probes' recording capabilities. These findings indicate that in ICMS experiments, the performance of linear multielectrode silicon probes is comparable to that of both single-tip and multielectrode stainless-steel probes, suggesting that the silicon probes can be successfully used for combined recording and stimulation studies in chronic conditions.

Chronic Ketamine Exposure Causes White Matter Microstructural Abnormalities in Adolescent Cynomolgus Monkeys.

PubMed

Li, Qi; Shi, Lin; Lu, Gang; Yu, Hong-Luan; Yeung, Fu-Ki; Wong, Nai-Kei; Sun, Lin; Liu, Kai; Yew, David; Pan, Fang; Wang, De-Feng; Sham, Pak C

2017-01-01

Acute and repeated exposures to ketamine mimic aspects of positive, negative, and cognitive symptoms of schizophrenia in humans. Recent studies by our group and others have shown that chronicity of ketamine use may be a key element for establishing a more valid model of cognitive symptoms of schizophrenia. However, current understanding on the long-term consequences of ketamine exposure on brain circuits has remained incomplete, particularly with regard to microstructural changes of white matter tracts that underpin the neuropathology of schizophrenia. Thus, the present study aimed to expand on previous investigations by examining causal effects of repeated ketamine exposure on white matter integrity in a non-human primate model. Ketamine or saline (control) was administered intravenously for 3 months to male adolescent cynomolgus monkeys ( n = 5/group). Diffusion tensor imaging (DTI) experiments were performed and tract-based spatial statistics (TBSS) was used for data analysis. Fractional anisotropy (FA) was quantified across the whole brain. Profoundly reduced FA on the right side of sagittal striatum, posterior thalamic radiation (PTR), retrolenticular limb of the internal capsule (RLIC) and superior longitudinal fasciculus (SLF), and on the left side of PTR, middle temporal gyrus and inferior frontal gyrus were observed in the ketamine group compared to controls. Diminished white matter integrity found in either fronto-thalamo-temporal or striato-thalamic connections with tracts including the SLF, PTR, and RLIC lends support to similar findings from DTI studies on schizophrenia in humans. This study suggests that chronic ketamine exposure is a useful pharmacological paradigm that might provide translational insights into the pathophysiology and treatment of schizophrenia.

Reproduction of Epstein-Barr Virus Infection and Pathogenesis in Humanized Mice

PubMed Central

2014-01-01

Epstein-Barr virus (EBV) is etiologically associated with a variety of diseases including lymphoproliferative diseases, lymphomas, carcinomas, and autoimmune diseases. Humans are the only natural host of EBV and limited species of new-world monkeys can be infected with the virus in experimental conditions. Small animal models of EBV infection, required for evaluation of novel therapies and vaccines for EBV-associated diseases, have not been available. Recently the development of severely immunodeficient mouse strains enabled production of humanized mice in which human immune system components are reconstituted and express their normal functions. Humanized mice can serve as infection models for human-specific viruses such as EBV that target cells of the immune system. This review summarizes recent studies by the author's group addressing reproduction of EBV infection and pathogenesis in humanized mice. PMID:24605074

Acute liver failure during treatment of interferon alpha 2a chronic hepatitis B and coinfection of parvovirus B19

PubMed

Sobala-Szczygieł, Barbara; Boroń-Kaczmarska, Anna; Kępa, Lucjan; Oczko-Grzesik, Barbara; Piotrowski, Damian; Stolarz, Wojciech

Parvovirus B19 infection is associated with a broad spectrum of clinical manifestations among which some are well known but others remain controversial. The role of this infection as a cause of acute hepatitis or exacerbation of chronic liver disease requires discussion regarding its significance in a strategy of prevention and treatment of patients with chronic hepatitis. Clinical importance of this infection in patients with chronic hepatitis B treated with pegylated interferon alpha 2a is still unclear but exactly in this population significant complications during treatment may arise. Parvovirus B19 infection is not rare among persons with chronic hepatitis B, therefore searching for co-infection should be placed in standard diagnostic procedures especially in case of exacerbation of chronic hepatitis, pancytopaenia or anaemia of unknown origin. Pegylated interferon alpha 2a still remains a gold standard of therapy of patients with chronic hepatitis B according to European (EASL) and Polish guidelines. We present a case of 35 years old woman treated with pegylated interferon alpha 2a who developed acute liver failure in 23rd week of chronic hepatitis B therapy. An exacerbation of hepatitis with encephalopathy and pancytopaenia have been observed. Parvovirus B19 and HBV co-infection does not increase the frequency of liver function abnormalities in patients with chronic hepatitis B. Further investigations should be done to describe the natural course of co-infection with parvovirus B19 and HBV and to establish possible association between parvovirus B19 infection and chronic hepatitis B and also the influence of interferon alpha 2a on the infections course.

Proteomic profiling in MPTP monkey model for early Parkinson disease biomarker discovery

PubMed Central

Lin, Xiangmin; Shi, Min; Gunasingh Masilamoni, Jeyaraj; Dator, Romel; Movius, James; Aro, Patrick; Smith, Yoland; Zhang, Jing

2015-01-01

Identification of reliable and robust biomarkers is crucial to enable early diagnosis of Parkinson disease (PD) and monitoring disease progression. While imperfect, the slow, chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced non-human primate animal model system of parkinsonism is an abundant source of pre-motor or early stage PD biomarker discovery. Here, we present a study of a MPTP rhesus monkey model of PD that utilizes complementary quantitative iTRAQ-based proteomic, glycoproteomics and phosphoproteomics approaches. We compared the glycoprotein, non-glycoprotein, and phosphoprotein profiles in the putamen of asymptomatic and symptomatic MPTP-treated monkeys as well as saline injected controls. We identified 86 glycoproteins, 163 non-glycoproteins, and 71 phosphoproteins differentially expressed in the MPTP-treated groups. Functional analysis of the data sets inferred the biological processes and pathways that link to neurodegeneration in PD and related disorders. Several potential biomarkers identified in this study have already been translated for their usefulness in PD diagnosis in human subjects and further validation investigations are currently under way. In addition to providing potential early PD biomarkers, this comprehensive quantitative proteomic study may also shed insights regarding the mechanisms underlying early PD development. This article is part of a Special Issue entitled: Neuroproteomics: Applications in neuroscience and neurology. PMID:25617661

Immunization against an IL-6 peptide induces anti-IL-6 antibodies and modulates the Delayed-Type Hypersensitivity reaction in cynomolgus monkeys.

PubMed

Desallais, Lucille; Bouchez, Caroline; Mouhsine, Hadley; Moreau, Gabriel; Ratsimandresy, Rojo; Montes, Matthieu; Do, Hervé; Quintin-Colonna, Françoise; Zagury, Jean-François

2016-01-19

Interleukin-6 (IL-6) overproduction has been involved in the pathogenesis of several chronic inflammatory diseases and the administration of an anti-IL-6 receptor monoclonal antibody has been proven clinically efficient to treat them. However, the drawbacks of monoclonal antibodies have led our group to develop an innovative anti-IL-6 strategy using a peptide-based active immunization. This approach has previously shown its efficacy in a mouse model of systemic sclerosis. Here the safety, immunogenicity, and efficacy of this strategy was assessed in non human primates. No unscheduled death and clinical signs of toxicity was observed during the study. Furthermore, the cynomolgus monkeys immunized against the IL-6 peptide produced high levels of anti-IL-6 antibodies as well as neutralizing antibodies compared to control groups. They also showed an important decrease of the cumulative inflammatory score following a delayed-type hypersensitivity reaction induced by the Tetanus vaccine compared to control groups (minus 57,9%, P = 0.014). These findings are highly significant because the immunizing IL-6 peptide used in this study is identical in humans and in monkeys and this novel anti-IL-6 strategy could thus represent a promising alternative to monoclonal antibodies.

