Lassa Virus Reverse Genetics.

PubMed

Martínez-Sobrido, Luis; Paessler, Slobodan; de la Torre, Juan Carlos

2017-01-01

The Old World (OW) arenavirus Lassa (LASV ) is estimated to infect several hundred thousand people yearly in West Africa, resulting in high numbers of Lassa fever (LF), a viral hemorrhagic fever (HF) disease associated with high morbidity and mortality. To date, no licensed vaccines are available to LASV infections, and anti-LASV drug therapy is limited to an off-label use of ribavirin (Rib) that is only partially effective. The development of reverse genetics has provided investigators with a novel and powerful approach for the investigation of the molecular, cell biology, and pathogenesis of LASV. The use of cell-based LASV minigenome (MG) systems has allowed examining the cis- and trans-acting factors involved in genome replication and gene transcription and the identification of novel drugable LASV targets. Likewise, it is now feasible to rescue infectious recombinant (r)LASV entirely from cloned cDNAs containing predetermined mutations in their genomes to investigate virus-host interactions and mechanisms of pathogenesis, as well as to facilitate screens to identify antiviral drugs against LASV and the implementation of novel strategies to develop live-attenuated vaccines (LAV). In this chapter we will summarize the state-of-the-art experimental procedures for implementation of LASV reverse genetics. In addition, we will briefly discuss some significant translational research developments that have been made possible upon the development of LASV reverse genetics.

Engaging Market Traders in Lassa Fever Campaign: Assessment of Knowledge and Risk Behaviour.

PubMed

Tobin, E A; Asogun, D A; Ehidiamen, G; Elugbe, B; Osiemi, B

2015-01-01

Markets provide a forum for reaching a large adult population with information on Lassa fever, and therefore understanding the food handling practices of traders may provide the foundation for an effective campaign against Lassa fever. This study was undertaken to provide baseline information on knowledge and food handling practices of traders in local markets in a Lassa fever endemic state of Nigeria. A structured questionnaire was used to obtain food handling habits that facilitate the transmission of Lassa virus from a cross sectional study involving 385 traders in three major markets in Edo state and data analyzed using SPSS version 15. Two hundred and ninety three (76.1%) had ever heard of Lassa fever, 27 (9.2%) had good knowledge. Good knowledge was significantly associated with higher educational status (p < 0.00) and male gender (p=0.03). Thirty seven (12.6%) respondents sun-dried their food frequently, 105 (35.8%) stored utensils in rodent proof containers, and 136 (46.4%) had the habit of eating garri soaked in water. One hundred and ninety (49.4%) respondents had food hygiene practices that were favorable for spread of Lassa fever. The observed gaps in knowledge of Lassa fever and food hygiene may be addressed through tailored health messages. In this way, market campaigns will be effective in increasing knowledge of Lassa fever, and traders can themselves become peer educators.

Acute abdominal pain in patients with lassa fever: Radiological assessment and diagnostic challenges.

PubMed

Eze, Kenneth C; Salami, Taofeek A; Kpolugbo, James U

2014-05-01

To highlight the problems of diagnosis and management of acute abdomen in patients with lassa fever. And to also highlight the need for high index of suspicion of lassa fever in patients presenting with acute abdominal pain in order to avoid surgical intervention with unfavourable prognosis and nosocomial transmission of infections, especially in Lassa fever-endemic regions. A review of experiences of the authors in the management of lassa fever over a 4-year period (2004-2008). Literature on lassa fever, available in the internet and other local sources, was studied in November 2010 and reviewed. Normal plain chest radiographic picture can change rapidly due to pulmonary oedema, pulmonary haemorrhage and acute respiratory distress syndrome. Plain abdominal radiograph may show dilated bowels with signs of paralytic ileus or dynamic intestinal obstruction due to bowel wall haemorrhage or inflamed and enlarged Peyer's patches. Ultrasound may show free intra-peritoneal fluid due to peritonitis and intra-peritoneal haemorrhage. Bleeding into the gall bladder wall may erroneously suggest infective cholecystitis. Pericardial effusion with or without pericarditis causing abdominal pain may be seen using echocardiography. High index of suspicion, antibody testing for lassa fever and viral isolation in a reference laboratory are critical for accurate diagnosis. Patients from lassa fever-endemic regions may present with features that suggest acute abdomen. Radiological studies may show findings that suggest acute abdomen but these should be interpreted in the light of the general clinical condition of the patient. It is necessary to know that acute abdominal pain and vomiting in lassa fever-endemic areas could be caused by lassa fever, which is a medical condition. Surgical option should be undertaken with restraint as it increases the morbidity, may worsen the prognosis and increase the risk of nosocomial transmission.

Lassa fever: another threat from West Africa.

PubMed

Brosh-Nissimov, Tal

2016-01-01

Lassa fever, a zoonotic viral infection, is endemic in West Africa. The disease causes annual wide spread morbidity and mortality in Africa, and can be imported by travelers. Possible importation of Lassa fever and the potential for the use of Lassa virus as an agent of bioterrorism mandate clinicians in Israel and other countries to be vigilant and familiar with the basic characteristics of this disease. The article reviews the basis of this infection and the clinical management of patients with Lassa fever. Special emphasis is given to antiviral treatment and infection control.

Diagnostic proficiency and reporting of Lassa fever by physicians in Osun State of Nigeria.

PubMed

Olowookere, Samuel Anu; Fatiregun, Akinola Ayoola; Gbolahan, Olalere Omoyosola; Adepoju, Ebenezer Gbenga

2014-06-20

Lassa fever is highly contagious and commonly results in death. It is therefore necessary to diagnose and report any suspected case of Lassa fever to facilitate preventive strategies. This study assessed the preparedness of physicians in the diagnosis and reporting of Lassa fever. The study design was descriptive cross-sectional. The consenting medical doctors completed a self-administered questionnaire on the diagnosis and reporting of Lassa fever. Descriptive and inferential statistics were used in data analyses. One hundred seventy-five physicians participated in the study. The mean age was 41.5 ± 10.9 years (range, 24-75 years). Most of the physicians were male (78.9%) and had practiced medicine ≥ 20 years (51.5%). Most of the physicians had a good knowledge regarding the diagnosis and reporting of Lassa fever; however, none of the physicians had ever diagnosed or reported a suspected case. Predictors of good knowledge include male sex, not practicing at a secondary health care level and post graduation year more than 20 years. There is disparity in knowledge and practices of physicians regarding the diagnosis and reporting of Lassa fever. Thus, it is necessary to improve the knowledge and practices of physicians regarding the diagnosis and reporting of Lassa fever.

Molecular diagnostics for lassa fever at Irrua specialist teaching hospital, Nigeria: lessons learnt from two years of laboratory operation.

PubMed

Asogun, Danny A; Adomeh, Donatus I; Ehimuan, Jacqueline; Odia, Ikponmwonsa; Hass, Meike; Gabriel, Martin; Olschläger, Stephan; Becker-Ziaja, Beate; Folarin, Onikepe; Phelan, Eric; Ehiane, Philomena E; Ifeh, Veritas E; Uyigue, Eghosasere A; Oladapo, Yemisi T; Muoebonam, Ekene B; Osunde, Osagie; Dongo, Andrew; Okokhere, Peter O; Okogbenin, Sylvanus A; Momoh, Mojeed; Alikah, Sylvester O; Akhuemokhan, Odigie C; Imomeh, Peter; Odike, Maxy A C; Gire, Stephen; Andersen, Kristian; Sabeti, Pardis C; Happi, Christian T; Akpede, George O; Günther, Stephan

2012-01-01

Lassa fever is a viral hemorrhagic fever endemic in West Africa. However, none of the hospitals in the endemic areas of Nigeria has the capacity to perform Lassa virus diagnostics. Case identification and management solely relies on non-specific clinical criteria. The Irrua Specialist Teaching Hospital (ISTH) in the central senatorial district of Edo State struggled with this challenge for many years. A laboratory for molecular diagnosis of Lassa fever, complying with basic standards of diagnostic PCR facilities, was established at ISTH in 2008. During 2009 through 2010, samples of 1,650 suspected cases were processed, of which 198 (12%) tested positive by Lassa virus RT-PCR. No remarkable demographic differences were observed between PCR-positive and negative patients. The case fatality rate for Lassa fever was 31%. Nearly two thirds of confirmed cases attended the emergency departments of ISTH. The time window for therapeutic intervention was extremely short, as 50% of the fatal cases died within 2 days of hospitalization--often before ribavirin treatment could be commenced. Fatal Lassa fever cases were older (p = 0.005), had lower body temperature (p<0.0001), and had higher creatinine (p<0.0001) and blood urea levels (p<0.0001) than survivors. Lassa fever incidence in the hospital followed a seasonal pattern with a peak between November and March. Lassa virus sequences obtained from the patients originating from Edo State formed--within lineage II--a separate clade that could be further subdivided into three clusters. Lassa fever case management was improved at a tertiary health institution in Nigeria through establishment of a laboratory for routine diagnostics of Lassa virus. Data collected in two years of operation demonstrate that Lassa fever is a serious public health problem in Edo State and reveal new insights into the disease in hospitalized patients.

Molecular Diagnostics for Lassa Fever at Irrua Specialist Teaching Hospital, Nigeria: Lessons Learnt from Two Years of Laboratory Operation

PubMed Central

Hass, Meike; Gabriel, Martin; Ölschläger, Stephan; Becker-Ziaja, Beate; Folarin, Onikepe; Phelan, Eric; Ehiane, Philomena E.; Ifeh, Veritas E.; Uyigue, Eghosasere A.; Oladapo, Yemisi T.; Muoebonam, Ekene B.; Osunde, Osagie; Dongo, Andrew; Okokhere, Peter O.; Okogbenin, Sylvanus A.; Momoh, Mojeed; Alikah, Sylvester O.; Akhuemokhan, Odigie C.; Imomeh, Peter; Odike, Maxy A. C.; Gire, Stephen; Andersen, Kristian; Sabeti, Pardis C.; Happi, Christian T.; Akpede, George O.; Günther, Stephan

2012-01-01

Background Lassa fever is a viral hemorrhagic fever endemic in West Africa. However, none of the hospitals in the endemic areas of Nigeria has the capacity to perform Lassa virus diagnostics. Case identification and management solely relies on non-specific clinical criteria. The Irrua Specialist Teaching Hospital (ISTH) in the central senatorial district of Edo State struggled with this challenge for many years. Methodology/Principal Findings A laboratory for molecular diagnosis of Lassa fever, complying with basic standards of diagnostic PCR facilities, was established at ISTH in 2008. During 2009 through 2010, samples of 1,650 suspected cases were processed, of which 198 (12%) tested positive by Lassa virus RT-PCR. No remarkable demographic differences were observed between PCR-positive and negative patients. The case fatality rate for Lassa fever was 31%. Nearly two thirds of confirmed cases attended the emergency departments of ISTH. The time window for therapeutic intervention was extremely short, as 50% of the fatal cases died within 2 days of hospitalization—often before ribavirin treatment could be commenced. Fatal Lassa fever cases were older (p = 0.005), had lower body temperature (p<0.0001), and had higher creatinine (p<0.0001) and blood urea levels (p<0.0001) than survivors. Lassa fever incidence in the hospital followed a seasonal pattern with a peak between November and March. Lassa virus sequences obtained from the patients originating from Edo State formed—within lineage II—a separate clade that could be further subdivided into three clusters. Conclusions/Significance Lassa fever case management was improved at a tertiary health institution in Nigeria through establishment of a laboratory for routine diagnostics of Lassa virus. Data collected in two years of operation demonstrate that Lassa fever is a serious public health problem in Edo State and reveal new insights into the disease in hospitalized patients. PMID:23029594

A historical look at the first reported cases of Lassa fever: IgG antibodies 40 years after acute infection.

PubMed

Bond, Nell; Schieffelin, John S; Moses, Lina M; Bennett, Andrew J; Bausch, Daniel G

2013-02-01

Lassa fever is an acute and sometimes severe viral hemorrhagic illness endemic in West Africa. One important question regarding Lassa fever is the duration of immunoglobulin G (IgG) antibody after infection. We were able to locate three persons who worked in Nigeria dating back to the 1940s, two of whom were integrally involved in the early outbreaks and investigations of Lassa fever in the late 1960s, including the person from whom Lassa virus was first isolated. Two persons had high titers of Lassa virus-specific IgG antibody over 40 years after infection, indicating the potential for long-term duration of these antibodies. One person was likely infected in 1952, 17 years before the first recognized outbreak. We briefly recount the fascinating stories of these three pioneers and their important contribution to our understanding of Lassa fever.

A Historical Look at the First Reported Cases of Lassa Fever: IgG Antibodies 40 Years After Acute Infection

PubMed Central

Bond, Nell; Schieffelin, John S.; Moses, Lina M.; Bennett, Andrew J.; Bausch, Daniel G.

2013-01-01

Lassa fever is an acute and sometimes severe viral hemorrhagic illness endemic in West Africa. One important question regarding Lassa fever is the duration of immunoglobulin G (IgG) antibody after infection. We were able to locate three persons who worked in Nigeria dating back to the 1940s, two of whom were integrally involved in the early outbreaks and investigations of Lassa fever in the late 1960s, including the person from whom Lassa virus was first isolated. Two persons had high titers of Lassa virus-specific IgG antibody over 40 years after infection, indicating the potential for long-term duration of these antibodies. One person was likely infected in 1952, 17 years before the first recognized outbreak. We briefly recount the fascinating stories of these three pioneers and their important contribution to our understanding of Lassa fever. PMID:23390223

Diagnostics for Lassa Fever: Detecting Host Antibody Responses.

PubMed

Salvato, Maria S; Lukashevich, Igor S; Medina-Moreno, Sandra; Zapata, Juan Carlos

2018-01-01

There are two types of viral diagnostics: (1) those that detect components of the pathogen (like viral RNA or proteins) and (2) those that detect host molecules that rise or fall as a consequence of pathogen infection (like anti-viral antibodies or virus-induced inflammatory cytokines). Quantitative PCR to detect Lassa RNA, and clinical chemistry to detect high liver enzymes (AST/ALT) are commonly used to diagnose Lassa fever. Here, we discuss the various types of diagnostics for Lassa fever and the urgent need for early diagnosis. We also describe a protocol for using the attenuated Lassa vaccine candidate, ML29 , as an antigen for detecting Lassa-specific antibodies. Since antibodies are developed late in the progression of Lassa fever disease, this is not an early diagnostic, but is more useful in surveillance of the population to determine the sero-prevalence of antibodies to Lassa virus (LASV ), and to define treatment options for people in close contact with a Lassa-infected person.

Diagnostic proficiency and reporting of Lassa fever by physicians in Osun State of Nigeria

PubMed Central

2014-01-01

Background Lassa fever is highly contagious and commonly results in death. It is therefore necessary to diagnose and report any suspected case of Lassa fever to facilitate preventive strategies. This study assessed the preparedness of physicians in the diagnosis and reporting of Lassa fever. Methods The study design was descriptive cross-sectional. The consenting medical doctors completed a self-administered questionnaire on the diagnosis and reporting of Lassa fever. Descriptive and inferential statistics were used in data analyses. Results One hundred seventy-five physicians participated in the study. The mean age was 41.5 ± 10.9 years (range, 24–75 years). Most of the physicians were male (78.9%) and had practiced medicine ≥ 20 years (51.5%). Most of the physicians had a good knowledge regarding the diagnosis and reporting of Lassa fever; however, none of the physicians had ever diagnosed or reported a suspected case. Predictors of good knowledge include male sex, not practicing at a secondary health care level and post graduation year more than 20 years. Conclusion There is disparity in knowledge and practices of physicians regarding the diagnosis and reporting of Lassa fever. Thus, it is necessary to improve the knowledge and practices of physicians regarding the diagnosis and reporting of Lassa fever. PMID:24950705

The first cases of Lassa fever in Ghana.

PubMed

Dzotsi, E K; Ohene, S-A; Asiedu-Bekoe, F; Amankwa, J; Sarkodie, B; Adjabeng, M; Thouphique, A M; Ofei, A; Oduro, J; Atitogo, D; Bonney, J H K; Paintsil, S C N; Ampofo, W

2012-09-01

Lassa fever is a zoonotic disease endemic in West Africa but with no previous case reported in Ghana. We describe the first two laboratory confirmed cases of Lassa fever from the Ashanti Region of Ghana detected in October and December, 2011.

Lassa fever presenting as acute abdomen: a case series.