Inhibition of human immunodeficiency virus type 1 replication by SDZ NIM 811, a nonimmunosuppressive cyclosporine analog.

PubMed Central

Rosenwirth, B; Billich, A; Datema, R; Donatsch, P; Hammerschmid, F; Harrison, R; Hiestand, P; Jaksche, H; Mayer, P; Peichl, P

1994-01-01

(Me-Ile-4)cyclosporin (SDZ NIM 811) is a 4-substituted cyclosporin which is devoid of immunosuppressive activity but retains full capacity for binding to cyclophilin and exhibits potent anti-human immunodeficiency virus type 1 (HIV-1) activity. SDZ NIM 811 selectively inhibits HIV-1 replication in T4 lymphocyte cell lines, in a monocytic cell line, and in HeLa T4 cells. Furthermore, its antiviral activity against laboratory strains and against clinical isolates from geographically distinct regions in primary T4 lymphocytes and in primary monocytes (50% inhibitory concentration = 0.011 to 0.057 micrograms/ml) was demonstrated. SDZ NIM 811 does not inhibit proviral gene expression or virus-specific enzyme functions, either free or bound to cyclophilin. The compound does not influence CD4 expression or inhibit fusion between virus-infected and uninfected cells. SDZ NIM 811 was, however, found to block formation of infectious particles from chronically infected cells. Oral administration to mice, rats, dogs, and monkeys resulted in levels in blood considerably exceeding the drug concentration, which completely blocked virus replication in primary cells. SDZ NIM 811 caused changes of toxicity parameters in rats to a smaller degree than cyclosporine (formerly cyclosporin A). Thus, the potent and selective anti-HIV-1 activity of SDZ NIM 811 and its favorable pharmacokinetic behavior together with its lower nephrotoxicity than that of cyclosporine make this compound a promising candidate for development as an anti-HIV drug. PMID:7527198

Inhibition of human immunodeficiency virus type 1 replication by SDZ NIM 811, a nonimmunosuppressive cyclosporine analog.

PubMed

Rosenwirth, B; Billich, A; Datema, R; Donatsch, P; Hammerschmid, F; Harrison, R; Hiestand, P; Jaksche, H; Mayer, P; Peichl, P

1994-08-01

(Me-Ile-4)cyclosporin (SDZ NIM 811) is a 4-substituted cyclosporin which is devoid of immunosuppressive activity but retains full capacity for binding to cyclophilin and exhibits potent anti-human immunodeficiency virus type 1 (HIV-1) activity. SDZ NIM 811 selectively inhibits HIV-1 replication in T4 lymphocyte cell lines, in a monocytic cell line, and in HeLa T4 cells. Furthermore, its antiviral activity against laboratory strains and against clinical isolates from geographically distinct regions in primary T4 lymphocytes and in primary monocytes (50% inhibitory concentration = 0.011 to 0.057 micrograms/ml) was demonstrated. SDZ NIM 811 does not inhibit proviral gene expression or virus-specific enzyme functions, either free or bound to cyclophilin. The compound does not influence CD4 expression or inhibit fusion between virus-infected and uninfected cells. SDZ NIM 811 was, however, found to block formation of infectious particles from chronically infected cells. Oral administration to mice, rats, dogs, and monkeys resulted in levels in blood considerably exceeding the drug concentration, which completely blocked virus replication in primary cells. SDZ NIM 811 caused changes of toxicity parameters in rats to a smaller degree than cyclosporine (formerly cyclosporin A). Thus, the potent and selective anti-HIV-1 activity of SDZ NIM 811 and its favorable pharmacokinetic behavior together with its lower nephrotoxicity than that of cyclosporine make this compound a promising candidate for development as an anti-HIV drug.

Primary peak and chronic malaria infection levels are correlated in experimentally infected great reed warblers.

PubMed

Asghar, Muhammad; Westerdahl, Helena; Zehtindjiev, Pavel; Ilieva, Mihaela; Hasselquist, Dennis; Bensch, Staffan

2012-09-01

Malaria parasites often manage to maintain an infection for several months or years in their vertebrate hosts. In humans, rodents and birds, most of the fitness costs associated with malaria infections are in the short initial primary (high parasitaemia) phase of the infection, whereas the chronic phase (low parasitaemia) is more benign to the host. In wild birds, malaria parasites have mainly been studied during the chronic phase of the infection. This is because the initial primary phase of infection is short in duration and infected birds with severe disease symptoms tend to hide in sheltered places and are thus rarely caught and sampled. We therefore wanted to investigate the relationship between the parasitaemia during the primary and chronic phases of the infection using an experimental infection approach. We found a significant positive correlation between parasitaemia in the primary peak and the subsequent chronic phase of infection when we experimentally infected great reed warblers (Acrocephalus arundinaceus) with Plasmodium ashfordi. The reason for this association remains to be understood, but might arise from individual variation in exoerythrocytic parasite reservoirs in hosts, parasite antigenic diversity and/or host genetics. Our results suggest that the chronic phase parasitaemia can be used to qualitatively infer the parasitaemia of the preceding and more severe primary phase, which is a very important finding for studies of avian malaria in wild populations.

Effects of Chronic Ascariasis and Trichuriasis on Cytokine Production and Gene Expression in Human Blood: A Cross-Sectional Study

PubMed Central

Benitez, Susana; Broncano, Nely; Chico, Martha E.; Vaca, Maritza; Alexander, Neal; Lewis, David J.; Dougan, Gordon; Cooper, Philip J.

2011-01-01

Background Chronic soil-transmitted helminth (STH) infections are associated with effects on systemic immune responses that could be caused by alterations in immune homeostasis. To investigate this, we measured the impact in children of STH infections on cytokine responses and gene expression in unstimulated blood. Methodology/Principal Findings Sixty children were classified as having chronic, light, or no STH infections. Peripheral blood mononuclear cells were cultured in medium for 5 days to measure cytokine accumulation. RNA was isolated from peripheral blood and gene expression analysed using microarrays. Different infection groups were compared for the purpose of analysis: STH infection (combined chronic and light vs. uninfected groups) and chronic STH infection (chronic vs. combined light and uninfected groups). The chronic STH infection effect was associated with elevated production of GM-CSF (P = 0.007), IL-2 (P = 0.03), IL-5 (P = 0.01), and IL-10 (P = 0.01). Data reduction suggested that chronic infections were primarily associated with an immune phenotype characterized by elevated IL-5 and IL-10, typical of a modified Th2-like response. Chronic STH infections were associated with the up-regulation of genes associated with immune homeostasis (IDO, P = 0.03; CCL23, P = 0.008, HRK, P = 0.005), down-regulation of microRNA hsa-let-7d (P = 0.01) and differential regulation of several genes associated with granulocyte-mediated inflammation (IL-8, down-regulated, P = 0.0002; RNASE2, up-regulated, P = 0.009; RNASE3, up-regulated, p = 0.03). Conclusions/Significance Chronic STH infections were associated with a cytokine response indicative of a modified Th2 response. There was evidence that STH infections were associated with a pattern of gene expression suggestive of the induction of homeostatic mechanisms, the differential expression of several inflammatory genes and the down-regulation of microRNA has-let-7d. Effects on immune homeostasis and the development of a modified Th2 immune response during chronic STH infections could explain the systemic immunologic effects that have been associated with these infections such as impaired immune responses to vaccines and the suppression of inflammatory diseases. PMID:21666788

Effects of chronic avian malaria (Plasmodium relictum) infection on reproductive success of Hawaii Amakihi (Hemignathus virens)

USGS Publications Warehouse

Kilpatrick, A.M.; Lapointe, D.A.; Atkinson, C.T.; Woodworth, B.L.; Lease, J.K.; Reiter, M.E.; Gross, K.

2006-01-01

We studied the effects of chronic avian malaria (Plasmodium relictum) infections on the reproductive success of a native Hawaiian honeycreeper, Hawaii Amakihi (Hemignathus virens). Chronic malaria infections in male and female parents did not significantly reduce reproductive success as measured by clutch size, hatching success, fledging mass, number of nestlings fledged, nesting success (daily survival rate), and minimum fledgling survival. In fact, nesting success of pairs with chronically infected males was significantly higher than those with uninfected males (76% vs. 38%), and offspring that had at least one parent that had survived the acute phase of malaria infection had a significantly greater chance of being resighted the following year (25% vs. 10%). The reproduction and survival of infected birds were sufficient for a per-capita population growth rate >1, which suggests that chronically infected Hawaii Amakihi could support a growing population.

Chronic bystander infections and immunity to unrelated antigens

PubMed Central

Stelekati, Erietta; Wherry, E. John

2012-01-01

Chronic infections with persistent pathogens such as helminths, mycobacteria, Plasmodium and hepatitis viruses affect more than a third of the human population and are associated with increased susceptibility to other pathogens as well as reduced vaccine efficacy. Although these observations suggest an impact of chronic infections in modulating immunity to unrelated antigens, little is known regarding the underlying mechanisms. Here, we summarize evidence of the most prevalent infections affecting immunity to unrelated pathogens and vaccines, and discuss potential mechanisms of how different bystander chronic infections might impact immune responses. We suggest that bystander chronic infections affect different stages of host responses and may impact transmission of other pathogens, recognition and innate immune responses, priming and differentiation of adaptive effector responses, as well as the development and maintenance of immunological memory. Further understanding of the immunological effects of co-infection should provide opportunities to enhance vaccine efficacy and control infectious diseases. PMID:23084915

Thermoregulation: long-term microwave effects. Final report 1 Feb 83-31 Jan 84

DOE Office of Scientific and Technical Information (OSTI.GOV)

Adair, E.R.

1984-04-17

A pilot study investigated the consequences of chronic exposure to 2450-MHz CW microwaves, or sham exposure, in a cold (18 degC) environment on the thermoregulatory responses, both behavioral and physiological, of squirrel monkeys. Two animals exposed to microwaves exhibited responses that were little different from those measured in animals residing in thermoneutral environments while two sham-exposed animals sustained thermoregulatory deficits. These tentative findings require replication.

Hepatitis E Virus in 3 Types of Laboratory Animals, China, 2012-2015.

PubMed

Wang, Lin; Zhang, Yulin; Gong, Wanyun; Song, William Tianshi; Wang, Ling

2016-12-01

We found seroprevalences for hepatitis E virus (HEV) of 7.5%, 18.5%, and 83.3% in specific pathogen-free (SPF) laboratory rabbits, monkeys, and pigs, respectively, in China. HEV RNA was detected in 4.8% of SPF rabbits, and 11 rabbits had latent infections. Screening for HEV in SPF animals before relevant experiments are conducted is recommended.

Effective protection of monkeys against death from street virus by post-exposure administration of tissue-culture rabies vaccine

PubMed Central

Sikes, R. K.; Cleary, W. F.; Koprowski, H.; Wiktor, T. J.; Kaplan, M. M.

1971-01-01

Three series of experiments on rabies vaccines were carried out on rhesus monkeys using suckling-mouse-brain vaccine, rabbit-brain vaccine, duck-embryo vaccine, and purified, concentrated tissue-culture vaccine. The latter was prepared in a human diploid cell strain and inactivated with β-propiolactone, and consisted of tissue-culture fluid concentrated 200-fold with a final infectivity titre of 109.8 plaque-forming units per ml before inactivation. In the first two series of experiments, several vaccines were tested for relative immunogenicity on a pre-exposure basis. In the third series, a successful model was developed in which a single inoculation of the tissue-culture vaccine administered after exposure to rabies virus, with or without accompanying standard doses of antirabies serum, was evaluated as a method of prevention. A single dose of the tissue-culture vaccine protected 7 out of 8 monkeys from death by street virus. Homologous or heterologous antirabies serum alone gave poor results. The results indicate great promise for prophylaxis in man with one dose, or perhaps a few doses, of highly concentrated, purified tissue-culture vaccine. PMID:5004004

Euthanasia assessment in ebola virus infected nonhuman primates.

PubMed

Warren, Travis K; Trefry, John C; Marko, Shannon T; Chance, Taylor B; Wells, Jay B; Pratt, William D; Johnson, Joshua C; Mucker, Eric M; Norris, Sarah L; Chappell, Mark; Dye, John M; Honko, Anna N

2014-11-24

Multiple products are being developed for use against filoviral infections. Efficacy for these products will likely be demonstrated in nonhuman primate models of filoviral disease to satisfy licensure requirements under the Animal Rule, or to supplement human data. Typically, the endpoint for efficacy assessment will be survival following challenge; however, there exists no standardized approach for assessing the health or euthanasia criteria for filovirus-exposed nonhuman primates. Consideration of objective criteria is important to (a) ensure test subjects are euthanized without unnecessary distress; (b) enhance the likelihood that animals exhibiting mild or moderate signs of disease are not prematurely euthanized; (c) minimize the occurrence of spontaneous deaths and loss of end-stage samples; (d) enhance the reproducibility of experiments between different researchers; and (e) provide a defensible rationale for euthanasia decisions that withstands regulatory scrutiny. Historic records were compiled for 58 surviving and non-surviving monkeys exposed to Ebola virus at the US Army Medical Research Institute of Infectious Diseases. Clinical pathology parameters were statistically analyzed and those exhibiting predicative value for survival are reported. These findings may be useful for standardization of objective euthanasia assessments in rhesus monkeys exposed to Ebola virus and may serve as a useful approach for other standardization efforts.

[Insertional Inactivation of Virulence Operon in Population of Persistent Bordetella pertussis Bacteria].

PubMed

Karataev, G I; Sinyashina, L N; Medkova, A Yu; Semin, E G; Shevtsova, Z V; Matua, A Z; Kondzariya, I G; Amichba, A A; Kubrava, D T; Mikvabia, Z Ya

2016-04-01

Avirulent B. pertussis bacteria containing IS elements in the bvgAS operon were detected during the study of whooping cough patients and bacilli carriers. The present work is devoted to the study of the accumulation dynamics and the mechanisms of generation of persistent forms of the B. pertussis bacteria in lower monkeys as the most adequate model for extrapolation ofthe experiment results to humans. By means of the real-time PCR method, it was established that the B. pertussis bacteria lived more than three months in the upper respiratory tract after a single intranasal monkey infection; the period was reduced to 14-28 days during repeated infection. An increase in the portion of B. pertussis Bvg mutants in the population to tens of percent from the total number of registered bacteria was registered. The experimental confirmation ofthe development and accumulation of avirulent B. pertussis Bvg mutants during the development of the infectious process was obtained. Further study of the composition of the B. pertussis persistent bacteria population at different stages of the disease will make it possible to formulate new approaches to the whooping cough diagnostics and prevention and creation of fundamentally new drugs.

Euthanasia Assessment in Ebola Virus Infected Nonhuman Primates

PubMed Central

Warren, Travis K.; Trefry, John C.; Marko, Shannon T.; Chance, Taylor B.; Wells, Jay B.; Pratt, William D.; Johnson, Joshua C.; Mucker, Eric M.; Norris, Sarah L.; Chappell, Mark; Dye, John M.; Honko, Anna N.