PubMed

Dongo, Andrew E; Kesieme, Emeka B; Iyamu, Christopher E; Okokhere, Peter O; Akhuemokhan, Odigie C; Akpede, George O

2013-04-19

Lassa fever, an endemic zoonotic viral infection in West Africa, presents with varied symptoms including fever, vomiting, retrosternal pain, abdominal pain, sore-throat, mucosal bleeding, seizures and coma. When fever and abdominal pain are the main presenting symptoms, and a diagnosis of acute abdomen is entertained, Lassa fever is rarely considered in the differential diagnosis, even in endemic areas. Rather the diagnosis of Lassa fever is suspected only after surgical intervention. Therefore, such patients often undergo unnecessary surgery with resultant delay in the commencement of ribavirin therapy. This increases morbidity and mortality and the risk of nosocomial transmission to hospital staff. We report 7 patients aged between 17 months and 40 years who had operative intervention for suspected appendicitis, perforated typhoid ileitis, intussuception and ruptured ectopic pregnancy after routine investigations. All seven were post-operatively confirmed as Lassa fever cases. Four patients died postoperatively, most before commencement of ribavirin, while the other three patients eventually recovered with appropriate antibiotic treatment including intravenous ribavirin. Surgeons working in West Africa should include Lassa fever in the differential diagnosis of acute abdomen, especially appendicitis. The presence of high grade fever, proteinuria and thrombocytopenia in patients with acute abdomen should heighten the suspicion of Lassa fever. Prolonged intra-operative bleeding should not only raise suspicion of the disease but also serve to initiate precautions to prevent nosocomial transmission.

Lassa fever presenting as acute abdomen: a case series

PubMed Central

2013-01-01

Lassa fever, an endemic zoonotic viral infection in West Africa, presents with varied symptoms including fever, vomiting, retrosternal pain, abdominal pain, sore-throat, mucosal bleeding, seizures and coma. When fever and abdominal pain are the main presenting symptoms, and a diagnosis of acute abdomen is entertained, Lassa fever is rarely considered in the differential diagnosis, even in endemic areas. Rather the diagnosis of Lassa fever is suspected only after surgical intervention. Therefore, such patients often undergo unnecessary surgery with resultant delay in the commencement of ribavirin therapy. This increases morbidity and mortality and the risk of nosocomial transmission to hospital staff. We report 7 patients aged between 17 months and 40 years who had operative intervention for suspected appendicitis, perforated typhoid ileitis, intussuception and ruptured ectopic pregnancy after routine investigations. All seven were post-operatively confirmed as Lassa fever cases. Four patients died postoperatively, most before commencement of ribavirin, while the other three patients eventually recovered with appropriate antibiotic treatment including intravenous ribavirin. Surgeons working in West Africa should include Lassa fever in the differential diagnosis of acute abdomen, especially appendicitis. The presence of high grade fever, proteinuria and thrombocytopenia in patients with acute abdomen should heighten the suspicion of Lassa fever. Prolonged intra-operative bleeding should not only raise suspicion of the disease but also serve to initiate precautions to prevent nosocomial transmission. PMID:23597024

Acute abdominal pain in patients with lassa fever: Radiological assessment and diagnostic challenges

PubMed Central

Eze, Kenneth C.; Salami, Taofeek A.; Kpolugbo, James U.

2014-01-01

Background: To highlight the problems of diagnosis and management of acute abdomen in patients with lassa fever. And to also highlight the need for high index of suspicion of lassa fever in patients presenting with acute abdominal pain in order to avoid surgical intervention with unfavourable prognosis and nosocomial transmission of infections, especially in Lassa fever-endemic regions. Materials and Methods: A review of experiences of the authors in the management of lassa fever over a 4-year period (2004-2008). Literature on lassa fever, available in the internet and other local sources, was studied in November 2010 and reviewed. Results: Normal plain chest radiographic picture can change rapidly due to pulmonary oedema, pulmonary haemorrhage and acute respiratory distress syndrome. Plain abdominal radiograph may show dilated bowels with signs of paralytic ileus or dynamic intestinal obstruction due to bowel wall haemorrhage or inflamed and enlarged Peyer's patches. Ultrasound may show free intra-peritoneal fluid due to peritonitis and intra-peritoneal haemorrhage. Bleeding into the gall bladder wall may erroneously suggest infective cholecystitis. Pericardial effusion with or without pericarditis causing abdominal pain may be seen using echocardiography. High index of suspicion, antibody testing for lassa fever and viral isolation in a reference laboratory are critical for accurate diagnosis. Conclusion: Patients from lassa fever-endemic regions may present with features that suggest acute abdomen. Radiological studies may show findings that suggest acute abdomen but these should be interpreted in the light of the general clinical condition of the patient. It is necessary to know that acute abdominal pain and vomiting in lassa fever-endemic areas could be caused by lassa fever, which is a medical condition. Surgical option should be undertaken with restraint as it increases the morbidity, may worsen the prognosis and increase the risk of nosocomial transmission. PMID:25013248

Laboratory Diagnosis of Lassa Fever

PubMed Central

Koehler, Jeffrey

2017-01-01

ABSTRACT Lassa virus remains an important cause of illness in West Africa and among the travelers returning from this region with an acute febrile illness. The symptoms of Lassa fever can be nonspecific and mimic those of other endemic infections, especially early in illness, making a clinical diagnosis difficult; therefore, laboratory testing is needed to confirm the diagnosis. An early identification of Lassa fever is crucial for maximizing the benefit of available antiviral therapy, as treatment efficacy rapidly decreases following the clinical onset of the disease. This minireview provides an overview of the currently available diagnostic tests for Lassa fever and their strengths and weaknesses. PMID:28404674

Laboratory Diagnosis of Lassa Fever.

PubMed

Raabe, Vanessa; Koehler, Jeffrey

2017-06-01

Lassa virus remains an important cause of illness in West Africa and among the travelers returning from this region with an acute febrile illness. The symptoms of Lassa fever can be nonspecific and mimic those of other endemic infections, especially early in illness, making a clinical diagnosis difficult; therefore, laboratory testing is needed to confirm the diagnosis. An early identification of Lassa fever is crucial for maximizing the benefit of available antiviral therapy, as treatment efficacy rapidly decreases following the clinical onset of the disease. This minireview provides an overview of the currently available diagnostic tests for Lassa fever and their strengths and weaknesses. Copyright © 2017 American Society for Microbiology.

Simian hemorrhagic fever virus infection of rhesus macaques as a model of viral hemorrhagic fever: clinical characterization and risk factors for severe disease.

PubMed

Johnson, Reed F; Dodd, Lori E; Yellayi, Srikanth; Gu, Wenjuan; Cann, Jennifer A; Jett, Catherine; Bernbaum, John G; Ragland, Dan R; St Claire, Marisa; Byrum, Russell; Paragas, Jason; Blaney, Joseph E; Jahrling, Peter B

2011-12-20

Simian Hemorrhagic Fever Virus (SHFV) has caused sporadic outbreaks of hemorrhagic fevers in macaques at primate research facilities. SHFV is a BSL-2 pathogen that has not been linked to human disease; as such, investigation of SHFV pathogenesis in non-human primates (NHPs) could serve as a model for hemorrhagic fever viruses such as Ebola, Marburg, and Lassa viruses. Here we describe the pathogenesis of SHFV in rhesus macaques inoculated with doses ranging from 50 PFU to 500,000 PFU. Disease severity was independent of dose with an overall mortality rate of 64% with signs of hemorrhagic fever and multiple organ system involvement. Analyses comparing survivors and non-survivors were performed to identify factors associated with survival revealing differences in the kinetics of viremia, immunosuppression, and regulation of hemostasis. Notable similarities between the pathogenesis of SHFV in NHPs and hemorrhagic fever viruses in humans suggest that SHFV may serve as a suitable model of BSL-4 pathogens. Published by Elsevier Inc.

Chimeric Mice with Competent Hematopoietic Immunity Reproduce Key Features of Severe Lassa Fever.

PubMed

Oestereich, Lisa; Lüdtke, Anja; Ruibal, Paula; Pallasch, Elisa; Kerber, Romy; Rieger, Toni; Wurr, Stephanie; Bockholt, Sabrina; Pérez-Girón, José V; Krasemann, Susanne; Günther, Stephan; Muñoz-Fontela, César

2016-05-01

Lassa fever (LASF) is a highly severe viral syndrome endemic to West African countries. Despite the annual high morbidity and mortality caused by LASF, very little is known about the pathophysiology of the disease. Basic research on LASF has been precluded due to the lack of relevant small animal models that reproduce the human disease. Immunocompetent laboratory mice are resistant to infection with Lassa virus (LASV) and, to date, only immunodeficient mice, or mice expressing human HLA, have shown some degree of susceptibility to experimental infection. Here, transplantation of wild-type bone marrow cells into irradiated type I interferon receptor knockout mice (IFNAR-/-) was used to generate chimeric mice that reproduced important features of severe LASF in humans. This included high lethality, liver damage, vascular leakage and systemic virus dissemination. In addition, this model indicated that T cell-mediated immunopathology was an important component of LASF pathogenesis that was directly correlated with vascular leakage. Our strategy allows easy generation of a suitable small animal model to test new vaccines and antivirals and to dissect the basic components of LASF pathophysiology.

Emergence of Lassa Fever Disease in Northern Togo: Report of Two Cases in Oti District in 2016.

PubMed

Patassi, Akouda Akessiwe; Landoh, Dadja Essoya; Mebiny-Essoh Tchalla, Agballa; Halatoko, Wemboo Afiwa; Assane, Hamadi; Saka, Bayaki; Naba, Mouchedou Abdoukarim; Yaya, Issifou; Edou, Kossi Atsissinta; Tamekloe, Tsidi Agbeko; Banla, Abiba Kere; Davi, Kokou Mawule; Manga, Magloire; Kassankogno, Yao; Salmon-Ceron, Dominique

2017-01-01

Lassa fever belongs to the group of potentially fatal hemorrhagic fevers, never reported in Togo. The aim of this paper is to report the first two cases of Lassa fever infection in Togo. The two first Lassa fever cases occurred in two expatriate's health professionals working in Togo for more than two years. The symptoms appeared among two health professionals of a clinic located in Oti district in the north of the country. The absence of clinical improvement after antimalarial treatment and the worsening of clinical symptoms led to the medical evacuation. The delayed diagnosis of the first case led to a fatal outcome. The second case recovered under ribavirin treatment. The emergence of this hemorrhagic fever confirms the existence of Lassa fever virus in Togo. After a period of intensive Ebola virus transmission from 2013 to 2015, this is an additional call for the establishment and enhancement of infection prevention and control measures in the health care setting in West Africa.

Undiagnosed Acute Viral Febrile Illnesses, Sierra Leone

PubMed Central

Rossi, Cynthia A.; Khan, Sheik H.; Goba, Augustine; Fair, Joseph N.

2014-01-01

Sierra Leone in West Africa is in a Lassa fever–hyperendemic region that also includes Guinea and Liberia. Each year, suspected Lassa fever cases result in submission of ≈500–700 samples to the Kenema Government Hospital Lassa Diagnostic Laboratory in eastern Sierra Leone. Generally only 30%–40% of samples tested are positive for Lassa virus (LASV) antigen and/or LASV-specific IgM; thus, 60%–70% of these patients have acute diseases of unknown origin. To investigate what other arthropod-borne and hemorrhagic fever viral diseases might cause serious illness in this region and mimic Lassa fever, we tested patient serum samples that were negative for malaria parasites and LASV. Using IgM-capture ELISAs, we evaluated samples for antibodies to arthropod-borne and other hemorrhagic fever viruses. Approximately 25% of LASV-negative patients had IgM to dengue, West Nile, yellow fever, Rift Valley fever, chikungunya, Ebola, and Marburg viruses but not to Crimean-Congo hemorrhagic fever virus. PMID:24959946

Molecular confirmation of Lassa fever imported into Ghana.

PubMed

Bonney, Joseph H K; Nyarko, Edward O; Ohene, Sally-Ann; Amankwa, Joseph; Ametepi, Ralph K; Nimo-Paintsil, Shirley C; Sarkodie, Badu; Agbenohevi, Prince; Adjabeng, Michael; Kyei, Nicholas N A; Bel-Nono, Samuel; Ampofo, William K

2016-01-01

Recent reports have shown an expansion of Lassa virus from the area where it was first isolated in Nigeria to other areas of West Africa. Two Ghanaian soldiers on a United Nations peacekeeping mission in Liberia were taken ill with viral haemorrhagic fever syndrome following the death of a sick colleague and were referred to a military hospital in Accra, Ghana, in May 2013. Blood samples from the soldiers and five asymptomatic close contacts were subjected to laboratory investigations. We report the results of these investigations to highlight the importance of molecular diagnostic applications and the need for heightened awareness about Lassa fever in West Africa. We used molecular assays on sera from the two patients to identify the causative organism. Upon detection of positive signals for Lassa virus ribonucleic material by two different polymerase chain reaction assays, sequencing and phylogenetic analyses were performed. The presence of Lassa virus in the soldiers' blood samples was shown by L-gene segment homology to be the Macenta and las803792 strains previously isolated in Liberia, with close relationships then confirmed by phylogenetic tree construction. The five asymptomatic close contacts were negative for Lassa virus. The Lassa virus strains identified in the two Ghanaian soldiers had molecular epidemiological links to strains from Liberia. Lassa virus was probably responsible for the outbreak of viral haemorrhagic fever in the military camp. These data confirm Lassa fever endemicity in West Africa.

United States Army Medical Materiel Development Activity - 1989

DTIC Science & Technology

1990-01-31

physicians to treat diseases such as Korean Hemorrhagic Fever and Lassa Fever. * J-5 Human Monoclonal Antibody is secreted by cultured hybridomas that were...volunteer studies involving a collaborative effort between WRAIR and the Swiss Serum and Vaccine Institute (SSVI). s Lassa Fever Immune Plasma is an...immune globulin used to treat Lassa fever infections. The collection of human immune plasma in Africa is an ongoing contract effort. USANRIID performs

Knowledge Attitude and Practices Toward Lassa Fever Control and Prevention Among Residents of Ile-Ife, Southwest Nigeria.

PubMed

Olowookere, S A; Adegbenro, C A; Idowu, A; Omisore, A G; Shabi, O M; Ikem, U R; Ekwere, G A; Oderinde, I F

2017-01-01

Lassa fever had been reported as a cause of death especially in endemic parts of Nigeria. This study assessed the knowledge, attitude, and practices toward Lassa fever control and prevention among residents of Ile-Ife, southwest Nigeria. Descriptive cross-sectional study was conducted among consenting randomly selected adults using an interviewer administered questionnaire. Data were analyzed using descriptive and inferential statistics. A total of 400 questionnaires with completed data were analyzed (response rate 96%). Majority, 207 (51.8%), were males while 193 (48.2%) were females. Most, 234 (58.5%), had tertiary education while 148 (37%) had secondary education. Fifty-nine percent had heard of Lassa fever with radio as their major source of information. About 76% had inadequate knowledge, 54% had negative attitude while 51% had poor practice toward Lassa fever. Determinants of knowledge of Lassa fever include having higher education (Adjusted Odd Ratio (AOR) = 11.49, 95% CI [3.10, 42.69], p = .0001), being in civil service (AOR = 0.22, 95% CI [0.09, 0.51], p = .01), and earning higher income (AOR = 4.23, 95% CI [2.61, 6.84], p = .0001). In conclusion, the knowledge, attitude, as well as preventive practices to Lassa fever were poor. It is necessary to increase public education and improve hygienic practices.

Knowledge of Secondary School Children in Edo State on Lassa Fever and its Implications for Prevention and Control.

PubMed

Tobin, E A; Asogun, D A; Esumeh, R; Omuninu, R; Ehidiamen, G; Giwa, R

2015-01-01

Seasonal outbreaks of Lassa fever in West Africa cause significant morbidity and mortality across all ages. In addition to present efforts to raise awareness, school children can be targeted to become peer and family health educators. The study was carried out to determine the knowledge of Lassa fever among secondary school children, and household practices that increase risk of the infection. In a cross sectional survey, 561 secondary school students randomly selected from schools in Edo State were interviewed by means of a self - administered questionnaire that sought information on knowledge of Lassa fever and practices within the home that favour rodent contact . Data were analyzed using Statistical Package for Social Sciences version 15. Knowledge of Lassa fever was poor among 259 (49.4%) respondents, fair in 216 (41.2%) and good in 49 (9.4%). Female gender (< 0.01), monogamous family structure (p < 0.04) , and being in senior secondary class ( p=0.01) were predictors of high knowledge score. Self- reported Lassa fever risk conditions were found to be of low prevalence in 311(55.4%) and high in 250 (44.6%) homes, and associated with educational status of mother ( p=0.00) and father, (p =0.00). School children in endemic communities lack good knowledge of Lassa fever, but when properly guided, have the potential to become peer and family educators.

Re-emerging Lassa fever outbreaks in Nigeria: Re-enforcing "One Health" community surveillance and emergency response practice.

PubMed

Tambo, Ernest; Adetunde, Oluwasegun T; Olalubi, Oluwasogo A

2018-04-28

We evaluated the impact of man-made conflict events and climate change impact in guiding evidence-based community "One Health" epidemiology and emergency response practice against re-/emerging epidemics. Increasing evidence of emerging and re-emerging zoonotic diseases including recent Lassa fever outbreaks in almost 20 states in Nigeria led to 101 deaths and 175 suspected and confirmed cases since August 2015. Of the 75 laboratory confirmed cases, 90 deaths occurred representing 120% laboratory-confirmed case fatality. The outbreak has been imported into neighbouring country such as Benin, where 23 deaths out of 68 cases has also been reported. This study assesses the current trends in re-emerging Lassa fever outbreak in understanding spatio-geographical reservoir(s), risk factors pattern and Lassa virus incidence mapping, inherent gaps and raising challenges in health systems. It is shown that Lassa fever peak endemicity incidence and prevalence overlap the dry season (within January to March) and reduced during the wet season (of May to November) annually in Sierra Leone, Senegal to Eastern Nigeria. We documented a scarcity of consistent data on rodent (reservoirs)-linked Lassa fever outbreak, weak culturally and socio-behavioural effective prevention and control measures integration, weak or limited community knowledge and awareness to inadequate preparedness capacity and access to affordable case management in affected countries. Hence, robust sub/regional leadership commitment and investment in Lassa fever is urgently needed in building integrated and effective community "One Health" surveillance and rapid response approach practice coupled with pest management and phytosanitation measures against Lassa fever epidemic. This offers new opportunities in understanding human-animal interactions in strengthening Lassa fever outbreak early detection and surveillance, warning alerts and rapid response implementation in vulnerable settings. Leveraging on Africa CDC centre, advances in cloud-sourcing and social media tools and solutions is core in developing and integrating evidence-based and timely risk communication, and reporting systems in improving contextual community-based immunization and control decision making policy to effectively defeat Lassa fever outbreak and other emerging pandemics public health emergencies in Africa and worldwide.

Housing equity for health equity: a rights-based approach to the control of Lassa fever in post-war Sierra Leone.

PubMed

Kelly, J Daniel; Barrie, M Bailor; Ross, Rachel A; Temple, Brian A; Moses, Lina M; Bausch, Daniel G

2013-01-02

Poor quality housing is an infringement on the rights of all humans to a standard of living adequate for health. Among the many vulnerabilities of those without adequate shelter is the risk of disease spread by rodents and other pests. One such disease is Lassa fever, an acute and sometimes severe viral hemorrhagic illness endemic in West Africa. Lassa virus is maintained in the rodent Mastomys natalensis, commonly known as the "multimammate rat," which frequently invades the domestic environment, putting humans at risk of Lassa fever. The highest reported incidence of Lassa fever in the world is consistently in the Kenema District of Sierra Leone, a region that was at the center of Sierra Leone's civil war in which tens of thousands of lives were lost and hundreds of thousands of dwellings destroyed. Despite the end of the war in 2002, most of Kenema's population still lives in inadequate housing that puts them at risk of rodent invasion and Lassa fever. Furthermore, despite years of health education and village hygiene campaigns, the incidence of Lassa fever in Kenema District appears to be increasing. We focus on Lassa fever as a matter of human rights, proposing a strategy to improve housing quality, and discuss how housing equity has the potential to improve health equity and ultimately economic productivity in Sierra Leone. The manuscript is designed to spur discussion and action towards provision of housing and prevention of disease in one of the world's most vulnerable populations.

Pediatric Lassa fever: a review of 33 Liberian cases.

PubMed

Monson, M H; Cole, A K; Frame, J D; Serwint, J R; Alexander, S; Jahrling, P B

1987-03-01

Thirty-three cases of pediatric Lassa fever were identified at Curran Lutheran Hospital and Phebe Hospital in Liberia between January 1980 and March 1984. All 18 fetal cases died and the case-fatality rate for 15 childhood cases was 27%. We identified four clinical presentations according to age, including a case of congenital Lassa fever, a condition not reported previously. Two cases of Lassa fever were found serologically during a one-month survey of all pediatric admissions at Curran Lutheran Hospital, 2.4% of those children who had serum pairs collected. We also identified a "swollen baby syndrome" consisting of widespread edema, abdominal distention, and bleeding. This distinctive clinical presentation of Lassa fever ended in death in three of four cases and was present in three of the four childhood deaths in this series. Its absence seems to be a good prognostic indicator in children.

Molecular confirmation of Lassa fever imported into Ghana

PubMed Central

Nyarko, Edward O.; Ohene, Sally-Ann; Amankwa, Joseph; Ametepi, Ralph K.; Nimo-Paintsil, Shirley C.; Sarkodie, Badu; Agbenohevi, Prince; Adjabeng, Michael; Kyei, Nicholas N.A.; Bel-Nono, Samuel; Ampofo, William K.

2016-01-01

Background Recent reports have shown an expansion of Lassa virus from the area where it was first isolated in Nigeria to other areas of West Africa. Two Ghanaian soldiers on a United Nations peacekeeping mission in Liberia were taken ill with viral haemorrhagic fever syndrome following the death of a sick colleague and were referred to a military hospital in Accra, Ghana, in May 2013. Blood samples from the soldiers and five asymptomatic close contacts were subjected to laboratory investigations. Objective We report the results of these investigations to highlight the importance of molecular diagnostic applications and the need for heightened awareness about Lassa fever in West Africa. Methods We used molecular assays on sera from the two patients to identify the causative organism. Upon detection of positive signals for Lassa virus ribonucleic material by two different polymerase chain reaction assays, sequencing and phylogenetic analyses were performed. Results The presence of Lassa virus in the soldiers’ blood samples was shown by L-gene segment homology to be the Macenta and las803792 strains previously isolated in Liberia, with close relationships then confirmed by phylogenetic tree construction. The five asymptomatic close contacts were negative for Lassa virus. Conclusions The Lassa virus strains identified in the two Ghanaian soldiers had molecular epidemiological links to strains from Liberia. Lassa virus was probably responsible for the outbreak of viral haemorrhagic fever in the military camp. These data confirm Lassa fever endemicity in West Africa. PMID:28879105

Emergence of Lassa Fever Disease in Northern Togo: Report of Two Cases in Oti District in 2016

PubMed Central

Patassi, Akouda Akessiwe; Mebiny-Essoh Tchalla, Agballa; Halatoko, Wemboo Afiwa; Assane, Hamadi; Naba, Mouchedou Abdoukarim; Yaya, Issifou; Edou, Kossi Atsissinta; Tamekloe, Tsidi Agbeko; Banla, Abiba Kere; Davi, Kokou Mawule; Manga, Magloire; Kassankogno, Yao; Salmon-Ceron, Dominique

2017-01-01

Background Lassa fever belongs to the group of potentially fatal hemorrhagic fevers, never reported in Togo. The aim of this paper is to report the first two cases of Lassa fever infection in Togo. Case Presentation The two first Lassa fever cases occurred in two expatriate's health professionals working in Togo for more than two years. The symptoms appeared among two health professionals of a clinic located in Oti district in the north of the country. The absence of clinical improvement after antimalarial treatment and the worsening of clinical symptoms led to the medical evacuation. The delayed diagnosis of the first case led to a fatal outcome. The second case recovered under ribavirin treatment. Conclusion The emergence of this hemorrhagic fever confirms the existence of Lassa fever virus in Togo. After a period of intensive Ebola virus transmission from 2013 to 2015, this is an additional call for the establishment and enhancement of infection prevention and control measures in the health care setting in West Africa. PMID:29391958

Undiagnosed Acute Viral Febrile Illnesses, Sierra Leone

DTIC Science & Technology

2014-07-01

Sierra Leone in West Africa is in a Lassa fever – hyperendemic region that also includes Guinea and Li- beria. Each year...suspected Lassa fever cases result in submission of ≈500–700 samples to the Kenema Govern- ment Hospital Lassa Diagnostic Laboratory in eastern Si- erra...patients have acute diseases of unknown origin. To investigate what other ar- thropod-borne and hemorrhagic fever viral diseases might cause serious

Lassa fever or lassa hemorrhagic fever risk to humans from rodent-borne zoonoses.

PubMed

El-Bahnasawy, Mamdouh M; Megahed, Laila Abdel-Mawla; Abdalla Saleh, Hala Ahmed; Morsy, Tosson A

2015-04-01

Viral hemorrhagic fevers (VHFs) typically manifest as rapidly progressing acute febrile syndromes with profound hemorrhagic manifestations and very high fatality rates. Lassa fever, an acute hemorrhagic fever characterized by fever, muscle aches, sore throat, nausea, vomiting, diarrhea and chest and abdominal pain. Rodents are important reservoirs of rodent-borne zoonosis worldwide. Transmission rodents to humans occur by aerosol spread, either from the genus Mastomys rodents' excreta (multimammate rat) or through the close contact with infected patients (nosocomial infection). Other rodents of the genera Rattus, Mus, Lemniscomys, and Praomys are incriminated rodents hosts. Now one may ask do the rodents' ectoparasites play a role in Lassa virus zoonotic transmission. This paper summarized the update knowledge on LHV; hopping it might be useful to the clinicians, nursing staff, laboratories' personals as well as those concerned zoonoses from rodents and rodent control.

Production of CXC and CC chemokines by human antigen-presenting cells in response to Lassa virus or closely related immunogenic viruses, and in cynomolgus monkeys with lassa fever.

PubMed

Pannetier, Delphine; Reynard, Stéphanie; Russier, Marion; Carnec, Xavier; Baize, Sylvain

2014-01-01

The pathogenesis of Lassa fever (LF), a hemorrhagic fever endemic to West Africa, remains unclear. We previously compared Lassa virus (LASV) with its genetically close, but nonpathogenic homolog Mopeia virus (MOPV) and demonstrated that the strong activation of antigen-presenting cells (APC), including type I IFN production, observed in response to MOPV probably plays a crucial role in controlling infection. We show here that human macrophages (MP) produce large amounts of CC and CXC chemokines in response to MOPV infection, whereas dendritic cells (DC) release only moderate amounts of CXC chemokines. However, in the presence of autologous T cells, DCs produced CC and CXC chemokines. Chemokines were produced in response to type I IFN synthesis, as the levels of both mediators were strongly correlated and the neutralization of type I IFN resulted in an inhibition of chemokine production. By contrast, LASV induced only low levels of CXCL-10 and CXCL-11 production. These differences in chemokine production may profoundly affect the generation of virus-specific T-cell responses and may therefore contribute to the difference of pathogenicity between these two viruses. In addition, a recombinant LASV (rLASV) harboring the NP-D389A/G392A mutations, which abolish the inhibition of type I IFN response by nucleoprotein (NP), induced the massive synthesis of CC and CXC chemokines in both DC and MP, confirming the crucial role of arenavirus NP in immunosuppression and pathogenicity. Finally, we confirmed, using PBMC samples and lymph nodes obtained from LASV-infected cynomolgus monkeys, that LF was associated with high levels of CXC chemokine mRNA synthesis, suggesting that the very early synthesis of these mediators may be correlated with a favourable outcome.

IGG Subclass and Isotype Specific Immunoglobulin Responses to Lassa Fever and Venezuelan Equine Encephalomyelitis: Natural Infection and Immunization

DTIC Science & Technology

1991-12-30

AD-A246 912 AD ARMY PROJECT ORDER 88PP8804 TITLE: IGG SUBCLASS AND ISOTYPE SPECIFIC IMMUNOGLOBULIN RESPONSES TO LASSA FEVER AND VENEZUELAN EQUINE ...and Isotype Specific Immunoglobulin responses Army Project Order to Lassa Fever and Venezuelan Equine Encephalitis: 88PP8804 Natual...unlimited 13. ABSTRACT (Maximum 200 words) Venezuelan Equine Encephalitis (VEE) specific inimunoglobulin responses to the two vaccines, TC-83 (A live

[Use of guinea pigs for assessing the efficacy of vaccines against Lassa fever].

PubMed

Firsova, I V; Shatokhina, I V; Borisevich, I V; Evseev, A A; Maksimov, V A; Pantiukhov, V B; Khmelev, A L

2003-01-01

The use of guinea pigs as a laboratory model was proven to be appropriate in investigating the vaccines developed against Lassa fever at the preclinical study stage. An adapted variant of Lassa virus was cultivated, which caused death of guinea pigs with respect for an agent's dose. Finally, it was shown to be possible to investigate the immunogenic and protective properties of the inactivated antigen of Lassa virus in experiments with guinea pigs.

Imported Lassa fever: a report of 2 cases in Ghana.

PubMed

Kyei, Nicholas N A; Abilba, Mark M; Kwawu, Foster K; Agbenohevi, Prince G; Bonney, Joseph H K; Agbemaple, Thomas K; Nimo-Paintsil, Shirley C; Ampofo, William; Ohene, Sally-Ann; Nyarko, Edward O

2015-05-29

Lassa fever is a potentially fatal acute viral illness caused by Lassa virus which is carried by rodents and is endemic in some West African countries. Importation of emerging infections such as Lassa fever, Ebola Virus Disease and other viral hemorrhagic fevers into non endemic regions is a growing threat particularly as international travel and commitments in resolving conflicts in endemic countries in the West Africa sub-region continue. We report the first two recorded imported cases of Lassa fever among Ghanaian Peace keepers in rural Liberia, who became ill while on Peace keeping mission. They were subsequently evacuated to the UN level IV hospital in Accra, where their illnesses were laboratory confirmed. One of the patients recovered with ribavirin treatment and supportive therapy. No secondary clinical cases occurred in Ghana. Healthcare providers at all levels of care should thus have a high index of suspicion for these infectious diseases and adopt standard infection control measures when treating patients in endemic regions or returning travelers from an endemic region with a febrile illness even of a known etiology.

Epidemic preparedness and management: A guide on Lassa fever outbreak preparedness plan.

PubMed

Fatiregun, Akinola Ayoola; Isere, Elvis Efe

2017-01-01

Epidemic prone diseases threaten public health security. These include diseases such as cholera, meningitis, and hemorrhagic fevers, especially Lassa fever for which Nigeria reports considerable morbidity and mortality annually. Interestingly, where emergency epidemic preparedness plans are in place, timely detection of outbreaks is followed by a prompt and appropriate response. Furthermore, due to the nature of spread of Lassa fever in an outbreak setting, there is the need for health-care workers to be familiar with the emerging epidemic management framework that has worked in other settings for effective preparedness and response. This paper, therefore, discussed the principles of epidemic management using an emergency operating center model, review the epidemiology of Lassa fever in Nigeria, and provide guidance on what is expected to be done in preparing for epidemic of the disease at the health facilities, local and state government levels in line with the Integrated Disease Surveillance and Response strategy.

The broad-spectrum antiviral favipiravir protects guinea pigs from lethal Lassa virus infection post-disease onset.

PubMed

Safronetz, David; Rosenke, Kyle; Westover, Jonna B; Martellaro, Cynthia; Okumura, Atsushi; Furuta, Yousuke; Geisbert, Joan; Saturday, Greg; Komeno, Takashi; Geisbert, Thomas W; Feldmann, Heinz; Gowen, Brian B

2015-10-12

With up to 500,000 infections annually, Lassa virus (LASV), the cause of Lassa fever, is one of the most prevalent etiological agents of viral hemorrhagic fever (VHF) in humans. LASV is endemic in several West African countries with sporadic cases and prolonged outbreaks observed most commonly in Sierra Leone, Liberia, Guinea and Nigeria. Additionally several cases of Lassa fever have been imported into North America, Europe and Asia making LASV a global threat to public health. Despite this, currently no approved therapeutic or vaccine exists to treat or prevent LASV infections. Here, using a passaged strain of LASV that is uniformly lethal in Hartley guinea pigs, we demonstrate that favipiravir, a broad-spectrum antiviral agent and leading treatment option for influenza, has potent activity against LASV infection. In this model, once daily treatment with favipiravir significantly reduced viral titers in tissue samples and reduced mortality rates when compared with animals receiving vehicle-only or ribavirin, the current standard of care for Lassa fever. Favipiravir remained highly effective against lethal LASV infection when treatments were initiated nine days post-infection, a time when animals were demonstrating advanced signs of disease. These results support the further preclinical evaluation of favipiravir for Lassa fever and other VHFs.

The broad-spectrum antiviral favipiravir protects guinea pigs from lethal Lassa virus infection post-disease onset

PubMed Central

Safronetz, David; Rosenke, Kyle; Westover, Jonna B.; Martellaro, Cynthia; Okumura, Atsushi; Furuta, Yousuke; Geisbert, Joan; Saturday, Greg; Komeno, Takashi; Geisbert, Thomas W.; Feldmann, Heinz; Gowen, Brian B.

2015-01-01

With up to 500,000 infections annually, Lassa virus (LASV), the cause of Lassa fever, is one of the most prevalent etiological agents of viral hemorrhagic fever (VHF) in humans. LASV is endemic in several West African countries with sporadic cases and prolonged outbreaks observed most commonly in Sierra Leone, Liberia, Guinea and Nigeria. Additionally several cases of Lassa fever have been imported into North America, Europe and Asia making LASV a global threat to public health. Despite this, currently no approved therapeutic or vaccine exists to treat or prevent LASV infections. Here, using a passaged strain of LASV that is uniformly lethal in Hartley guinea pigs, we demonstrate that favipiravir, a broad-spectrum antiviral agent and leading treatment option for influenza, has potent activity against LASV infection. In this model, once daily treatment with favipiravir significantly reduced viral titers in tissue samples and reduced mortality rates when compared with animals receiving vehicle-only or ribavirin, the current standard of care for Lassa fever. Favipiravir remained highly effective against lethal LASV infection when treatments were initiated nine days post-infection, a time when animals were demonstrating advanced signs of disease. These results support the further preclinical evaluation of favipiravir for Lassa fever and other VHFs. PMID:26456301

Aseptic Meningitis Caused by Lassa Virus: Case Series Report

PubMed Central

Bankole, Idowu A.; Iruolagbe, Christopher O.; Muoebonam, Benard E.; Okonofua, Martha O.; Dawodu, Simeon O.; Akpede, George O.