2014-01-01

Multiple products are being developed for use against filoviral infections. Efficacy for these products will likely be demonstrated in nonhuman primate models of filoviral disease to satisfy licensure requirements under the Animal Rule, or to supplement human data. Typically, the endpoint for efficacy assessment will be survival following challenge; however, there exists no standardized approach for assessing the health or euthanasia criteria for filovirus-exposed nonhuman primates. Consideration of objective criteria is important to (a) ensure test subjects are euthanized without unnecessary distress; (b) enhance the likelihood that animals exhibiting mild or moderate signs of disease are not prematurely euthanized; (c) minimize the occurrence of spontaneous deaths and loss of end-stage samples; (d) enhance the reproducibility of experiments between different researchers; and (e) provide a defensible rationale for euthanasia decisions that withstands regulatory scrutiny. Historic records were compiled for 58 surviving and non-surviving monkeys exposed to Ebola virus at the US Army Medical Research Institute of Infectious Diseases. Clinical pathology parameters were statistically analyzed and those exhibiting predicative value for survival are reported. These findings may be useful for standardization of objective euthanasia assessments in rhesus monkeys exposed to Ebola virus and may serve as a useful approach for other standardization efforts. PMID:25421892

A PfRH5-Based Vaccine Is Efficacious against Heterologous Strain Blood-Stage Plasmodium falciparum Infection in Aotus Monkeys

PubMed Central

Douglas, Alexander D.; Baldeviano, G. Christian; Lucas, Carmen M.; Lugo-Roman, Luis A.; Crosnier, Cécile; Bartholdson, S. Josefin; Diouf, Ababacar; Miura, Kazutoyo; Lambert, Lynn E.; Ventocilla, Julio A.; Leiva, Karina P.; Milne, Kathryn H.; Illingworth, Joseph J.; Spencer, Alexandra J.; Hjerrild, Kathryn A.; Alanine, Daniel G.W.; Turner, Alison V.; Moorhead, Jeromy T.; Edgel, Kimberly A.; Wu, Yimin; Long, Carole A.; Wright, Gavin J.; Lescano, Andrés G.; Draper, Simon J.

2015-01-01

Summary Antigenic diversity has posed a critical barrier to vaccine development against the pathogenic blood-stage infection of the human malaria parasite Plasmodium falciparum. To date, only strain-specific protection has been reported by trials of such vaccines in nonhuman primates. We recently showed that P. falciparum reticulocyte binding protein homolog 5 (PfRH5), a merozoite adhesin required for erythrocyte invasion, is highly susceptible to vaccine-inducible strain-transcending parasite-neutralizing antibody. In vivo efficacy of PfRH5-based vaccines has not previously been evaluated. Here, we demonstrate that PfRH5-based vaccines can protect Aotus monkeys against a virulent vaccine-heterologous P. falciparum challenge and show that such protection can be achieved by a human-compatible vaccine formulation. Protection was associated with anti-PfRH5 antibody concentration and in vitro parasite-neutralizing activity, supporting the use of this in vitro assay to predict the in vivo efficacy of future vaccine candidates. These data suggest that PfRH5-based vaccines have potential to achieve strain-transcending efficacy in humans. PMID:25590760

Maternal Azithromycin Therapy for Ureaplasma Intra-Amniotic Infection Delays Preterm Delivery and Reduces Fetal Lung Injury in a Primate Model

PubMed Central

Grigsby, Peta L.; Novy, Miles J.; Sadowsky, Drew W.; Morgan, Terry K.; Long, Mary; Acosta, Ed; Duffy, Lynn B; Waites, Ken B.

2012-01-01

Objective We assessed the efficacy of a maternal multi–dose azithromycin (AZI) regimen, with and without anti–inflammatory agents to delay preterm birth and to mitigate fetal lung injury associated with Ureaplasma parvum intra–amniotic infection (IAI). Study Design Long–term catheterized rhesus monkeys (n=16) received intra–amniotic inoculation of U. parvum (107 CFU/ml, serovar 1). After contraction onset, rhesus monkeys received either no treatment (n=6); AZI (12.5mg/kg, q12h, IV for 10 days; n=5); or AZI plus dexamethasone (DEX) and indomethacin (INDO; n=5). Outcomes included amniotic fluid pro–inflammatory mediators, U. parvum cultures & PCR, AZI pharmacokinetics and the extent of fetal lung inflammation. Results Maternal AZI therapy eradicated U. parvum IAI from the amniotic fluid within 4 days. Placenta and fetal tissues were 90% culture negative at delivery. AZI therapy significantly delayed preterm delivery and prevented advanced fetal lung injury, although residual acute chorioamnionitis persisted. Conclusions Specific maternal antibiotic therapy can eradicate U. parvum from the amniotic fluid and key fetal organs, with subsequent prolongation of pregnancy which provides a therapeutic window of opportunity to effectively reduce the severity of fetal lung injury. PMID:23111115

Seroprevalence of Toxoplasma gondii infection in captive mammals in three zoos in Mexico City, Mexico.

PubMed

Alvarado-Esquivel, Cosme; Gayosso-Dominguez, Edgar Arturo; Villena, Isabelle; Dubey, J P

2013-09-01

Antibodies to Toxoplasma gondii were determined in 167 mammals in three zoos in Mexico City, Mexico, using the modified agglutination test (MAT). Overall, antibodies to T. gondii were found in 89 (53.3%) of the 167 animals tested. Antibodies were found in 35 of 43 wild Felidae: 2 of 2 bobcats (Lynx rufus); 4 of 4 cougars (Puma concolor); 10 of 13 jaguars (Panthera onca); 5 of 5 leopards (Panthera pardus); 7 of 7 lions (Panthera leo); 2 of 3 tigers (Panthera tigris); 2 of 3 ocelots (Leopardus pardalis); 2 of 2 Sumatran tigers (Panthera tigris sumatrae); lof 2 Jaguarundi (Herpailurus jagouaroundi); but not in 0 of 2 oncillas (Leopardus tigrinus). Such high seroprevalence in wild felids is of public health significance because of the potential of oocyst shedding. Four of 6 New World primates (2 of 2 Geoffroy's spider monkeys [Ateles geoffroyi], 1 of 3 Patas monkeys [Erythrocebus patas], and 1 of 1 white-headed capuchin [Cebus capucinus]) had high MAT titers of 3,200, suggesting recently acquired infection; these animals are highly susceptible to clinical toxoplasmosis. However, none of these animals were ill. Seropositivity to T. gondii was found for the first time in a number of species.

One time quantitative PCR detection of Pseudomonas aeruginosa to discriminate intermittent from chronic infection in cystic fibrosis.

PubMed

Boutin, Sébastien; Weitnauer, Michael; Hassel, Selina; Graeber, Simon Y; Stahl, Mirjam; Dittrich, A Susanne; Mall, Marcus A; Dalpke, Alexander H

2018-05-01

Chronic airway infection with Pseudomonas aeruginosa is a major risk factor of progression of lung disease in patients with cystic fibrosis (CF). Chronic P. aeruginosa infection evolves from intermittent infection that is amenable to antibiotic eradication, whereas chronically adapted P. aeruginosa becomes resistant to antibiotic therapy. Discrimination of intermittent versus chronic infection is therefore of high therapeutic relevance, yet the available diagnostic methods are only partly satisfactory. The aim of the present study was, therefore, to evaluate the usage of quantitative PCR (qPCR) to measure pathogen abundance and to discriminate between intermittent and chronic Pseudomonas infection in patients with CF. Using an established qPCR protocol, we analyzed the abundance of P. aeruginosa in 141 throats swabs and 238 sputa from CF patients with intermittent or chronic infection with P. aeruginosa, as determined by standard culture based diagnostics. We observed a large increase of abundance of P. aeruginosa in throat swabs and sputum samples from patients with chronic compared to intermittent infections with P. aeruginosa. The data show that abundance of P. aeruginosa as measured by qPCR is a valuable tool to discriminate intermittent from chronic infection. Of note, P. aeruginosa burden seems more sensitive than mucoidity phenotype to discriminate chronic from intermittent strains. Furthermore we observed that molecular detection in throat swabs was linked to a viable culture in the sputum when sputum was available. This result is of special interest in young patients with cystic fibrosis that often cannot expectorate sputum. We also observed that qPCR in comparison to culture detected the infection earlier. The results suggest that qPCR detection and quantification of P. aeruginosa is a precious tool to be added to the diagnostic toolbox in cystic fibrosis. Copyright © 2018 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