2016-01-01

The Lassa virus is known to cause disease in different organ systems of the human body, with varying clinical manifestations. The features of severe clinical disease may include bleeding and/or central nervous system manifestations. Whereas Lassa fever encephalopathy and encephalitis are well described in the literature, there is paucity of data on Lassa virus meningitis. We present the clinical description, laboratory diagnosis, and management of 4 consecutive cases of aseptic meningitis associated with Lassa virus infection without bleeding seen in a region of Nigeria known to be endemic for both the reservoir rodent and Lassa fever. The 4 patients recovered fully following intravenous ribavirin treatment and suffered no neurologic complications. PMID:27957363

A recombinant vesicular stomatitis virus-based Lassa fever vaccine protects guinea pigs and macaques against challenge with geographically and genetically distinct Lassa viruses.

PubMed

Safronetz, David; Mire, Chad; Rosenke, Kyle; Feldmann, Friederike; Haddock, Elaine; Geisbert, Thomas; Feldmann, Heinz

2015-04-01

Lassa virus (LASV) is endemic in several West African countries and is the etiological agent of Lassa fever. Despite the high annual incidence and significant morbidity and mortality rates, currently there are no approved vaccines to prevent infection or disease in humans. Genetically, LASV demonstrates a high degree of diversity that correlates with geographic distribution. The genetic heterogeneity observed between geographically distinct viruses raises concerns over the potential efficacy of a "universal" LASV vaccine. To date, several experimental LASV vaccines have been developed; however, few have been evaluated against challenge with various genetically unique Lassa virus isolates in relevant animal models. Here we demonstrate that a single, prophylactic immunization with a recombinant vesicular stomatitis virus (VSV) expressing the glycoproteins of LASV strain Josiah from Sierra Leone protects strain 13 guinea pigs from infection / disease following challenge with LASV isolates originating from Liberia, Mali and Nigeria. Similarly, the VSV-based LASV vaccine yields complete protection against a lethal challenge with the Liberian LASV isolate in the gold-standard macaque model of Lassa fever. Our results demonstrate the VSV-based LASV vaccine is capable of preventing morbidity and mortality associated with non-homologous LASV challenge in two animal models of Lassa fever. Additionally, this work highlights the need for the further development of disease models for geographical distinct LASV strains, particularly those from Nigeria, in order to comprehensively evaluate potential vaccines and therapies against this prominent agent of viral hemorrhagic fever.

Lassa and Mopeia virus replication in human monocytes/macrophages and in endothelial cells: different effects on IL-8 and TNF-alpha gene expression.

PubMed

Lukashevich, I S; Maryankova, R; Vladyko, A S; Nashkevich, N; Koleda, S; Djavani, M; Horejsh, D; Voitenok, N N; Salvato, M S

1999-12-01

Cells of the mononuclear and endothelial lineages are targets for viruses which cause hemorrhagic fevers (HF) such as the filoviruses Marburg and Ebola, and the arenaviruses Lassa and Junin. A recent model of Marburg HF pathogenesis proposes that virus directly causes endothelial cell damage and macrophage release of TNF-alpha which increases the permeability of endothelial monolayers [Feldmann et al. , 1996]. We show that Lassa virus replicates in human monocytes/macrophages and endothelial cells without damaging them. Human endothelial cells (HUVEC) are highly susceptible to infection by both Lassa and Mopeia (a non-pathogenic Lassa-related arenavirus). Whereas monocytes must differentiate into macrophages before supporting even low level production of these viruses, the virus yields in the culture medium of infected HUVEC cells reach more than 7 log10 PFU/ml without cellular damage. In contrast to filovirus, Lassa virus replication in monocytes/macrophages fails to stimulate TNF-alpha gene expression and even down-regulates LPS-stimulated TNF-alpha mRNA synthesis. The expression of IL-8, a prototypic proinflammatory CXC chemokine, was also suppressed in Lassa virus infected monocytes/macrophages and HUVEC on both the protein and mRNA levels. This contrasts with Mopeia virus infection of HUVEC in which neither IL-8 mRNA nor protein are reduced. The cumulative down-regulation of TNF-alpha and IL-8 expression could explain the absence of inflammatory and effective immune responses in severe cases of Lassa HF. Copyright 1999 Wiley-Liss, Inc.

Lassa Fever Immune Plasma.

DTIC Science & Technology

1984-08-01

three instances, and one each for sickle cell crisis , severe anemia, pyelonephritis, cerebral malaria and tonsillitis. Treatment of LF with LFIP under...diagnosis of 46 LF and Presumptive LF patients treated at CLH April 1983 - March 1984. Clinical diagnosis No. Lassa fever 38 Typhoid fever 3 Sickle cell crisis 1

A fatal case of Lassa fever in London, January 2009.

PubMed

Kitching, A; Addiman, S; Cathcart, S; Bischop, L; Krahé, D; Nicholas, M; Coakley, J; Lloyd, G; Brooks, T; Morgan, D; Turbitt, D

2009-02-12

In January 2009, the eleventh [corrected] case of Lassa fever imported to the United Kingdom was diagnosed in London. Risk assessment of 328 healthcare contacts with potential direct exposure to Lassa virus - through contact with the case or exposure to bodily fluids - was undertaken. No contacts were assessed to be at high risk of infection and no secondary clinical cases identified.

Clinical features and patient management of Lujo hemorrhagic fever.

PubMed

Sewlall, Nivesh H; Richards, Guy; Duse, Adriano; Swanepoel, Robert; Paweska, Janusz; Blumberg, Lucille; Dinh, Thu Ha; Bausch, Daniel

2014-01-01

In 2008 a nosocomial outbreak of five cases of viral hemorrhagic fever due to a novel arenavirus, Lujo virus, occurred in Johannesburg, South Africa. Lujo virus is only the second pathogenic arenavirus, after Lassa virus, to be recognized in Africa and the first in over 40 years. Because of the remote, resource-poor, and often politically unstable regions where Lassa fever and other viral hemorrhagic fevers typically occur, there have been few opportunities to undertake in-depth study of their clinical manifestations, transmission dynamics, pathogenesis, or response to treatment options typically available in industrialized countries. We describe the clinical features of five cases of Lujo hemorrhagic fever and summarize their clinical management, as well as providing additional epidemiologic detail regarding the 2008 outbreak. Illness typically began with the abrupt onset of fever, malaise, headache, and myalgias followed successively by sore throat, chest pain, gastrointestinal symptoms, rash, minor hemorrhage, subconjunctival injection, and neck and facial swelling over the first week of illness. No major hemorrhage was noted. Neurological signs were sometimes seen in the late stages. Shock and multi-organ system failure, often with evidence of disseminated intravascular coagulopathy, ensued in the second week, with death in four of the five cases. Distinctive treatment components of the one surviving patient included rapid commencement of the antiviral drug ribavirin and administration of HMG-CoA reductase inhibitors (statins), N-acetylcysteine, and recombinant factor VIIa. Lujo virus causes a clinical syndrome remarkably similar to Lassa fever. Considering the high case-fatality and significant logistical impediments to controlled treatment efficacy trials for viral hemorrhagic fever, it is both logical and ethical to explore the use of the various compounds used in the treatment of the surviving case reported here in future outbreaks. Clinical observations should be systematically recorded to facilitate objective evaluation of treatment efficacy. Due to the risk of secondary transmission, viral hemorrhagic fever precautions should be implemented for all cases of Lujo virus infection, with specialized precautions to protect against aerosols when performing enhanced-risk procedures such as endotracheal intubation.

Review of the literature and proposed guidelines for the use of oral ribavirin as postexposure prophylaxis for Lassa fever.

PubMed

Bausch, Daniel G; Hadi, Christiane M; Khan, Sheik Humarr; Lertora, Juan J L

2010-12-15

Lassa fever is an acute viral hemorrhagic illness; the virus is endemic in West Africa and also of concern with regard to bioterrorism. Transmission of Lassa virus between humans may occur through direct contact with infected blood or bodily secretions. Oral administration of the antiviral drug ribavirin is often considered for postexposure prophylaxis, but no systematically collected data or uniform guidelines exist for this indication. Furthermore, the relatively low secondary attack rates for Lassa fever, the restriction of the area of endemicity to West Africa, and the infrequency of high-risk exposures make it unlikely that controlled prospective efficacy trials will ever be possible. Recommendations for postexposure use of ribavirin can therefore be made only on the basis of a thorough understanding and logical extrapolation of existing data. Here, we review the pertinent issues and propose guidelines based on extensive review of the literature, as well as our experience in this field. We recommend oral ribavirin postexposure prophylaxis for Lassa fever exclusively for definitive high-risk exposures. These guidelines may also serve for exposure to other hemorrhagic fever viruses susceptible to ribavirin.

Lassa Virus Seroprevalence in Sibirilia Commune, Bougouni District, Southern Mali.

PubMed

Sogoba, Nafomon; Rosenke, Kyle; Adjemian, Jennifer; Diawara, Sory Ibrahim; Maiga, Ousmane; Keita, Moussa; Konaté, Drissa; Keita, Abdoul Salam; Sissoko, Ibrahim; Boisen, Matt; Nelson, Diana; Oottamasathien, Darin; Millett, Molly; Garry, Robert F; Branco, Luis M; Traoré, Sékou F; Doumbia, Seydou; Feldmann, Heinz; Safronetz, David

2016-04-01

Lassa virus (LASV) is endemic to several nations in West Africa. In Mali, LASV was unknown until an exported case of Lassa fever was reported in 2009. Since that time, rodent surveys have found evidence of LASV-infected Mastomys natalensis rats in several communities in southern Mali, near the border with Côte d'Ivoire. Despite increased awareness, to date only a single case of Lassa fever has been confirmed in Mali. We conducted a survey to determine the prevalence of LASV exposure among persons in 3 villages in southern Mali where the presence of infected rodents has been documented. LASV IgG seroprevalence ranged from 14.5% to 44% per village. No sex bias was noted; however, seropositivity rates increased with participant age. These findings confirm human LASV exposure in Mali and suggest that LASV infection/Lassa fever is a potential public health concern in southern Mali.

Movement Patterns of Small Rodents in Lassa Fever-Endemic Villages in Guinea.

PubMed

Mariën, Joachim; Kourouma, Fodé; Magassouba, N'Faly; Leirs, Herwig; Fichet-Calvet, Elisabeth

2018-03-23

The Natal multimammate mouse (Mastomys natalensis) is the reservoir host of Lassa arenavirus, the etiological agent of Lassa fever in humans. Because there exists no vaccine for human use, rodent control and adjusting human behavior are currently considered to be the only options for Lassa fever control. In order to develop efficient rodent control programs, more information about the host's ecology is needed. In this study, we investigated the spatial behavior of M. natalensis and other small rodents in two capture-mark-recapture and four dyed bait (Rhodamine B) experiments in Lassa fever-endemic villages in Upper Guinea. During the capture-mark-recapture studies, 23% of the recaptured M. natalensis moved between the houses and proximate fields. While M. natalensis was found over the entire study grid (2 ha), other rodent species (Praomys daltoni, Praomys rostratus, Lemniscomys striatus, Mus spp.) were mostly trapped in the surrounding fields. Distances between recapture occasions never exceeded 100 m for all rodent species. During the dyed bait experiments, 11% of M. natalensis and 41% of P. daltoni moved from the fields to houses. We conclude that commensal M. natalensis easily moves between houses and proximate fields in Guinea. We therefore consider occasional domestic rodent elimination to be an unsustainable approach to reduce Lassa virus transmission risk to humans, as M. natalensis is likely to reinvade houses quickly from fields in which rodents are not controlled. A combination of permanent rodent elimination with other control strategies (e.g., make houses rodent proof or attract predators) could be more effective for Lassa fever control, but must be further investigated.

A Recombinant Vesicular Stomatitis Virus-Based Lassa Fever Vaccine Protects Guinea Pigs and Macaques against Challenge with Geographically and Genetically Distinct Lassa Viruses

PubMed Central

Safronetz, David; Mire, Chad; Rosenke, Kyle; Feldmann, Friederike; Haddock, Elaine; Geisbert, Thomas; Feldmann, Heinz

2015-01-01

Background Lassa virus (LASV) is endemic in several West African countries and is the etiological agent of Lassa fever. Despite the high annual incidence and significant morbidity and mortality rates, currently there are no approved vaccines to prevent infection or disease in humans. Genetically, LASV demonstrates a high degree of diversity that correlates with geographic distribution. The genetic heterogeneity observed between geographically distinct viruses raises concerns over the potential efficacy of a “universal” LASV vaccine. To date, several experimental LASV vaccines have been developed; however, few have been evaluated against challenge with various genetically unique Lassa virus isolates in relevant animal models. Methodologies/principle findings Here we demonstrate that a single, prophylactic immunization with a recombinant vesicular stomatitis virus (VSV) expressing the glycoproteins of LASV strain Josiah from Sierra Leone protects strain 13 guinea pigs from infection / disease following challenge with LASV isolates originating from Liberia, Mali and Nigeria. Similarly, the VSV-based LASV vaccine yields complete protection against a lethal challenge with the Liberian LASV isolate in the gold-standard macaque model of Lassa fever. Conclusions/significance Our results demonstrate the VSV-based LASV vaccine is capable of preventing morbidity and mortality associated with non-homologous LASV challenge in two animal models of Lassa fever. Additionally, this work highlights the need for the further development of disease models for geographical distinct LASV strains, particularly those from Nigeria, in order to comprehensively evaluate potential vaccines and therapies against this prominent agent of viral hemorrhagic fever. PMID:25884628

Pathogenesis of Lassa fever virus infection: I. Susceptibility of mice to recombinant Lassa Gp/LCMV chimeric virus.

PubMed

Lee, Andrew M; Cruite, Justin; Welch, Megan J; Sullivan, Brian; Oldstone, Michael B A

2013-08-01

Lassa virus (LASV) is a BSL-4 restricted agent. To allow study of infection by LASV under BSL-2 conditions, we generated a recombinant virus in which the LASV glycoprotein (Gp) was placed on the backbone of lymphocytic choriomeningitis virus (LCMV) Cl13 nucleoprotein, Z and polymerase genes (rLCMV Cl13/LASV Gp). The recombinant virus displayed high tropism for dendritic cells following in vitro or in vivo infection. Inoculation of immunocompetent adults resulted in an acute infection, generation of virus-specific CD8(+) T cells and clearance of the infection. Inoculation of newborn mice with rLCMV Cl13/LASV Gp resulted in a life-long persistent infection. Interestingly, adoptive transfer of rLCMV Cl13/LASV Gp immune memory cells into such persistently infected mice failed to purge virus but, in contrast, cleared virus from mice persistently infected with wt LCMV Cl13. Copyright © 2013 Elsevier Inc. All rights reserved.

Metabolomics analyses identify platelet activating factors and heme breakdown products as Lassa fever biomarkers.

PubMed

Gale, Trevor V; Horton, Timothy M; Grant, Donald S; Garry, Robert F

2017-09-01

Lassa fever afflicts tens of thousands of people in West Africa annually. The rapid progression of patients from febrile illness to fulminant syndrome and death provides incentive for development of clinical prognostic markers that can guide case management. The small molecule profile of serum from febrile patients triaged to the Viral Hemorrhagic Fever Ward at Kenema Government Hospital in Sierra Leone was assessed using untargeted Ultra High Performance Liquid Chromatography Mass Spectrometry. Physiological dysregulation resulting from Lassa virus (LASV) infection occurs at the small molecule level. Effects of LASV infection on pathways mediating blood coagulation, and lipid, amino acid, nucleic acid metabolism are manifest in changes in the levels of numerous metabolites in the circulation. Several compounds, including platelet activating factor (PAF), PAF-like molecules and products of heme breakdown emerged as candidates that may prove useful in diagnostic assays to inform better care of Lassa fever patients.

Metabolomics analyses identify platelet activating factors and heme breakdown products as Lassa fever biomarkers

PubMed Central

Gale, Trevor V.; Horton, Timothy M.; Grant, Donald S.

2017-01-01

Lassa fever afflicts tens of thousands of people in West Africa annually. The rapid progression of patients from febrile illness to fulminant syndrome and death provides incentive for development of clinical prognostic markers that can guide case management. The small molecule profile of serum from febrile patients triaged to the Viral Hemorrhagic Fever Ward at Kenema Government Hospital in Sierra Leone was assessed using untargeted Ultra High Performance Liquid Chromatography Mass Spectrometry. Physiological dysregulation resulting from Lassa virus (LASV) infection occurs at the small molecule level. Effects of LASV infection on pathways mediating blood coagulation, and lipid, amino acid, nucleic acid metabolism are manifest in changes in the levels of numerous metabolites in the circulation. Several compounds, including platelet activating factor (PAF), PAF-like molecules and products of heme breakdown emerged as candidates that may prove useful in diagnostic assays to inform better care of Lassa fever patients. PMID:28922385

Control measures following a case of imported Lassa fever from Togo, North Rhine Westphalia, Germany, 2016.

PubMed

Lehmann, Clara; Kochanek, Matthias; Abdulla, Diana; Becker, Stephan; Böll, Boris; Bunte, Anne; Cadar, Daniel; Dormann, Arno; Eickmann, Markus; Emmerich, Petra; Feldt, Torsten; Frank, Christina; Fries, Jochen; Gabriel, Martin; Goetsch, Udo; Gottschalk, René; Günther, Stephan; Hallek, Michael; Häussinger, Dieter; Herzog, Christian; Jensen, Björn; Kolibay, Felix; Krakau, Michael; Langebartels, Georg; Rieger, Toni; Schaade, Lars; Schmidt-Chanasit, Jonas; Schömig, Edgar; Schüttfort, Gundolf; Shimabukuro-Vornhagen, Alexander; von Bergwelt-Baildon, Michael; Wieland, Ulrike; Wiesmüller, Gerhard; Wolf, Timo; Fätkenheuer, Gerd

2017-09-01

In a patient transferred from Togo to Cologne, Germany, Lassa fever was diagnosed 12 days post mortem. Sixty-two contacts in Cologne were categorised according to the level of exposure, and gradual infection control measures were applied. No clinical signs of Lassa virus infection or Lassa specific antibodies were observed in the 62 contacts. Thirty-three individuals had direct contact to blood, other body fluids or tissue of the patients. Notably, with standard precautions, no transmission occurred between the index patient and healthcare workers. However, one secondary infection occurred in an undertaker exposed to the corpse in Rhineland-Palatinate, who was treated on the isolation unit at the University Hospital of Frankfurt. After German authorities raised an alert regarding the imported Lassa fever case, an American healthcare worker who had cared for the index patient in Togo, and who presented with diarrhoea, vomiting and fever, was placed in isolation and medevacked to the United States. The event and the transmission of Lassa virus infection outside of Africa underlines the need for early diagnosis and use of adequate personal protection equipment (PPE), when highly contagious infections cannot be excluded. It also demonstrates that larger outbreaks can be prevented by infection control measures, including standard PPE.

Temporal Progression of Lesions in Guinea Pigs Infected With Lassa Virus.

PubMed

Bell, T M; Shaia, C I; Bearss, J J; Mattix, M E; Koistinen, K A; Honnold, S P; Zeng, X; Blancett, C D; Donnelly, G C; Shamblin, J D; Wilkinson, E R; Cashman, K A

2017-05-01

Lassa virus (LASV) infection causes an acute, multisystemic viral hemorrhagic fever that annually infects an estimated 100 000 to 300 000 persons in West Africa. This pathogenesis study evaluated the temporal progression of disease in guinea pigs following aerosol and subcutaneous inoculation of the Josiah strain of LASV as well as the usefulness of Strain 13 guinea pigs as an animal model for Lassa fever. After experimental infection, guinea pigs ( Cavia porcellus; n = 67) were serially sampled to evaluate the temporal progression of infection, gross and histologic lesions, and serum chemistry and hematologic changes. Guinea pigs developed viremia on day 5 to 6 postexposure (PE), with clinical signs appearing by day 7 to 8 PE. Complete blood counts revealed lymphopenia and thrombocytopenia. Gross pathologic findings included skin lesions and congested lungs. Histologic lesions consisted of cortical lymphoid depletion by day 6 to 7 PE with lymphohistiocytic interstitial pneumonia at 7 to 8 days PE. Scattered hepatocellular degeneration and cell death were also noted in the liver and, to a lesser extent, in other tissues including the haired skin, lung, heart, adrenal gland, lymph nodes, thymus, and spleen. The first cell types to demonstrate staining for viral antigen were fibroblastic reticular cells and macrophages/dendritic cells in the lymph nodes on day 5 to 6 PE. This study demonstrates similarities between Lassa viral disease in human infections and experimental guinea pig infection. These shared pathologic characteristics support the utility of guinea pigs as an additional animal model for vaccine and therapeutic development under the Food and Drug Administration's Animal Rule.

Sensitivity analysis in a Lassa fever deterministic mathematical model

NASA Astrophysics Data System (ADS)

Abdullahi, Mohammed Baba; Doko, Umar Chado; Mamuda, Mamman

2015-05-01

Lassa virus that causes the Lassa fever is on the list of potential bio-weapons agents. It was recently imported into Germany, the Netherlands, the United Kingdom and the United States as a consequence of the rapid growth of international traffic. A model with five mutually exclusive compartments related to Lassa fever is presented and the basic reproduction number analyzed. A sensitivity analysis of the deterministic model is performed. This is done in order to determine the relative importance of the model parameters to the disease transmission. The result of the sensitivity analysis shows that the most sensitive parameter is the human immigration, followed by human recovery rate, then person to person contact. This suggests that control strategies should target human immigration, effective drugs for treatment and education to reduced person to person contact.

Human-monoclonal-antibody therapy protects nonhuman primates against advanced Lassa fever.

PubMed

Mire, Chad E; Cross, Robert W; Geisbert, Joan B; Borisevich, Viktoriya; Agans, Krystle N; Deer, Daniel J; Heinrich, Megan L; Rowland, Megan M; Goba, Augustine; Momoh, Mambu; Boisen, Mathew L; Grant, Donald S; Fullah, Mohamed; Khan, Sheik Humarr; Fenton, Karla A; Robinson, James E; Branco, Luis M; Garry, Robert F; Geisbert, Thomas W

2017-10-01

There are no approved treatments for Lassa fever, which is endemic to the same regions of West Africa that were recently devastated by Ebola. Here we show that a combination of human monoclonal antibodies that cross-react with the glycoproteins of all four clades of Lassa virus is able to rescue 100% of cynomolgus macaques when treatment is initiated at advanced stages of disease, including up to 8 d after challenge.

Lassa Fever Immune Plasma.

DTIC Science & Technology

1986-05-01

obtained and 317 forwarded to USAMRIID, with 272 having LNI’s of 0.3 or higher. Testing of febrile patients for evidence of Lassa virus (LV) infection ...at a rehabilitation center near GWH revealed evidence of previous LV infection in 22 of 288 leprosy patients, 4 of 52 family members of these patients...Virus Infections in the Families of Lassa Fever Patients Annex 3. Record of Household Epidemiology Study 49 Annex 4. Means of Obtaining Samples for IFA

Risk maps of Lassa fever in West Africa.

PubMed

Fichet-Calvet, Elisabeth; Rogers, David John

2009-01-01

Lassa fever is caused by a viral haemorrhagic arenavirus that affects two to three million people in West Africa, causing a mortality of between 5,000 and 10,000 each year. The natural reservoir of Lassa virus is the multi-mammate rat Mastomys natalensis, which lives in houses and surrounding fields. With the aim of gaining more information to control this disease, we here carry out a spatial analysis of Lassa fever data from human cases and infected rodent hosts covering the period 1965-2007. Information on contemporary environmental conditions (temperature, rainfall, vegetation) was derived from NASA Terra MODIS satellite sensor data and other sources and for elevation from the GTOPO30 surface for the region from Senegal to the Congo. All multi-temporal data were analysed using temporal Fourier techniques to generate images of means, amplitudes and phases which were used as the predictor variables in the models. In addition, meteorological rainfall data collected between 1951 and 1989 were used to generate a synoptic rainfall surface for the same region. Three different analyses (models) are presented, one superimposing Lassa fever outbreaks on the mean rainfall surface (Model 1) and the other two using non-linear discriminant analytical techniques. Model 2 selected variables in a step-wise inclusive fashion, and Model 3 used an information-theoretic approach in which many different random combinations of 10 variables were fitted to the Lassa fever data. Three combinations of absenceratiopresence clusters were used in each of Models 2 and 3, the 2 absenceratio1 presence cluster combination giving what appeared to be the best result. Model 1 showed that the recorded outbreaks of Lassa fever in human populations occurred in zones receiving between 1,500 and 3,000 mm rainfall annually. Rainfall, and to a much lesser extent temperature variables, were most strongly selected in both Models 2 and 3, and neither vegetation nor altitude seemed particularly important. Both Models 2 and 3 produced mean kappa values in excess of 0.91 (Model 2) or 0.86 (Model 3), making them 'Excellent'. The Lassa fever areas predicted by the models cover approximately 80% of each of Sierra Leone and Liberia, 50% of Guinea, 40% of Nigeria, 30% of each of Côte d'Ivoire, Togo and Benin, and 10% of Ghana.

Development and evaluation of antibody-capture immunoassays for detection of Lassa virus nucleoprotein-specific immunoglobulin M and G.

PubMed

Gabriel, Martin; Adomeh, Donatus I; Ehimuan, Jacqueline; Oyakhilome, Jennifer; Omomoh, Emmanuel O; Ighodalo, Yemisi; Olokor, Thomas; Bonney, Kofi; Pahlmann, Meike; Emmerich, Petra; Lelke, Michaela; Brunotte, Linda; Ölschläger, Stephan; Thomé-Bolduan, Corinna; Becker-Ziaja, Beate; Busch, Carola; Odia, Ikponmwosa; Ogbaini-Emovon, Ephraim; Okokhere, Peter O; Okogbenin, Sylvanus A; Akpede, George O; Schmitz, Herbert; Asogun, Danny A; Günther, Stephan

2018-03-01

The classical method for detection of Lassa virus-specific antibodies is the immunofluorescence assay (IFA) using virus-infected cells as antigen. However, IFA requires laboratories of biosafety level 4 for assay production and an experienced investigator to interpret the fluorescence signals. Therefore, we aimed to establish and evaluate enzyme-linked immunosorbent assays (ELISA) using recombinant Lassa virus nucleoprotein (NP) as antigen. The IgM ELISA is based on capturing IgM antibodies using anti-IgM, and the IgG ELISA is based on capturing IgG antibody-antigen complexes using rheumatoid factor or Fc gamma receptor CD32a. Analytical and clinical evaluation was performed with 880 sera from Lassa fever endemic (Nigeria) and non-endemic (Ghana and Germany) areas. Using the IFA as reference method, we observed 91.5-94.3% analytical accuracy of the ELISAs in detecting Lassa virus-specific antibodies. Evaluation of the ELISAs for diagnosis of Lassa fever on admission to hospital in an endemic area revealed a clinical sensitivity for the stand-alone IgM ELISA of 31% (95% CI 25-37) and for combined IgM/IgG detection of 26% (95% CI 21-32) compared to RT-PCR. The specificity of IgM and IgG ELISA was estimated at 96% (95% CI 93-98) and 100% (95% CI 99-100), respectively, in non-Lassa fever patients from non-endemic areas. In patients who seroconverted during follow-up, Lassa virus-specific IgM and IgG developed simultaneously rather than sequentially. Consistent with this finding, isolated IgM reactivity, i.e. IgM in the absence of IgG, had no diagnostic value. The ELISAs are not equivalent to RT-PCR for early diagnosis of Lassa fever; however, they are of value in diagnosing patients at later stage. The IgG ELISA may be useful for epidemiological studies and clinical trials due its high specificity, and the higher throughput rate and easier operation compared to IFA.

International Disease Surveillance: United States Government Goals and Paths Forward

DTIC Science & Technology

2010-06-01

convincing case to funders (ie, the U.S. Congress) showing how investment in surveillance for routine disease (eg, rotavirus ) prepares countries to detect...Hemorrhagic Fevers (Lassa, Marburg, Ebola) Viral Hemorrhagic Fevers (Lassa, Marburg, Ebola) Rotavirus Center for Biosecurity of UPMC | June 2010 Page 18

Favipiravir and Ribavirin Treatment of Epidemiologically Linked Cases of Lassa Fever.

PubMed

Raabe, Vanessa N; Kann, Gerrit; Ribner, Bruce S; Morales, Andres; Varkey, Jay B; Mehta, Aneesh K; Lyon, G Marshall; Vanairsdale, Sharon; Faber, Kelly; Becker, Stephan; Eickmann, Markus; Strecker, Thomas; Brown, Shelley; Patel, Ketan; De Leuw, Philipp; Schuettfort, Gundolf; Stephan, Christoph; Rabenau, Holger; Klena, John D; Rollin, Pierre E; McElroy, Anita; Ströher, Ute; Nichol, Stuart; Kraft, Colleen S; Wolf, Timo

2017-09-01

Two patients with Lassa fever are described who are the first human cases treated with a combination of ribavirin and favipiravir. Both patients survived but developed transaminitis and had prolonged detectable virus RNA in blood and semen, suggesting that the possibility of sexual transmission of Lassa virus should be considered. © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

Lassa virus infection in experimentally infected marmosets: liver pathology and immunophenotypic alterations in target tissues.

PubMed

Carrion, Ricardo; Brasky, Kathleen; Mansfield, Keith; Johnson, Curtis; Gonzales, Monica; Ticer, Anysha; Lukashevich, Igor; Tardif, Suzette; Patterson, Jean

2007-06-01

Lassa virus causes thousands of deaths annually in western Africa and is considered a potential biological weapon. In an attempt to develop a small nonhuman primate model of Lassa fever, common marmosets were subcutaneously inoculated with Lassa virus strain Josiah. This inoculation resulted in a systemic disease with clinical and morphological features mirroring those in fatal human Lassa infection: fever, weight loss, high viremia and viral RNA load in tissues, elevated liver enzymes, and severe morbidity between days 15 and 20. The most prominent histopathology findings included multifocal hepatic necrosis with mild inflammation and hepatocyte proliferation, lymphoid depletion, and interstitial nephritis. Cellular aggregates in regions of hepatocellular necrosis were largely composed of HAM56-positive macrophages, devoid of CD3-positive and CD20-positive cells, and characterized by marked reductions in the intensity of HLA-DP, DQ, DR staining. A marked reduction in the major histocompatibility complex class II expression was also observed in the lymph nodes. Immunophenotypic alterations in spleen included reductions in overall numbers of CD20-positive and CD3-positive cells and the disruption of lymphoid follicular architecture. These findings identify the common marmoset as an appropriate model of human Lassa fever and present the first experimental evidence that replication of Lassa virus in tissues is associated with alterations that would be expected to impair adaptive immunity.

Advanced Development of Antiviral Prophylactics and Therapeutics (ADAPT) - Research Area 10

DTIC Science & Technology

2014-11-17

various Prosetta compounds against Rift Valley Fever Virus (RVFV), Lassa virus (LASV) and Marburg virus (MARV), respectively. Activity is demonstrated as...USAMRIID for in vitro efficacy testing against various hemorrhagic fever viruses, including Ebola (EBOV), Marburg (MARV), Lassa (LASV), Rift Valley...unless so designated by other documentation. 14. ABSTRACT The pmpose of the proposed work is to continue the promising anti-hemonhagic fever vims (HFV

Aeromedical evacuation using an aircraft transit isolator of a patient with Lassa fever.

PubMed

Lotz, Eric; Raffin, Hervé

2012-05-01

Lassa fever is a viral hemorrhagic fever only present in West Africa. The mortality rate is 1% and may reach 15% among hospitalized patients. Transmission between humans is mostly due to direct contact with infected body fluids. Aeromedical evacuation of patients with viral hemorrhagic fevers (such as Lassa fever) demands strict isolation measures. Only a few cases of such evacuations have been reported in the literature during the last 40 yr. The use of an aircraft transit isolator device could be helpful. We report the aeromedical evacuation of a confirmed Lassa fever patient from Sierra Leone to Sweden with a dedicated air ambulance using an aircraft transit isolator. The patient was a 30-yr-old physician working for a nonprofit organization. The patient contracted the disease working with infected hospitalized patients. The duration of the mission between activation and arrival at the Swedish hospital was 36 h, which is within the World Health Organization recommendations. Evacuation of patients with potentially lethal contagious infections is possible, but only with strict isolation measures. Specific protective equipment and isolator are mandatory. Medical and technical crews performing such evacuations should be trained in proper equipment use and the isolator should first be used with a low-risk patient to create minimal risk transport conditions.

Lassa fever: the challenges of curtailing a deadly disease.

PubMed

Ibekwe, Titus

2012-01-01

Today Lassa fever is mainly a disease of the developing world, however several imported cases have been reported in different parts of the world and there are growing concerns of the potentials of Lassa fever Virus as a biological weapon. Yet no tangible solution to this problem has been developed nearly half a decade after its identification. Hence, the paper is aimed at appraising the problems associated with LAF illness; the challenges in curbing the epidemic and recommendations on important focal points. A Review based on the documents from the EFAS conference 2011 and literature search on PubMed, Scopus and Science direct. The retrieval of relevant papers was via the University of British Columbia and University of Toronto Libraries. The two major search engines returned 61 and 920 articles respectively. Out of these, the final 26 articles that met the criteria were selected. Relevant information on epidemiology, burden of management and control were obtained. Prompt and effective containment of the Lassa fever disease in Lassa village four decades ago could have saved the West African sub-region and indeed the entire globe from the devastating effect and threats posed by this illness. That was a hard lesson calling for much more proactive measures towards the eradication of the illness at primary, secondary and tertiary levels of health care.