No evidence for transmission of SIVwrc from western red colobus monkeys (piliocolobus badius badius) to wild west african chimpanzees (pan troglodytes verus) despite high exposure through hunting

PubMed Central

2011-01-01

Background Simian Immunodeficiency Viruses (SIVs) are the precursors of Human Immunodeficiency Viruses (HIVs) which have lead to the worldwide HIV/AIDS pandemic. By studying SIVs in wild primates we can better understand the circulation of these viruses in their natural hosts and habitat, and perhaps identify factors that influence susceptibility and transmission within and between various host species. We investigated the SIV status of wild West African chimpanzees (Pan troglodytes verus) which frequently hunt and consume the western red colobus monkey (Piliocolobus badius badius), a species known to be infected to a high percentage with its specific SIV strain (SIVwrc). Results Blood and plasma samples from 32 wild chimpanzees were tested with INNO-LIA HIV I/II Score kit to detect cross-reactive antibodies to HIV antigens. Twenty-three of the samples were also tested for antibodies to 43 specific SIV and HIV lineages, including SIVwrc. Tissue samples from all but two chimpanzees were tested for SIV by PCRs using generic SIV primers that detect all known primate lentiviruses as well as primers designed to specifically detect SIVwrc. Seventeen of the chimpanzees showed varying degrees of cross-reactivity to the HIV specific antigens in the INNO-LIA test; however no sample had antibodies to SIV or HIV strain - and lineage specific antigens in the Luminex test. No SIV DNA was found in any of the samples. Conclusions We could not detect any conclusive trace of SIV infection from the red colobus monkeys in the chimpanzees, despite high exposure to this virus through frequent hunting. The results of our study raise interesting questions regarding the host-parasite relationship of SIVwrc and wild chimpanzees in their natural habitat. PMID:21284842

Detection of circulating Mycobacterium tuberculosis-specific DNA by droplet digital PCR for vaccine evaluation in challenged monkeys and TB diagnosis.

PubMed

Song, Neng; Tan, Yang; Zhang, Lingyun; Luo, Wei; Guan, Qing; Yan, Ming-Zhe; Zuo, Ruiqi; Liu, Weixiang; Luo, Feng-Ling; Zhang, Xiao-Lian

2018-04-24

Mycobacterium tuberculosis (M. tb) is emerging as a more serious pathogen due to the increased multidrug-resistant TB and co-infection of human immunodeficiency virus (HIV). The development of an effective and sensitive detection method is urgently needed for bacterial load evaluation in vaccine development, early TB diagnosis, and TB treatment. Droplet digital polymerase chain reaction (ddPCR) is a newly developed sensitive PCR method for the absolute quantification of nucleic acid concentrations. Here, we used ddPCR to quantify the circulating virulent M. tb-specific CFP10 (10-kDa culture filtrate protein, Rv3874) and Rv1768 DNA copy numbers in the blood samples from Bacille Calmette-Guerin (BCG)-vaccinated and/or virulent M. tb H37Rv-challenged rhesus monkeys. We found that ddPCR was more sensitive compared to real-time fluorescence quantitative PCR (qPCR), as the detection limits of CFP10 were 1.2 copies/μl for ddPCR, but 15.8 copies/μl for qPCR. We demonstrated that ddPCR could detect CFP10 and Rv1768 DNA after 3 weeks of infection and at least two weeks earlier than qPCR in M.tb H37Rv-challenged rhesus monkey models. DdPCR could also successfully quantify CFP10 and Rv1768 DNA copy numbers in clinical TB patients' blood samples (active pulmonary TB, extrapulmonary TB (EPTB), and infant TB). To our knowledge, this study is the first to demonstrate that ddPCR is an effective and sensitive method of measuring the circulating CFP10 and Rv1768 DNA for vaccine development, bacterial load evaluation in vivo, and early TB (including EPTB and infant TB) diagnosis as well.

Autoreactive T Cells and Chronic Fungal Infection Drive Esophageal Carcinogenesis

PubMed Central

Zhu, Feng; Willette-Brown, Jami; Song, Na-Young; Lomada, Dakshayani; Song, Yongmei; Xue, Liyan; Gray, Zane; Zhao, Zitong; Davis, Sean R.; Sun, Zhonghe; Zhang, Peilin; Wu, Xiaolin; Zhan, Qimin; Richie, Ellen R.; Hu, Yinling

2018-01-01

SUMMARY Humans with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), a T cell–driven autoimmune disease caused by impaired central tolerance, are susceptible to developing chronic fungal infection and esophageal squamous cell carcinoma (ESCC). However, the relationship between autoreactive T cells and chronic fungal infection in ESCC development remains unclear. We find that kinase-dead Ikkα knockin mice develop phenotypes reminiscent of APECED, including impaired central tolerance, autoreactive T cells, chronic fungal infection, and ESCCs expressing specific human ESCC markers. Using this model, we investigated the potential link between ESCC and fungal infection. Autoreactive CD4 T cells permit fungal infection and incite tissue injury and inflammation. Antifungal treatment or depletion of autoreactive CD4 T cells rescues, whereas oral fungal administration promotes, ESCC development. Inhibition of inflammation or EGFR activity decreases fungal burden. Importantly, fungal infection is highly associated with ESCCs in non-autoimmune human patients. Therefore, autoreactive T cells and chronic fungal infection, fostered by inflammation and epithelial injury, promote ESCC development. PMID:28407484

New imidazolidinedione derivatives as antimalarial agents

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang, Liang; Sathunuru, Ramadas; Luong, ThuLan

2012-04-30

A series of new N-alky- and N-alkoxy-imidazolidinediones was prepared and assessed for prophylactic and radical curative activities in mouse and Rhesus monkey models. New compounds are generally metabolically stable, weakly active in vitro against Plasmodium falciparum clones (D6 and W2) and in mice infected with Plasmodium berghei sporozoites. Representative compounds 8e and 9c showed good causal prophylactic activity in Rhesus monkeys dosed 30 mg/kg/day for 3 consecutive days by IM, delayed patency for 19-21 days and 54-86 days, respectively, as compared to the untreated control. By oral, 9c showed only marginal activity in causal prophylactic and radical curative tests atmore » 50 mg/kg/day x 3 and 30 mg/kg/day x 7 plus chloroquine 10 mg/kg for 7 days, respectively.« less

[Chronic active Epstein-Barr virus infection].

PubMed

Kimura, Hiroshi

2011-12-01

The ubiquitous Epstein-Barr virus (EBV), which establishes latency after primary infection, does not cause any symptomatic diseases as long as cellular immunity is intact. In apparently immunocompetent individuals, a chronic infection can develop, and this has been called as chronic active EBV infection (CAEBV). CAEBV is characterized by chronic or recurrent infectious mononucleosis-like symptoms, such as fever, extensive lymphadenopathy, and, hepatosplenomegaly. This disease is rare but severe with high morbidity and mortality. Recently, its pathophysiology is not an infection but a clonal expansion of EBV-infected T or natural killer NK cells. In this review, I discuss our current understanding of the pathogenesis of CAEBV and summarize its clinical features, therapies, and prognosis.