An Outbreak of Ebola Virus Disease in the Lassa Fever Zone

PubMed Central

Goba, Augustine; Khan, S. Humarr; Fonnie, Mbalu; Fullah, Mohamed; Moigboi, Alex; Kovoma, Alice; Sinnah, Vandi; Yoko, Nancy; Rogers, Hawa; Safai, Siddiki; Momoh, Mambu; Koroma, Veronica; Kamara, Fatima K.; Konowu, Edwin; Yillah, Mohamed; French, Issa; Mustapha, Ibraham; Kanneh, Franklyn; Foday, Momoh; McCarthy, Helena; Kallon, Tiangay; Kallon, Mustupha; Naiebu, Jenneh; Sellu, Josephine; Jalloh, Abdul A.; Gbakie, Michael; Kanneh, Lansana; Massaly, James L. B.; Kargbo, David; Kargbo, Brima; Vandi, Mohamed; Gbetuwa, Momoh; Gevao, Sahr M.; Sandi, John D.; Jalloh, Simbirie C.; Grant, Donald S.; Blyden, Sylvia O.; Crozier, Ian; Schieffelin, John S.; McLellan, Susan L.; Jacob, Shevin T.; Boisen, Matt L.; Hartnett, Jessica N.; Cross, Robert W.; Branco, Luis M.; Andersen, Kristian G.; Yozwiak, Nathan L.; Gire, Stephen K.; Tariyal, Ridhi; Park, Daniel J.; Haislip, Allyson M.; Bishop, Christopher M.; Melnik, Lilia I.; Gallaher, William R.; Wimley, William C.; He, Jing; Shaffer, Jeffrey G.; Sullivan, Brian M.; Grillo, Sonia; Oman, Scott; Garry, Courtney E.; Edwards, Donna R.; McCormick, Stephanie J.; Elliott, Deborah H.; Rouelle, Julie A.; Kannadka, Chandrika B.; Reyna, Ashley A.; Bradley, Benjamin T.; Yu, Haini; Yenni, Rachael E.; Hastie, Kathryn M.; Geisbert, Joan B.; Kulakosky, Peter C.; Wilson, Russell B.; Oldstone, Michael B. A.; Pitts, Kelly R.; Henderson, Lee A.; Robinson, James E.; Geisbert, Thomas W.; Saphire, Erica Ollmann; Happi, Christian T.; Asogun, Danny A.; Sabeti, Pardis C.; Garry, Robert F.

2016-01-01

Background. Kenema Government Hospital (KGH) has developed an advanced clinical and laboratory research capacity to manage the threat of Lassa fever, a viral hemorrhagic fever (VHF). The 2013–2016 Ebola virus (EBOV) disease (EVD) outbreak is the first to have occurred in an area close to a facility with established clinical and laboratory capacity for study of VHFs. Methods. Because of its proximity to the epicenter of the EVD outbreak, which began in Guinea in March 2014, the KGH Lassa fever Team mobilized to establish EBOV surveillance and diagnostic capabilities. Results. Augustine Goba, director of the KGH Lassa laboratory, diagnosed the first documented case of EVD in Sierra Leone, on 25 May 2014. Thereafter, KGH received and cared for numbers of patients with EVD that quickly overwhelmed the capacity for safe management. Numerous healthcare workers contracted and lost their lives to EVD. The vast majority of subsequent EVD cases in West Africa can be traced back to a single transmission chain that includes this first diagnosed case. Conclusions. Responding to the challenges of confronting 2 hemorrhagic fever viruses will require continued investments in the development of countermeasures (vaccines, therapeutic agents, and diagnostic assays), infrastructure, and human resources. PMID:27402779

Geographic distribution and genetic characterization of Lassa virus in sub-Saharan Mali.

PubMed

Safronetz, David; Sogoba, Nafomon; Lopez, Job E; Maiga, Ousmane; Dahlstrom, Eric; Zivcec, Marko; Feldmann, Friederike; Haddock, Elaine; Fischer, Robert J; Anderson, Jennifer M; Munster, Vincent J; Branco, Luis; Garry, Robert; Porcella, Stephen F; Schwan, Tom G; Feldmann, Heinz

2013-01-01

Lassa fever is an acute viral illness characterized by multi-organ failure and hemorrhagic manifestations. Lassa fever is most frequently diagnosed in Nigeria, Sierra Leone, Liberia, and Guinea, although sporadic cases have been recorded in other West African countries, including Mali. The etiological agent of Lassa fever is Lassa virus (LASV), an Arenavirus which is maintained in nature and frequently transmitted to humans by Mastomys natalensis. The purpose of this study was to better define the geographic distribution of LASV-infected rodents in sub-Saharan Mali. Small mammals were live-trapped at various locations across Mali for the purpose of identifying potential zoonotic pathogens. Serological and molecular assays were employed and determined LASV infected rodents were exclusively found in the southern Mali near the border of Côte d'Ivoire. Overall, 19.4% of Mastomys natalensis sampled in this region had evidence of LASV infection, with prevalence rates for individual villages ranging from 0 to 52%. Full-length genomic sequences were determined using high throughput sequencing methodologies for LASV isolates generated from tissue samples of rodents collected in four villages and confirmed the phylogenetic clustering of Malian LASV with strain AV. The risk of human infections with LASV is greatest in villages in southern Mali. Lassa fever should be considered in the differential diagnosis for febrile individuals and appropriate diagnostic techniques need to be established to determine the incidence of infection and disease in these regions.

Clinical and laboratory predictors of Lassa fever outcome in a dedicated treatment facility in Nigeria: a retrospective, observational cohort study.

PubMed

Okokhere, Peter; Colubri, Andres; Azubike, Chukwuemeka; Iruolagbe, Christopher; Osazuwa, Omoregie; Tabrizi, Shervin; Chin, Elizabeth; Asad, Sara; Ediale, Ehi; Rafiu, Mojeed; Adomeh, Donatus; Odia, Ikponmwosa; Atafo, Rebecca; Aire, Chris; Okogbenin, Sylvanus; Pahlman, Meike; Becker-Ziaja, Beate; Asogun, Danny; Fradet, Terrence; Fry, Ben; Schaffner, Stephen F; Happi, Christian; Akpede, George; Günther, Stephan; Sabeti, Pardis C

2018-03-06

Lassa fever is a viral haemorrhagic disease endemic to west Africa. No large-scale studies exist from Nigeria, where the Lassa virus (LASV) is most diverse. LASV diversity, coupled with host genetic and environmental factors, might cause differences in disease pathophysiology. Small-scale studies in Nigeria suggest that acute kidney injury is an important clinical feature and might be a determinant of survival. We aimed to establish the demographic, clinical, and laboratory factors associated with mortality in Nigerian patients with Lassa fever, and hypothesised that LASV was the direct cause of intrinsic renal damage for a subset of the patients with Lassa fever. We did a retrospective, observational cohort study of consecutive patients in Nigeria with Lassa fever, who tested positive for LASV with RT-PCR, and were treated in Irrua Specialist Teaching Hospital. We did univariate and multivariate statistical analyses, including logistic regression, of all demographic, clinical, and laboratory variables available at presentation to identify the factors associated with patient mortality. Of 291 patients treated in Irrua Specialist Teaching Hospital between Jan 3, 2011, and Dec 11, 2015, 284 (98%) had known outcomes (died or survived) and seven (2%) were discharged against medical advice. Overall case-fatality rate was 24% (68 of 284 patients), with a 1·4 times increase in mortality risk for each 10 years of age (p=0·00017), reaching 39% (22 of 57) for patients older than 50 years. Of 284 patients, 81 (28%) had acute kidney injury and 104 (37%) had CNS manifestations and thus both were considered important complications of acute Lassa fever in Nigeria. Acute kidney injury was strongly associated with poor outcome (case-fatality rate of 60% [49 of 81 patients]; odds ratio [OR] 15, p<0·00001). Compared with patients without acute kidney injury, those with acute kidney injury had higher incidence of proteinuria (32 [82%] of 39 patients) and haematuria (29 [76%] of 38) and higher mean serum potassium (4·63 [SD 1·04] mmol/L) and lower blood urea nitrogen to creatinine ratio (8·6 for patients without clinical history of fluid loss), suggesting intrinsic renal damage. Normalisation of creatinine concentration was associated with recovery. Elevated serum creatinine (OR 1·3; p=0·046), aspartate aminotransferase (OR 1·5; p=0·075), and potassium (OR 3·6; p=0·0024) were independent predictors of death. Our study presents detailed clinical and laboratory data for Nigerian patients with Lassa fever and provides strong evidence for intrinsic renal dysfunction in acute Lassa fever. Early recognition and treatment of acute kidney injury might significantly reduce mortality. German Research Foundation, German Center for Infection Research, Howard Hughes Medical Institute, US National Institutes of Health, and World Bank. Copyright © 2018 Elsevier Ltd. All rights reserved.

Hyperglycemic crisis precipitated by Lassa fever in a patient with previously undiagnosed type 2 diabetes mellitus.

PubMed

Edo, A E; Okaka, E; Ezeani, I U

2014-01-01

Hyperglycemic crisis (HC) is an acute complication of diabetes mellitus (DM) that is commonly precipitated by infections and non-compliance with therapy. Viral precipitant of HC is uncommon. To report a rare case of HC unmasked by Lassa fever in a patient previously not known to have diabetes mellitus. A 54 year old lady presented with complaints of generalized body weakness, inability to pass stool, and fever. There was no abdominal pain, vomiting and nausea. There were no features of DM. She is not a known case of diabetes mellitus or hypertension. Patient does not drink alcoholic beverages. There was no history of bleeding from any orifices. She was acutely ill-looking, afebrile, not pale, anicteric, nil pedal oedema. Pulse rate was 110 beats per minute, regular, normal volume. Blood pressure was 110/80 mmHg. Respiratory rate was 26 cycles/minute, breath sound was vesicular. Abdomen was full and moved with respiration. There were no areas of tenderness, no organomegaly, no ascites, and bowel sounds were normoactive. Neurologic examination revealed a conscious patient who was restless. Casual blood glucose was 600mg/dl. Urinalysis: Glycosuria (+++), HbA1c was 12.4%. Lassa PCR done was positive. Patient was managed for hyperglycemic crisis with intravenous normal saline and soluble insulin. She was also commenced on Ribavirin but died of complications of lassa fever. Lassa fever should be included as a precipitant of hyperglycemic crisis in endemic countries.

Development and evaluation of antibody-capture immunoassays for detection of Lassa virus nucleoprotein-specific immunoglobulin M and G

PubMed Central

Gabriel, Martin; Adomeh, Donatus I.; Ehimuan, Jacqueline; Oyakhilome, Jennifer; Omomoh, Emmanuel O.; Ighodalo, Yemisi; Olokor, Thomas; Bonney, Kofi; Pahlmann, Meike; Emmerich, Petra; Lelke, Michaela; Brunotte, Linda; Ölschläger, Stephan; Thomé-Bolduan, Corinna; Becker-Ziaja, Beate; Busch, Carola; Odia, Ikponmwosa; Ogbaini-Emovon, Ephraim; Okokhere, Peter O.; Okogbenin, Sylvanus A.; Akpede, George O.; Schmitz, Herbert; Asogun, Danny A.

2018-01-01

Background The classical method for detection of Lassa virus-specific antibodies is the immunofluorescence assay (IFA) using virus-infected cells as antigen. However, IFA requires laboratories of biosafety level 4 for assay production and an experienced investigator to interpret the fluorescence signals. Therefore, we aimed to establish and evaluate enzyme-linked immunosorbent assays (ELISA) using recombinant Lassa virus nucleoprotein (NP) as antigen. Methodology/Principal findings The IgM ELISA is based on capturing IgM antibodies using anti-IgM, and the IgG ELISA is based on capturing IgG antibody–antigen complexes using rheumatoid factor or Fc gamma receptor CD32a. Analytical and clinical evaluation was performed with 880 sera from Lassa fever endemic (Nigeria) and non-endemic (Ghana and Germany) areas. Using the IFA as reference method, we observed 91.5–94.3% analytical accuracy of the ELISAs in detecting Lassa virus-specific antibodies. Evaluation of the ELISAs for diagnosis of Lassa fever on admission to hospital in an endemic area revealed a clinical sensitivity for the stand-alone IgM ELISA of 31% (95% CI 25–37) and for combined IgM/IgG detection of 26% (95% CI 21–32) compared to RT-PCR. The specificity of IgM and IgG ELISA was estimated at 96% (95% CI 93–98) and 100% (95% CI 99–100), respectively, in non-Lassa fever patients from non-endemic areas. In patients who seroconverted during follow-up, Lassa virus-specific IgM and IgG developed simultaneously rather than sequentially. Consistent with this finding, isolated IgM reactivity, i.e. IgM in the absence of IgG, had no diagnostic value. Conclusions/Significance The ELISAs are not equivalent to RT-PCR for early diagnosis of Lassa fever; however, they are of value in diagnosing patients at later stage. The IgG ELISA may be useful for epidemiological studies and clinical trials due its high specificity, and the higher throughput rate and easier operation compared to IFA. PMID:29596412

Prevalence of Lassa virus among rodents trapped in three South-South States of Nigeria.

PubMed

Agbonlahor, D E; Erah, A; Agba, I M; Oviasogie, F E; Ehiaghe, A F; Wankasi, M; Eremwanarue, O A; Ehiaghe, I J; Ogbu, E C; Iyen, R I; Abbey, S; Tatfeng, M Y; Uhunmwangho, J

2017-01-01

Lassa fever has been endemic in Nigeria since 1969. The rodent Mastomys natalensis has been widely claimed to be the reservoir host of the Lassa virus. This study was designed to investigate the dis- tribution of species of rodents in three states (Edo, Delta and Bayelsa) of Nigeria and to determine the prevalence of Lassa virus amongst trapped rodents in the selected states. Rodents were trapped during November 2015 to October 2016 from the three states in South-South re- gion of Nigeria. Total RNA was extracted from the blood collected from the trapped rodents. Reverse transcription polymerase chain reaction (RT-PCR) was used to confirm the presence of Lassa virus in the rodents. The results revealed that six species of rodents were predominantly present in these geographical locations. Mus musculus (39.4%) had the highest prevalence, closely followed by Rattus rattus (36.1%), R. fuscipus (20.3%), M. natalensis (2%), Myosoricinae soricidae (1.2%) and R. norvegicus (1%). The overall positivity (carrier rate) of Lassa virus was 1.6% amongst the 1500 rodents caught in the three states. In Edo and Delta States, the RT-PCR results showed presence of Lassa virus in R. rattus, M. musculus and M. natalensis. On the other hand, only M. na- talensis was detected with the virus, amongst the species of rodents caught in Bayelsa State. M. natalensis recorded the highest Lassa virus among rodents trapped in Edo (87%), Delta (50%) and Bayelsa (11%) States respectively. The rather low Lassa virus positive among rodents in Bayelsa State of Nigeria may explain the absence of reports of outbreak of Lassa fever over the past 48 yr in the state. The results also confirmed that apart from Mastomys natalensis, other rodents such as Rattus rattus and Mus musculus may also serve as res- ervoirs for Lassa virus. From the findings of this cross-sectional study, it was concluded that a more comprehensive study on rodents as reservoir host, need to be undertaken across the entire states of Nigeria, for better understanding of the epidemiology and endemicity of Lassa fever.

Safety, immunogenicity, and efficacy of the ML29 reassortant vaccine for Lassa fever in small non-human primates✩

PubMed Central

Lukashevich, Igor S.; Carrion, Ricardo; Salvato, Maria S.; Mansfield, Keith; Brasky, Kathleen; Zapata, Juan; Cairo, Cristiana; Goicochea, Marco; Hoosien, Gia E.; Ticer, Anysha; Bryant, Joseph; Davis, Harry; Hammamieh, Rasha; Mayda, Maria; Jett, Marti; Patterson, Jean

2008-01-01

A single injection of ML29 reassortant vaccine for Lassa fever induces low, transient viremia, and low or moderate levels of ML29 replication in tissues of common marmosets depending on the dose of the vaccination. The vaccination elicits specific immune responses and completely protects marmosets against fatal disease by induction of sterilizing cell-mediated immunity. DNA array analysis of human peripheral blood mononuclear cells from healthy donors exposed to ML29 revealed that gene expression patterns in ML29-exposed PBMC and control, media-exposed PBMC, clustered together confirming safety profile of the ML29 in non-human primates. The ML29 reassortant is a promising vaccine candidate for Lassa fever. PMID:18692539

Lymphocytic choriomeningitis virus (LCMV) infection of macaques: a model for Lassa fever

PubMed Central

Zapata, Juan C.; Pauza, C. David; Djavani, Mahmoud M.; Rodas, Juan D.; Moshkoff, Dmitry; Bryant, Joseph; Ateh, Eugene; Garcia, Cybele; Lukashevich, Igor S.; Salvato, Maria S.