[Comorbidities as risk factors of chronic kidney disease in HIV-infected persons].

PubMed

Marchewka, Zofia; Szymczak, Aleksandra; Knysz, Brygida

2015-12-16

Significant survival prolongation in HIV-infected patients due to effective antiretroviral therapy is connected with increasing prevalence of chronic non-infective diseases in this population, among them chronic kidney disease. The pathogenesis of kidney disease in the setting of HIV includes conditions specific for HIV infection: direct effect of the virus, stage of immunodeficiency and drug toxicity. Chronic comorbidities, such as diabetes mellitus, hypertension, and hyperlipidemia, are additional significant risk factors of kidney disease. In HIV-infected individuals some distinct features of these conditions are observed, which are partly related to the virus and antiretroviral therapy. The article summarizes the effect of comorbidities on kidney function in HIV-infected persons.

Activation of chronic toxoplasmosis by transportation stress in a mouse model.

PubMed

Shen, Bang; Yuan, Yuan; Cheng, Jianxi; Pan, Ming; Xia, Ningbo; Zhang, Weichao; Wang, Yifan; Zhou, Yanqin; Zhao, Junlong

2016-12-27

Toxoplasma gondii is an obligate intracellular parasite infecting 25% of the world population and enormous number of animals. It can exist in two forms in intermediate hosts: the fast replicating tachyzoites responsible for acute infection and the slowly replicating bradyzoites responsible for life-long chronic infection. The interconversion between tachyzoites and bradyzoites plays critical roles in the transmission and pathogenesis of T. gondii. However, the molecular mechanisms that govern the interconversion are largely unknown. In this study, we established a chronic infection model in mice and examined the impact of transportation stress on the status of chronic infection. Our results demonstrated that, treating chronically infected mice with conditions mimicking transportation stress reduced the levels of several key cytokines that restrict the infection at chronic stage. Increased expression of the tachyzoite specific gene SAG1 (surface antigen 1) was detected in brain cysts of stress treated mice, indicating activation and conversion of bradyzoites to tachyzoites. Using this model, we identified fifteen toxoplasmic proteins that had significant abundance changes during stress induced cysts reactivation. These proteins serve as a basis for further investigation of the mechanisms governing bradyzoite conversion.

Early Presymptomatic and Long-Term Changes of Rest Activity Cycles and Cognitive Behavior in a MPTP-Monkey Model of Parkinson's Disease

PubMed Central

Vezoli, Julien; Fifel, Karim; Leviel, Vincent; Dehay, Colette; Kennedy, Henry; Cooper, Howard M.; Gronfier, Claude; Procyk, Emmanuel

2011-01-01

Background It is increasingly recognized that non-motor symptoms are a prominent feature of Parkinson's disease and in the case of cognitive deficits can precede onset of the characteristic motor symptoms. Here, we examine in 4 monkeys chronically treated with low doses of the neurotoxin MPTP the early and long-term alterations of rest-activity rhythms in relationship to the appearance of motor and cognitive symptoms. Methodology/Principal Findings Behavioral activity recordings as well as motor and cognitive assessments were carried out continuously and in parallel before, during and for several months following MPTP-treatment (12–56 weeks). Cognitive abilities were assessed using a task that is dependent on the functional integrity of the fronto-striatal axis. Rest-activity cycles were monitored continuously using infrared movement detectors of locomotor activity. Motor impairment was evaluated using standardized scales for primates. Results show that MPTP treatment led to an immediate alteration (within one week) of rest-activity cycles and cognitive deficits. Parkinsonian motor deficits only became apparent 3 to 5 weeks after initiating chronic MPTP administration. In three of the four animals studied, clinical scores returned to control levels 5–7 weeks following cessation of MPTP treatment. In contrast, both cognitive deficits and chronobiological alterations persisted for many months. Levodopa treatment led to an improvement of cognitive performance but did not affect rest-activity rhythms in the two cases tested. Conclusions/Significance Present results show that i) changes in the rest activity cycles constituted early detectable consequences of MPTP treatment and, along with cognitive alterations, characterize the presymptomatic stage; ii) following motor recovery there is a long-term persistence of non-motor symptoms that could reflect differential underlying compensatory mechanisms in these domains; iii) the progressive MPTP-monkey model of presymptomatic ongoing parkinsonism offers possibilities for in-depth studies of early non-motor symptoms including sleep alterations and cognitive deficits. PMID:21887350

Zika virus in Asia.

PubMed

Duong, Veasna; Dussart, Philippe; Buchy, Philippe

2017-01-01

Zika virus (ZIKV) is an emerging mosquito-borne virus that was first isolated from a sentinel rhesus monkey in the Zika Forest in Uganda in 1947. In Asia, the virus was isolated in Malaysia from Aedes aegypti mosquitoes in 1966, and the first human infections were reported in 1977 in Central Java, Indonesia. In this review, all reported cases of ZIKV infection in Asia as of September 1, 2016 are summarized and some of the hypotheses that could currently explain the apparently low incidence of Zika cases in Asia are explored. Copyright © 2016 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Chronic Stenotrophomonas maltophilia infection and mortality or lung transplantation in cystic fibrosis patients.

PubMed

Waters, Valerie; Atenafu, Eshetu G; Lu, Annie; Yau, Yvonne; Tullis, Elizabeth; Ratjen, Felix

2013-09-01

Chronic Stenotrophomonas maltophilia infection is an independent risk factor for severe pulmonary exacerbations in cystic fibrosis (CF) patients. The goal of this study was to determine the effect of chronic S. maltophilia infection on mortality and the need for lung transplantation in a longitudinal study of children and adults with CF. This was a cohort study of CF patients from the Hospital for Sick Children and St Michael's Hospital (Toronto, Canada) from 1997 to 2008. A Cox Regression model was used to estimate the hazard ratio (HR) to time of death or lung transplantation adjusting for age, gender, genotype, pancreatic status, CF related diabetes (CFRD), forced expiratory volume in 1 s (FEV1), body mass index, number of pulmonary exacerbations, Pseudomonas aeruginosa, Burkholderia cepacia complex, Aspergillus and chronic S. maltophilia infection. A total of 687 patients were followed over the 12 year study period; 95 patients underwent a lung transplantation (of which 26 died) and an additional 49 patients died (total 144 events). In a Cox Regression model adjusting for baseline FEV1, baseline infection with B. cepacia complex (HR 1.72, 95% CI 1.09-2.71) and baseline chronic S. maltophilia infection (HR 2.80, 95% CI 1.65-4.76) were significantly associated with death or lung transplant. However, in a time-varying model, infection with B. cepacia complex and chronic S. maltophilia infection were no longer significant. Baseline chronic S. maltophilia infection is associated with an almost three-fold increased risk of death or lung transplant in CF patients. It is still unclear, however, whether chronic S. maltophilia infection is simply a marker of severity of disease and ultimate mortality or whether it is causally related to disease progression. Copyright © 2012 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

Metabolic and cardiovascular risk profiles and hepatitis C virus infection in rural Egypt.