2011-01-01

Arenaviruses such as Lassa fever virus (LASV) and lymphocytic choriomeningitis virus (LCMV) are benign in their natural reservoir hosts, and can occasionally cause severe viral hemorrhagic fever (VHF) in non-human primates and in human beings. LCMV is considerably more benign for human beings than Lassa virus, however certain strains, like the LCMV-WE strain, can cause severe disease when the virus is delivered as a high-dose inoculum. Here we describe a rhesus macaque model for Lassa fever that employs a virulent strain of LCMV. Since LASV must be studied within Biosafety Level-4 (BSL-4) facilities, the LCMV-infected macaque model has the advantage that it can be used at BSL-3. LCMV-induced disease is rarely as severe as other VHF, but it is similar in cases where vascular leakage leads to lethal systemic failure. The LCMV-infected macaque has been valuable for describing the course of disease with differing viral strains, doses and routes of infection. By monitoring system-wide changes in physiology and gene expression in a controlled experimental setting, it is possible to identify events that are pathognomonic for developing VHF and potential treatment targets. PMID:21820469

DNA vaccines elicit durable protective immunity against individual or simultaneous infections with Lassa and Ebola viruses in guinea pigs.

PubMed

Cashman, Kathleen A; Wilkinson, Eric R; Wollen, Suzanne E; Shamblin, Joshua D; Zelko, Justine M; Bearss, Jeremy J; Zeng, Xiankun; Broderick, Kate E; Schmaljohn, Connie S

2017-12-02

We previously developed optimized DNA vaccines against both Lassa fever and Ebola hemorrhagic fever viruses and demonstrated that they were protective individually in guinea pig and nonhuman primate models. In this study, we vaccinated groups of strain 13 guinea pigs two times, four weeks apart with 50 µg of each DNA vaccine or a mock vaccine at discrete sites by intradermal electroporation. Five weeks following the second vaccinations, guinea pigs were exposed to lethal doses of Lassa virus, Ebola virus, or a combination of both viruses simultaneously. None of the vaccinated guinea pigs, regardless of challenge virus and including the coinfected group, displayed weight loss, fever or other disease signs, and all survived to the study endpoint. All of the mock-vaccinated guinea pigs that were infected with Lassa virus, and all but one of the EBOV-infected mock-vaccinated guinea pigs succumbed. In order to determine if the dual-agent vaccination strategy could protect against both viruses if exposures were temporally separated, we held the surviving vaccinates in BSL-4 for approximately 120 days to perform a cross-challenge experiment in which guinea pigs originally infected with Lassa virus received a lethal dose of Ebola virus and those originally infected with Ebola virus were infected with a lethal dose of Lassa virus. All guinea pigs remained healthy and survived to the study endpoint. This study clearly demonstrates that DNA vaccines against Lassa and Ebola viruses can elicit protective immunity against both individual virus exposures as well as in a mixed-infection environment.

DNA vaccines elicit durable protective immunity against individual or simultaneous infections with Lassa and Ebola viruses in guinea pigs

PubMed Central

Cashman, Kathleen A.; Wilkinson, Eric R.; Wollen, Suzanne E.; Shamblin, Joshua D.; Zelko, Justine M.; Bearss, Jeremy J.; Zeng, Xiankun; Broderick, Kate E.; Schmaljohn, Connie S.

2017-01-01

ABSTRACT We previously developed optimized DNA vaccines against both Lassa fever and Ebola hemorrhagic fever viruses and demonstrated that they were protective individually in guinea pig and nonhuman primate models. In this study, we vaccinated groups of strain 13 guinea pigs two times, four weeks apart with 50 µg of each DNA vaccine or a mock vaccine at discrete sites by intradermal electroporation. Five weeks following the second vaccinations, guinea pigs were exposed to lethal doses of Lassa virus, Ebola virus, or a combination of both viruses simultaneously. None of the vaccinated guinea pigs, regardless of challenge virus and including the coinfected group, displayed weight loss, fever or other disease signs, and all survived to the study endpoint. All of the mock-vaccinated guinea pigs that were infected with Lassa virus, and all but one of the EBOV-infected mock-vaccinated guinea pigs succumbed. In order to determine if the dual-agent vaccination strategy could protect against both viruses if exposures were temporally separated, we held the surviving vaccinates in BSL-4 for approximately 120 days to perform a cross-challenge experiment in which guinea pigs originally infected with Lassa virus received a lethal dose of Ebola virus and those originally infected with Ebola virus were infected with a lethal dose of Lassa virus. All guinea pigs remained healthy and survived to the study endpoint. This study clearly demonstrates that DNA vaccines against Lassa and Ebola viruses can elicit protective immunity against both individual virus exposures as well as in a mixed-infection environment. PMID:29135337

An Outbreak of Ebola Virus Disease in the Lassa Fever Zone.

PubMed

Goba, Augustine; Khan, S Humarr; Fonnie, Mbalu; Fullah, Mohamed; Moigboi, Alex; Kovoma, Alice; Sinnah, Vandi; Yoko, Nancy; Rogers, Hawa; Safai, Siddiki; Momoh, Mambu; Koroma, Veronica; Kamara, Fatima K; Konowu, Edwin; Yillah, Mohamed; French, Issa; Mustapha, Ibraham; Kanneh, Franklyn; Foday, Momoh; McCarthy, Helena; Kallon, Tiangay; Kallon, Mustupha; Naiebu, Jenneh; Sellu, Josephine; Jalloh, Abdul A; Gbakie, Michael; Kanneh, Lansana; Massaly, James L B; Kargbo, David; Kargbo, Brima; Vandi, Mohamed; Gbetuwa, Momoh; Gevao, Sahr M; Sandi, John D; Jalloh, Simbirie C; Grant, Donald S; Blyden, Sylvia O; Crozier, Ian; Schieffelin, John S; McLellan, Susan L; Jacob, Shevin T; Boisen, Matt L; Hartnett, Jessica N; Cross, Robert W; Branco, Luis M; Andersen, Kristian G; Yozwiak, Nathan L; Gire, Stephen K; Tariyal, Ridhi; Park, Daniel J; Haislip, Allyson M; Bishop, Christopher M; Melnik, Lilia I; Gallaher, William R; Wimley, William C; He, Jing; Shaffer, Jeffrey G; Sullivan, Brian M; Grillo, Sonia; Oman, Scott; Garry, Courtney E; Edwards, Donna R; McCormick, Stephanie J; Elliott, Deborah H; Rouelle, Julie A; Kannadka, Chandrika B; Reyna, Ashley A; Bradley, Benjamin T; Yu, Haini; Yenni, Rachael E; Hastie, Kathryn M; Geisbert, Joan B; Kulakosky, Peter C; Wilson, Russell B; Oldstone, Michael B A; Pitts, Kelly R; Henderson, Lee A; Robinson, James E; Geisbert, Thomas W; Saphire, Erica Ollmann; Happi, Christian T; Asogun, Danny A; Sabeti, Pardis C; Garry, Robert F

2016-10-15

 Kenema Government Hospital (KGH) has developed an advanced clinical and laboratory research capacity to manage the threat of Lassa fever, a viral hemorrhagic fever (VHF). The 2013-2016 Ebola virus (EBOV) disease (EVD) outbreak is the first to have occurred in an area close to a facility with established clinical and laboratory capacity for study of VHFs.  Because of its proximity to the epicenter of the EVD outbreak, which began in Guinea in March 2014, the KGH Lassa fever Team mobilized to establish EBOV surveillance and diagnostic capabilities.  Augustine Goba, director of the KGH Lassa laboratory, diagnosed the first documented case of EVD in Sierra Leone, on 25 May 2014. Thereafter, KGH received and cared for numbers of patients with EVD that quickly overwhelmed the capacity for safe management. Numerous healthcare workers contracted and lost their lives to EVD. The vast majority of subsequent EVD cases in West Africa can be traced back to a single transmission chain that includes this first diagnosed case.  Responding to the challenges of confronting 2 hemorrhagic fever viruses will require continued investments in the development of countermeasures (vaccines, therapeutic agents, and diagnostic assays), infrastructure, and human resources. © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

Vaccine platforms to control Lassa fever.

PubMed

Lukashevich, Igor S; Pushko, Peter

2016-09-01

Lassa virus (LASV), the most prominent human pathogen of the Arenaviridae, is transmitted to humans from infected rodents and can cause Lassa Fever (LF). The sizeable disease burden in West Africa, numerous imported LF cases worldwide, and the possibility that LASV can be used as an agent of biological warfare make a strong case for vaccine development. There are no licensed LASV vaccines and the antiviral treatment is limited to an off-label use of ribavirin that is only partially effective. LASV vaccine development is hampered by high cost of biocontainment requirement, the absence of appropriate small animal models, genetic diversity of LASV species, and by high HIV-1 prevalence in LASV endemic areas. Over the past 15 years several vaccine platforms have been developed. Natural history of LASV and pathogenesis of the disease provide strong justification for replication-competent (RC) vaccine as one of the most feasible approaches to control LF. Development of LASV vaccine candidates based on reassortant, recombinant, and alphavirus replicon technologies is covered in this review. Expert commentary: Two lead RC vaccine candidates, reassortant ML29 and recombinant VSV/LASV, have been successfully tested in non-human primates and have been recommended by international vaccine experts for rapid clinical development. Both platforms have powerful molecular tools to further secure safety, improve immunogenicity, and cross-protection. These platforms are well positioned to design multivalent vaccines to protect against all LASV strains citculatrd in West Africa. The regulatory pathway of Candid #1, the first live-attenuated arenaviral vaccine against Argentine hemorrhagic, will be a reasonable guideline for LASV vaccine efficacy trials.

Efficacy of Favipiravir Alone and in Combination With Ribavirin in a Lethal, Immunocompetent Mouse Model of Lassa Fever.

PubMed

Oestereich, Lisa; Rieger, Toni; Lüdtke, Anja; Ruibal, Paula; Wurr, Stephanie; Pallasch, Elisa; Bockholt, Sabrina; Krasemann, Susanne; Muñoz-Fontela, César; Günther, Stephan

2016-03-15

We studied the therapeutic potential of favipiravir (T-705) for Lassa fever, both alone and in combination with ribavirin. Favipiravir suppressed Lassa virus replication in cell culture by 5 log10 units. In a novel lethal mouse model, it lowered the viremia level and the virus load in organs and normalized levels of cell-damage markers. Treatment with 300 mg/kg per day, commenced 4 days after infection, when the viremia level had reached 4 log10 virus particles/mL, rescued 100% of Lassa virus-infected mice. We found a synergistic interaction between favipiravir and ribavirin in vitro and an increased survival rate and extended survival time when combining suboptimal doses in vivo. © The Author 2015. Published by Oxford University Press for the Infectious Diseases Society of America.

Synthetic Vaccines for the Control of Arenavirus Infections

DTIC Science & Technology

1992-03-31

is envel- tions. For example. Lassa fever and CH have several sopcd apparently buds from the cytoplasmic membrane (no similarities, including an acutc...course, involvement of mul- intact virions were seen intra-ellularly). has a glycoprotein tiple organs (including liver and spleen), petechial hemor...c fringe ,ontains ribosomelike interna! structures, and has a rhale, (although not prominent in either CH or Lassa fever ). A diameter ranging from 67

Hemorrhagic Fevers

MedlinePlus

... by four families of viruses. These include the Ebola and Marburg, Lassa fever, and yellow fever viruses. ... Some VHFs cause mild disease, but some, like Ebola or Marburg, cause severe disease and death. VHFs ...

The rubber plantation environment and Lassa fever epidemics in Liberia, 2008-2012: a spatial regression.

PubMed

Olugasa, Babasola O; Dogba, John B; Ogunro, Bamidele; Odigie, Eugene A; Nykoi, Jomah; Ojo, Johnson F; Taiwo, Olalekan; Kamara, Abraham; Mulbah, Charles K; Fasunla, Ayotunde J

2014-10-01

As Lassa fever continues to be a public health challenge in West Africa, it is critical to produce good maps of its risk pattern for use in active surveillance and control intervention. We identified eight spatial features related to the rubber plantation environment and used them as explanatory variables for Lassa fever (LF) outbreaks on the Uniroyal Liberian Agricultural Company (LAC) rubber plantation environment in Grand Bassa County, Liberia. We computed classical and spatial lag regression models on all spatial features, including proximity of residential camp to rubber tree-edge, main road in the plantation, LAC hospital, rice farmland, household refuse dump, human population density, post-harvest storage density of rice and density of rodent deterrent on rice storage. We found significant (p=0.0024) spatial autocorrelation between LF cases and the spatial features we have considered. We concluded that the rubber plantation environment influenced Mastomys species' breeding and transmission of Lassa virus along spatial scale to humans. The risk factors identified in this study offered a baseline for more effective surveillance and control of LF in the post-civil conflict Liberia. Copyright © 2014 Elsevier Ltd. All rights reserved.

Emerging intracellular receptors for hemorrhagic fever viruses.

PubMed

Jae, Lucas T; Brummelkamp, Thijn R

2015-07-01

Ebola virus and Lassa virus belong to different virus families that can cause viral hemorrhagic fever, a life-threatening disease in humans with limited treatment options. To infect a target cell, Ebola and Lassa viruses engage receptors at the cell surface and are subsequently shuttled into the endosomal compartment. Upon arrival in late endosomes/lysosomes, the viruses trigger membrane fusion to release their genome into the cytoplasm. Although contact sites at the cell surface were recognized for Ebola virus and Lassa virus, it was postulated that Ebola virus requires a critical receptor inside the cell. Recent screens for host factors identified such internal receptors for both viruses: Niemann-Pick disease type C1 protein (NPC1) for Ebola virus and lysosome-associated membrane protein 1 (LAMP1) for Lassa virus. A cellular trigger is needed to permit binding of the viral envelope protein to these intracellular receptors. This 'receptor switch' represents a previously unnoticed step in virus entry with implications for host-pathogen interactions and viral tropism. Copyright © 2015 Elsevier Ltd. All rights reserved.

Most neutralizing human monoclonal antibodies target novel epitopes requiring both Lassa virus glycoprotein subunits

PubMed Central

Robinson, James E.; Hastie, Kathryn M.; Cross, Robert W.; Yenni, Rachael E.; Elliott, Deborah H.; Rouelle, Julie A.; Kannadka, Chandrika B.; Smira, Ashley A.; Garry, Courtney E.; Bradley, Benjamin T.; Yu, Haini; Shaffer, Jeffrey G.; Boisen, Matt L.; Hartnett, Jessica N.; Zandonatti, Michelle A.; Rowland, Megan M.; Heinrich, Megan L.; Martínez-Sobrido, Luis; Cheng, Benson; de la Torre, Juan C.; Andersen, Kristian G.; Goba, Augustine; Momoh, Mambu; Fullah, Mohamed; Gbakie, Michael; Kanneh, Lansana; Koroma, Veronica J.; Fonnie, Richard; Jalloh, Simbirie C.; Kargbo, Brima; Vandi, Mohamed A.; Gbetuwa, Momoh; Ikponmwosa, Odia; Asogun, Danny A.; Okokhere, Peter O.; Follarin, Onikepe A.; Schieffelin, John S.; Pitts, Kelly R.; Geisbert, Joan B.; Kulakoski, Peter C.; Wilson, Russell B.; Happi, Christian T.; Sabeti, Pardis C.; Gevao, Sahr M.; Khan, S. Humarr; Grant, Donald S.; Geisbert, Thomas W.; Saphire, Erica Ollmann; Branco, Luis M.; Garry, Robert F.

2016-01-01

Lassa fever is a severe multisystem disease that often has haemorrhagic manifestations. The epitopes of the Lassa virus (LASV) surface glycoproteins recognized by naturally infected human hosts have not been identified or characterized. Here we have cloned 113 human monoclonal antibodies (mAbs) specific for LASV glycoproteins from memory B cells of Lassa fever survivors from West Africa. One-half bind the GP2 fusion subunit, one-fourth recognize the GP1 receptor-binding subunit and the remaining fourth are specific for the assembled glycoprotein complex, requiring both GP1 and GP2 subunits for recognition. Notably, of the 16 mAbs that neutralize LASV, 13 require the assembled glycoprotein complex for binding, while the remaining 3 require GP1 only. Compared with non-neutralizing mAbs, neutralizing mAbs have higher binding affinities and greater divergence from germline progenitors. Some mAbs potently neutralize all four LASV lineages. These insights from LASV human mAb characterization will guide strategies for immunotherapeutic development and vaccine design. PMID:27161536

Identification of Cell Surface Molecules Involved in Dystroglycan-Independent Lassa Virus Cell Entry

PubMed Central

Ströher, Ute; Ebihara, Hideki; Feldmann, Heinz

2012-01-01

Although O-mannosylated dystroglycan is a receptor for Lassa virus, a causative agent of Lassa fever, recent findings suggest the existence of an alternative receptor(s). Here we identified four molecules as receptors for Lassa virus: Axl and Tyro3, from the TAM family, and dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin (DC-SIGN) and liver and lymph node sinusoidal endothelial calcium-dependent lectin (LSECtin), from the C-type lectin family. These molecules enhanced the binding of Lassa virus to cells and mediated infection independently of dystroglycan. Axl- or Tyro3-mediated infection required intracellular signaling via the tyrosine kinase activity of Axl or Tyro3, whereas DC-SIGN- or LSECtin-mediated infection and binding were dependent on a specific carbohydrate and on ions. The identification of these four molecules as Lassa virus receptors advances our understanding of Lassa virus cell entry. PMID:22156524

[Characterization of contacts of the population of Guinea with synanthropic rodents as Lassa fever virus carriers].