PubMed

Marzouk, D; Sass, J; Bakr, I; El Hosseiny, M; Abdel-Hamid, M; Rekacewicz, C; Chaturvedi, N; Mohamed, M K; Fontanet, A

2007-08-01

To investigate the relationship between lipid profiles and diabetes with past and chronic hepatitis C virus (HCV) infection among village residents of Egypt. Fasting lipids and glucose profiles were compared among adults never infected with HCV (negative HCV antibodies), infected in the past (positive HCV antibodies and negative HCV RNA) and chronically infected (positive HCV antibodies and HCV RNA). Of the 765 participants, 456 (59.6%) were female, and median age was 40 (range 25-88) years. Chronic HCV infection was present in 113 (14.8%) and past infection in 67 (8.8%). After adjustment for age and sex, participants with chronic HCV infection had lower plasma low density lipoproteins (LDL) cholesterol and triglyceride levels compared with those never infected (age and sex adjusted differences (95% CI) were -19.0 (-26.3 to -11.7) mg/dl and -26.2 (-39.0 to -13.3) mg/dl, respectively). In contrast, participants with cleared HCV infection had higher triglyceride levels compared with those never infected (age and sex adjusted difference (95% CI) was +16.0 (0.03 to 31.9) mg/dl). In multivariate analysis, participants with chronic HCV infection were more likely to have diabetes (OR 3.05, 95% CI 1.19 to 7.81) compared with those never infected, independent of LDL cholesterol levels. In conclusion, this community based study has shown that in a single population, chronic HCV infection is associated with glucose intolerance and, despite that, a favourable lipid pattern. An intriguing finding was the high triglyceride levels observed among participants with past infection, suggesting that elevated triglycerides at the time of acute infection may facilitate viral clearance.

Chronic Mycobacterium marinum Infection Acts as a Tumor Promoter in Japanese Medaka (Oryzias latipes)

EPA Science Inventory

An accumulating body of research indicates there is an increased cancer risk associated with chronic infections. The genus Mycobacterium contains a number of species, including M tuberculosis, which mount chronic infections and have been implicated in higher cancer risk. Several ...

PPARγ-mediated increase in glucose availability sustains chronic Brucella abortus infection in alternatively activated macrophages

PubMed Central

Xavier, Mariana N.; Winter, Maria G.; Spees, Alanna M.; den Hartigh, Andreas B.; Nguyen, Kim; Roux, Christelle M.; Silva, Teane M. A.; Atluri, Vidya L.; Kerrinnes, Tobias; Keestra, A. Marijke; Monack, Denise M.; Luciw, Paul A.; Eigenheer, Richard A.; Bäumler, Andreas J.; Santos, Renato L.; Tsolis, Renée M.

2013-01-01

SUMMARY Eradication of persistent intracellular bacterial pathogens with antibiotic therapy is often slow or incomplete. However, strategies to augment antibiotics are hampered by our poor understanding of the nutritional environment that sustains chronic infection. Here we show that the intracellular pathogen Brucella abortus survives and replicates preferentially in alternatively activated macrophages (AAM), which are more abundant during chronic infection. A metabolic shift induced by peroxisome proliferator activated receptor γ (PPARγ), which increases intracellular glucose availability, is identified as a causal mechanism promoting enhanced bacterial survival in AAM. Glucose uptake was crucial for increased replication of B. abortus in AAM, and chronic infection, as inactivation of the bacterial glucose transporter gluP reduced both intracellular survival in AAM and persistence in mice. Thus, a shift in intracellular nutrient availability induced by PPARγ promotes chronic persistence of B. abortus within AAM and targeting this pathway may aid in eradicating chronic infection. PMID:23954155

Multiple roles of the coagulation protease cascade during virus infection.

PubMed

Antoniak, Silvio; Mackman, Nigel

2014-04-24

The coagulation cascade is activated during viral infections. This response may be part of the host defense system to limit spread of the pathogen. However, excessive activation of the coagulation cascade can be deleterious. In fact, inhibition of the tissue factor/factor VIIa complex reduced mortality in a monkey model of Ebola hemorrhagic fever. Other studies showed that incorporation of tissue factor into the envelope of herpes simplex virus increases infection of endothelial cells and mice. Furthermore, binding of factor X to adenovirus serotype 5 enhances infection of hepatocytes but also increases the activation of the innate immune response to the virus. Coagulation proteases activate protease-activated receptors (PARs). Interestingly, we and others found that PAR1 and PAR2 modulate the immune response to viral infection. For instance, PAR1 positively regulates TLR3-dependent expression of the antiviral protein interferon β, whereas PAR2 negatively regulates expression during coxsackievirus group B infection. These studies indicate that the coagulation cascade plays multiple roles during viral infections.

Ethanol self-administration and nicotine treatment increase brain levels of CYP2D in African green monkeys

PubMed Central

Miller, R T; Miksys, S; Hoffmann, E; Tyndale, R F

2014-01-01

BACKGROUND AND PURPOSE CYP2D6 metabolizes many centrally acting drugs, neurotoxins and endogenous neurochemicals, and differences in brain levels of CYP2D have been associated with brain function and drug response. Alcohol consumers and smokers have higher levels of CYP2D6 in brain, but not liver, suggesting ethanol and/or nicotine may induce human brain CYP2D6. We investigated the independent and combined effects of chronic ethanol self-administration and nicotine treatment on CYP2D expression in African green monkeys. EXPERIMENTAL APPROACH Forty monkeys were randomized into control, ethanol-only, nicotine-only and ethanol + nicotine groups. Two groups voluntarily self-administered 10% ethanol in sucrose solution for 4 h·day−1, whereas two groups consumed sucrose solution on the same schedule. Two groups received daily s.c. injections of 0.5 mg·kg−1 nicotine in saline bid, whereas two groups were injected with saline on the same schedule. KEY RESULTS Both nicotine and ethanol dose-dependently increased CYP2D in brain; brain mRNA was unaffected, and neither drug altered hepatic CYP2D protein or mRNA. The combination of ethanol and nicotine increased brain CYP2D protein levels to a greater extent than either drug alone (1.2–2.2-fold, P < 0.05 among the eight brain regions assessed). Immunohistochemistry revealed the induction of brain CYP2D protein within specific cell types and regions in the treatment groups. CONCLUSIONS AND IMPLICATIONS Ethanol and nicotine increase brain CYP2D protein levels in monkeys, in a region and treatment-specific manner, suggesting that CNS drug responses, neurodegeneration and personality may be affected among people who consume alcohol and/or nicotine. PMID:24611668

The Connective Tissue Components of Optic Nerve Head Cupping in Monkey Experimental Glaucoma Part 1: Global Change

PubMed Central

Yang, Hongli; Ren, Ruojin; Lockwood, Howard; Williams, Galen; Libertiaux, Vincent; Downs, Crawford; Gardiner, Stuart K.; Burgoyne, Claude F.

2015-01-01

Purpose To characterize optic nerve head (ONH) connective tissue change within 21 monkey experimental glaucoma (EG) eyes, so as to identify its principal components. Methods Animals were imaged three to five times at baseline then every 2 weeks following chronic unilateral IOP elevation, and euthanized early through end-stage confocal scanning laser tomographic change. Optic nerve heads were serial-sectioned, three-dimensionally (3D) reconstructed, delineated, and quantified. Overall EG versus control eye differences were assessed by general estimating equations (GEE). Significant, animal-specific, EG eye change was required to exceed the maximum physiologic intereye differences in six healthy animals. Results Overall EG eye change was significant (P < 0.0026) and animal-specific EG eye change most frequent, for five phenomena (number of EG eyes and range of animal-specific change): posterior laminar deformation (21, −29 to −437 μm), laminar thickening (11, 20–73 μm) and thinning (3, −23 to −31 μm), scleral canal expansion (17, 20–139 μm), outward anterior (16, −16 to −124 μm) and posterior (17, −22 to −279 μm) laminar insertion migration, and peripapillary scleral bowing (11, 21–77 μm). Experimental glaucoma versus control eye laminar thickness differences were bimodal in behavior, being thickened in most EG eyes demonstrating the least deformation and less thickened or thinned in most EG eyes demonstrating the greatest deformation. Conclusions Our postmortem studies retrospectively identify five connective tissue components of ONH “cupping” in monkey EG which serve as targets for longitudinally staging and phenotyping ONH connective tissue alteration within all forms of monkey and human optic neuropathy. PMID:26641545

Sucrose acetate isobutyrate (SAIB): historical aspects of its use in beverages and a review of toxicity studies prior to 1988.

PubMed

Reynolds, R C; Chappel, C I

1998-02-01

Sucrose acetate isobutyrate (SAIB), a mixture of esters of sucrose with a composition approximating the name sucrose diacetate hexaisobutyrate, has been used for over 30 yr in many countries as a 'weighting' or 'density-adjusting' agent in non-alcoholic carbonated and non-carbonated beverages. As part of the demonstration of safety of SAIB as a direct food additive in human diets, a program of toxicity testing was started in the late 1950s that culminated in extensive studies of SAIB in rodents, monkeys and humans over the last decade. This review summarizes the toxicity data, accrued up until 1988, that precede the safety studies published elsewhere in this issue. SAIB has been shown to have very low acute and chronic toxicities in rats, monkeys, and, except for effects on the liver, in dogs at feeding levels of up to 10% in the diet. Slight effects seen in rats and monkeys at levels of 10% in the diet are unlikely to be directly caused by exposure to SAIB. In dogs, however, SAIB causes decreases in bromosulfophthalein (BSP) and indocyanine green (ICG) elimination from the serum immediately following a single dose, indicative of interference with biliary excretion. On repeated feeding in dogs, SAIB caused increases in serum alkaline phosphatase levels, but enzymes indicative of toxic effects on the liver were unaffected. On prolonged feeding to dogs, SAIB caused changes in liver morphology revealed by electron microscopy. All of these effects were reversed when SAIB was withdrawn from the diet. The no-effect level for these effects in dogs was near 5 mg/kg body weight, but these effects were not seen in rats fed up to 4 g/kg body weight/day, monkeys fed up to 10 g/kg body weight/day, or humans fed up to 20 mg/kg body weight/day. The toxicity and pharmacological studies in dogs, rats and monkeys suggest that the effect of SAIB on biliary excretion and liver morphology in dogs is essentially pharmacological rather than toxicological in nature and that the difference between the effects in dogs at levels as low as 5 mg/kg body weight/day, and the lack of effects in rats or monkeys at levels up to 10 g/kg/day is not merely a quantitative difference between species, but an absolute qualitative difference.

Left Ventricular, Systemic Arterial and Baroreflex Responses to Ketamine and TEE in Chronically Instrumented Monkeys

DTIC Science & Technology

2001-12-01

instrumented with a high fidelity, dual-sensor micromanometer to measure left ventricular and aortic pressure and a transit-time ultrasound probe to...isoflurane in 100% oxy- gen) prior to insertion of the high -fidelity pressure micromanome- ters during cardiac fluoroscopy. Once the micromanometer trans...and allowed to fully recover from the isoflurane seda- tion for a period of 60 min, during which blood pressure and aortic flow were monitored to ensure

Leprosy

MedlinePlus

... Seniors, WomenTags: ancient infections, blindness, chronic granulomatous disease, chronic infection, hand and foot deformities, hansen's disease, infections, leprosy, mycobacterium, rashes, skin lesions, testicle damage November 1, 2009 Copyright © American ...

Electron Microscopy of Intracellular Protozoa.

DTIC Science & Technology

1979-08-15

parxysm due to the increased metabolism during the fever or to hepatic cell damage. In P. knowlesi infection in monkeys, 23 I. I hypoglyceinia has...convoluted and collecting tubules (Winslow et al. , 1975). Blackwater fever is an acute hemolytic condition associated with fever , anemia, jaundice, and...history of irregular chemosuppression or inadequate chemotherapy, especially with quinine. The diagnosis of blackwatcr fever can be made only in patients

Maternal Brain Reactive Antibodies and Autism Spectrum Disorder

DTIC Science & Technology

2016-10-01

a child with ASD can affect fetal brain development and lead to behaviors analogous to ASD phenotypes. These studies indeed move the field forward...from mothers of children with autism alter brain growth and social behavior development in the rhesus monkey. Transl Psychiatry 3, e278 (2013). 6...maternal immune contribution has been the focus of studies demonstrating that autoimmune disorders, infections, and maternal brain-reactive antibodies

Characterization of replication-competent retroviruses from nonhuman primates with virus-induced T-cell lymphomas and observations regarding the mechanism of oncogenesis.

PubMed Central

Vanin, E F; Kaloss, M; Broscius, C; Nienhuis, A W

1994-01-01

Rapidly progressive T-cell lymphomas were observed in 3 of 10 rhesus monkeys several months after autologous transplantation of enriched bone marrow stem cells that had been transduced with a retroviral vector preparation containing replication-competent virus (R. E. Donahue, S. W. Kessler, D. Bodice, K. McDonagh, C. Dunbar, S. Goodman, B. Agricola, E. Byrne, M. Raffeld, R. Moen, J. Bacher, K. M. Zsebo, and A. W. Nienhuis, J. Exp. Med. 176:1124-1135, 1992). The animals with lymphoma appeared to be tolerant to retroviral antigens in that their sera lacked antibodies reactive with viral proteins and contained 10(4) to 10(5) infectious virus particles per ml. By molecular cloning and DNA sequencing, we have now demonstrated that the serum from one of the monkeys contained a replication-competent retrovirus that arose by recombination between vector and packaging encoding sequences (vector/helper [V/H] recombinant) in the producer clone used for transduction of bone marrow stem cells. Southern blot analysis demonstrated 14 or 25 copies of this genome per cell where present in two animals. The genome of a second replication-competent virus was also recovered by molecular cloning; it arose by recombination involving the genome of the V/H recombinant and endogenous murine retroviral genomes in the producer clone. Twelve copies of this amphotropic virus/mink cell focus-forming virus genome were present in tumor DNA of one animal, but it was not found in tumor DNA of the other two animals with lymphoma. Southern blot analysis of DNA from various tissues demonstrated common insertion site bands in several samples of tumor DNA from one animal, suggesting clonal origin of the lymphoma. Our data are most consistent with a pathogenic mechanism in which chronic productive retroviral infection allowed insertional mutagenesis of critical growth control genes, leading to cell transformation and clonal tumor evolution. Images PMID:8207799

Alterations of red blood cell sodium transport during malarial infection

PubMed Central

Dunn, Michael J.

1969-01-01

Previous studies have suggested that malaria induces changes in erythrocytic membrane permeability and susceptibility to osmotic lysis. The present study investigated erythrocytic transport of sodium with cells from Rhesus monkeys infected with Plasmodium knowlesi. Red blood cell sodium concentration was significantly elevated in 37 parasitized animals (21.8±1.2 mM; mean ±SEM), as compared to 23 control animals (10.0±0.38 mM). The cellular sodium increased with the density of parasitemia and the cellular potassium decreased in proportion to the elevation of sodium. Nonparasitized as well as parasitized erythrocytes possessed this abnormality of cation metabolism. Effective chloroquine therapy reversed the changes over a period of 4 days. Active sodium outflux rate constants were depressed in animals with malaria (0.202±0.012), as compared to controls (0.325±0.027). Passive sodium influx rate constants were higher in infected monkeys (0.028±0.002) than in control animals (0.019±0.002). The cross incubation of malarial plasma with normal red blood cells induced a 22% diminution in active sodium outflux but no changes were observed in sodium influx. It is concluded that malaria alters erythrocytic sodium transport in all erythrocytes. The elevated intracellular sodium concentration is the net result of decreased sodium outflux and increased sodium influx. The plasmodium organism or the affected host may produce a circulating substance that is deleterious to erythrocytic membrane cation transport. PMID:4975361