PubMed

Inapogui, A P; Konstantinov, O K; Lapshov, V N; Comara, S K

2007-01-01

Questionnaire surveys made in 17 villages from 3 ecological zones of Guinea have provided evidence for the population's contact with synanthropic rodents as Lassa fever virus carriers. Over 100 rodents are quarterly captured in the houses of the traditional type in the villages located in the savanna woodland. Less than 10 specimens are captured at the food warehouses. There are more than 100 rodents in the majority of houses of the traditional type in the villages located in the secondary forest. In the villages of rainy tropical forests, the capture rate is low--10 to 100 rodents. The main rodent capturers are boys and young men (aged 7 to 20 years) who are principal rodent meat eaters; although almost the whole population, particularly in rural areas, consumes this meat in varying degrees. The proportion of captured rats of the genus Mastomys (the carrier of Lassa fever virus) in the town of Kindia is 11%. In the rural area, it is much higher (as high as 94%) in the villages located in the rainy tropical forests. It is estimated that one trapper quarterly catches 0.2 (in the savanna woodland) to 6.9 (in the secondary forests) infected rats, which agrees with the data of a serological survey of Guinea's population. By and large, the majority of the Guinean population may be referred to as a group at risk for Lassa fever due to their permanent contacts with rodents.

The search for animal models for Lassa fever vaccine development

PubMed Central

Lukashevich, Igor S

2013-01-01

Lassa virus (LASV) is the most prevalent arenavirus in West Africa and is responsible for several hundred thousand infections and thousands of deaths annually. The sizeable disease burden, numerous imported cases of Lassa fever (LF) and the possibility that LASV can be used as an agent of biological warfare make a strong case for vaccine development. Currently there is no licensed LF vaccine and research and devlopment is hampered by the high cost of nonhuman primate animal models and by biocontainment requirements (BSL-4). In addition, a successful LF vaccine has to induce a strong cell-mediated cross-protective immunity against different LASV lineages. All of these challenges will be addressed in this review in the context of available and novel animal models recently described for evaluation of LF vaccine candidates. PMID:23256740

The search for animal models for Lassa fever vaccine development.

PubMed

Lukashevich, Igor S

2013-01-01

Lassa virus (LASV) is the most prevalent arenavirus in West Africa and is responsible for several hundred thousand infections and thousands of deaths annually. The sizeable disease burden, numerous imported cases of Lassa fever (LF) and the possibility that LASV can be used as an agent of biological warfare make a strong case for vaccine development. Currently there is no licensed LF vaccine and research and devlopment is hampered by the high cost of nonhuman primate animal models and by biocontainment requirements (BSL-4). In addition, a successful LF vaccine has to induce a strong cell-mediated cross-protective immunity against different LASV lineages. All of these challenges will be addressed in this review in the context of available and novel animal models recently described for evaluation of LF vaccine candidates.

Immunobiology of Ebola and Lassa virus infections.

PubMed

Prescott, Joseph B; Marzi, Andrea; Safronetz, David; Robertson, Shelly J; Feldmann, Heinz; Best, Sonja M

2017-03-01

Two of the most important contemporary emerging viruses that affect human health in Africa are Ebola virus (EBOV) and Lassa virus (LASV). The 2013-2016 West African outbreak of EBOV was responsible for more than 11,000 deaths, primarily in Guinea, Sierra Leone and Liberia. LASV is constantly emerging in these and surrounding West African countries, with an estimate of more than 500,000 cases of Lassa fever, and approximately 5,000 deaths, annually. Both EBOV and LASV are zoonotic, and human infection often results in a severe haemorrhagic fever in both cases. However, the contribution of specific immune responses to disease differs between EBOV and LASV. This Review examines innate and adaptive immune responses to these viruses with the goal of delineating responses that are associated with protective versus pathogenic outcomes.

Yellow fever 17D-vectored vaccines expressing Lassa virus GP1 and GP2 glycoproteins provide protection against fatal disease in guinea pigs

PubMed Central

Jiang, Xiaohong; Dalebout, Tim J.; Bredenbeek, Peter J.; Carrion, Ricardo; Brasky, Kathleen; Patterson, Jean; Goicochea, Marco; Bryant, Joseph; Salvato, Maria S.; Lukashevich, Igor S.

2010-01-01

Yellow Fever (YF) and Lassa Fever (LF) are two prevalent hemorrhagic fevers co-circulating in West Africa and responsible for thousands of deaths annually. The YF vaccine 17D has been used as a vector for the Lassa virus glycoprotein precursor (LASV-GPC) or their subunits, GP1 (attachment glycoprotein) and GP2 (fusion glycoprotein). Cloning shorter inserts, LASV GP1 and GP2, between YF17D E and NS1 genes enhanced genetic stability of recombinant viruses, YF17D/LASV-GP1 and –GP2, in comparison with YF17D/LASV-GPC recombinant. The recombinant viruses were replication competent and properly processed YF and LASV GP proteins in infected cells. YF17D/LASV-GP1&GP2 induced specific CD8+ T cell responses in mice and protected strain 13 guinea pigs against fatal LF. Unlike immunization with live attenuated reassortant vaccine ML29, immunization with YF17D/LASV-GP1&GP2 did not provide sterilizing immunity. This study demonstrates the feasibility of YF17D-based vaccine to control LF in West Africa. PMID:21145373

Prevalence and Risk Factors of Lassa Seropositivity in Inhabitants of the Forest Region of Guinea: A Cross-Sectional Study

PubMed Central

Kernéis, Solen; Koivogui, Lamine; Magassouba, N'Faly; Koulemou, Kekoura; Lewis, Rosamund; Aplogan, Aristide; Grais, Rebecca F.; Guerin, Philippe J.; Fichet-Calvet, Elisabeth

2009-01-01

Background Lassa fever is a viral hemorrhagic fever endemic in West Africa. The reservoir host of the virus is a multimammate rat, Mastomys natalensis. Prevalence estimates of Lassa virus antibodies in humans vary greatly between studies, and the main modes of transmission of the virus from rodents to humans remain unclear. We aimed to (i) estimate the prevalence of Lassa virus–specific IgG antibodies (LV IgG) in the human population of a rural area of Guinea, and (ii) identify risk factors for positive LV IgG. Methods and Findings A population-based cross-sectional study design was used. In April 2000, all individuals one year of age and older living in three prefectures located in the tropical secondary forest area of Guinea (Gueckedou, Lola and Yomou) were sampled using two-stage cluster sampling. For each individual identified by the sampling procedure and who agreed to participate, a standardized questionnaire was completed to collect data on personal exposure to potential risk factors for Lassa fever (mainly contact with rodents), and a blood sample was tested for LV IgG. A multiple logistic regression model was used to determine risk factors for positive LV IgG. A total of 1424 subjects were interviewed and 977 sera were tested. Prevalence of positive LV Ig was of 12.9% [10.8%–15.0%] and 10.0% [8.1%–11.9%] in rural and urban areas, respectively. Two risk factors of positive LV IgG were identified: to have, in the past twelve months, undergone an injection (odds ratio [OR] = 1.8 [1.1–3.1]), or lived with someone displaying a haemorrhage (OR = 1.7 [1.1–2.9]). No factors related to contacts with rats and/or mice remained statistically significant in the multivariate analysis. Conclusions Our study underlines the potential importance of person-to-person transmission of Lassa fever, via close contact in the same household or nosocomial exposure. PMID:19924222

Lassa Fever Immune Plasma

DTIC Science & Technology

1988-07-31

cases are likely to be seen. Finally, further studies into the nature of the virus or viruses of LF are needed. Clinical experience suggests that there...OF ReIPRIt r ~M. u iav Is. PAGE COUNT Annual Rpnnrt T FROM 1,.1IR7 j ,O 30 lunB 88-7-31 22 1. SUPPUMENTARY NOTATION 17. COSATI CODES 10. SUSJECT...TERMS (Connimm on nwmw ,o neceiawt &W ide I No& num IELD IGROUP suS.GROUP Lassa fever Immunotherapy RA 1 06 1) 6 LLassa virus Liberia nf i Pl,:m haiman 19

Lassa virus-like particles displaying all major immunological determinants as a vaccine candidate for Lassa hemorrhagic fever.

PubMed

Branco, Luis M; Grove, Jessica N; Geske, Frederick J; Boisen, Matt L; Muncy, Ivana J; Magliato, Susan A; Henderson, Lee A; Schoepp, Randal J; Cashman, Kathleen A; Hensley, Lisa E; Garry, Robert F

2010-10-20

Lassa fever is a neglected tropical disease with significant impact on the health care system, society, and economy of Western and Central African nations where it is endemic. Treatment of acute Lassa fever infections has successfully utilized intravenous administration of ribavirin, a nucleotide analogue drug, but this is not an approved use; efficacy of oral administration has not been demonstrated. To date, several potential new vaccine platforms have been explored, but none have progressed toward clinical trials and commercialization. Therefore, the development of a robust vaccine platform that could be generated in sufficient quantities and at a low cost per dose could herald a subcontinent-wide vaccination program. This would move Lassa endemic areas toward the control and reduction of major outbreaks and endemic infections. To this end, we have employed efficient mammalian expression systems to generate a Lassa virus (LASV)-like particle (VLP)-based modular vaccine platform. A mammalian expression system that generated large quantities of LASV VLP in human cells at small scale settings was developed. These VLP contained the major immunological determinants of the virus: glycoprotein complex, nucleoprotein, and Z matrix protein, with known post-translational modifications. The viral proteins packaged into LASV VLP were characterized, including glycosylation profiles of glycoprotein subunits GP1 and GP2, and structural compartmentalization of each polypeptide. The host cell protein component of LASV VLP was also partially analyzed, namely glycoprotein incorporation, though the identity of these proteins remain unknown. All combinations of LASV Z, GPC, and NP proteins that generated VLP did not incorporate host cell ribosomes, a known component of native arenaviral particles, despite detection of small RNA species packaged into pseudoparticles. Although VLP did not contain the same host cell components as the native virion, electron microscopy analysis demonstrated that LASV VLP appeared structurally similar to native virions, with pleiomorphic distribution in size and shape. LASV VLP that displayed GPC or GPC+NP were immunogenic in mice, and generated a significant IgG response to individual viral proteins over the course of three immunizations, in the absence of adjuvants. Furthermore, sera from convalescent Lassa fever patients recognized VLP in ELISA format, thus affirming the presence of native epitopes displayed by the recombinant pseudoparticles. These results established that modular LASV VLP can be generated displaying high levels of immunogenic viral proteins, and that small laboratory scale mammalian expression systems are capable of producing multi-milligram quantities of pseudoparticles. These VLP are structurally and morphologically similar to native LASV virions, but lack replicative functions, and thus can be safely generated in low biosafety level settings. LASV VLP were immunogenic in mice in the absence of adjuvants, with mature IgG responses developing within a few weeks after the first immunization. These studies highlight the relevance of a VLP platform for designing an optimal vaccine candidate against Lassa hemorrhagic fever, and warrant further investigation in lethal challenge animal models to establish their protective potential.

MassTag Polymerase Chain Reaction for Differential Diagnosis of Viral Hemorrhagic Fevers

DTIC Science & Technology

2006-04-01

fever virus (RVFV), Crimean - Congo hemorrhagic fever virus (CCHFV), and hantaviruses (Bunyaviridae); and...ribavirin may be helpful if given early in the course of Lassa fever (9), Crimean - Congo hemorrhagic fever (10), or hemorrhagic fever with renal...I, Erol S, Erdem F, Yilmaz N, Parlak M, et al. Crimean - Congo hemorrhagic fever in eastern Turkey: clinical fea- tures, risk factors and efficacy

Mapping the zoonotic niche of Lassa fever in Africa

PubMed Central

Mylne, Adrian Q. N.; Pigott, David M.; Longbottom, Joshua; Shearer, Freya; Duda, Kirsten A.; Messina, Jane P.; Weiss, Daniel J.; Moyes, Catherine L.; Golding, Nick; Hay, Simon I.

2015-01-01

Background Lassa fever is a viral haemorrhagic illness responsible for disease outbreaks across West Africa. It is a zoonosis, with the primary reservoir species identified as the Natal multimammate mouse, Mastomys natalensis. The host is distributed across sub-Saharan Africa while the virus' range appears to be restricted to West Africa. The majority of infections result from interactions between the animal reservoir and human populations, although secondary transmission between humans can occur, particularly in hospital settings. Methods Using a species distribution model, the locations of confirmed human and animal infections with Lassa virus (LASV) were used to generate a probabilistic surface of zoonotic transmission potential across sub-Saharan Africa. Results Our results predict that 37.7 million people in 14 countries, across much of West Africa, live in areas where conditions are suitable for zoonotic transmission of LASV. Four of these countries, where at-risk populations are predicted, have yet to report any cases of Lassa fever. Conclusions These maps act as a spatial guide for future surveillance activities to better characterise the geographical distribution of the disease and understand the anthropological, virological and zoological interactions necessary for viral transmission. Combining this zoonotic niche map with detailed patient travel histories can aid differential diagnoses of febrile illnesses, enabling a more rapid response in providing care and reducing the risk of onward transmission. PMID:26085474

Mapping the zoonotic niche of Lassa fever in Africa.

PubMed

Mylne, Adrian Q N; Pigott, David M; Longbottom, Joshua; Shearer, Freya; Duda, Kirsten A; Messina, Jane P; Weiss, Daniel J; Moyes, Catherine L; Golding, Nick; Hay, Simon I

2015-08-01

Lassa fever is a viral haemorrhagic illness responsible for disease outbreaks across West Africa. It is a zoonosis, with the primary reservoir species identified as the Natal multimammate mouse, Mastomys natalensis. The host is distributed across sub-Saharan Africa while the virus' range appears to be restricted to West Africa. The majority of infections result from interactions between the animal reservoir and human populations, although secondary transmission between humans can occur, particularly in hospital settings. Using a species distribution model, the locations of confirmed human and animal infections with Lassa virus (LASV) were used to generate a probabilistic surface of zoonotic transmission potential across sub-Saharan Africa. Our results predict that 37.7 million people in 14 countries, across much of West Africa, live in areas where conditions are suitable for zoonotic transmission of LASV. Four of these countries, where at-risk populations are predicted, have yet to report any cases of Lassa fever. These maps act as a spatial guide for future surveillance activities to better characterise the geographical distribution of the disease and understand the anthropological, virological and zoological interactions necessary for viral transmission. Combining this zoonotic niche map with detailed patient travel histories can aid differential diagnoses of febrile illnesses, enabling a more rapid response in providing care and reducing the risk of onward transmission. © The Author 2015. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene.

Lassa fever in post-conflict sierra leone.

PubMed

Shaffer, Jeffrey G; Grant, Donald S; Schieffelin, John S; Boisen, Matt L; Goba, Augustine; Hartnett, Jessica N; Levy, Danielle C; Yenni, Rachael E; Moses, Lina M; Fullah, Mohammed; Momoh, Mambo; Fonnie, Mbalu; Fonnie, Richard; Kanneh, Lansana; Koroma, Veronica J; Kargbo, Kandeh; Ottomassathien, Darin; Muncy, Ivana J; Jones, Abigail B; Illick, Megan M; Kulakosky, Peter C; Haislip, Allyson M; Bishop, Christopher M; Elliot, Deborah H; Brown, Bethany L; Zhu, Hu; Hastie, Kathryn M; Andersen, Kristian G; Gire, Stephen K; Tabrizi, Shervin; Tariyal, Ridhi; Stremlau, Mathew; Matschiner, Alex; Sampey, Darryl B; Spence, Jennifer S; Cross, Robert W; Geisbert, Joan B; Folarin, Onikepe A; Happi, Christian T; Pitts, Kelly R; Geske, F Jon; Geisbert, Thomas W; Saphire, Erica Ollmann; Robinson, James E; Wilson, Russell B; Sabeti, Pardis C; Henderson, Lee A; Khan, S Humarr; Bausch, Daniel G; Branco, Luis M; Garry, Robert F

2014-03-01

Lassa fever (LF), an often-fatal hemorrhagic disease caused by Lassa virus (LASV), is a major public health threat in West Africa. When the violent civil conflict in Sierra Leone (1991 to 2002) ended, an international consortium assisted in restoration of the LF program at Kenema Government Hospital (KGH) in an area with the world's highest incidence of the disease. Clinical and laboratory records of patients presenting to the KGH Lassa Ward in the post-conflict period were organized electronically. Recombinant antigen-based LF immunoassays were used to assess LASV antigenemia and LASV-specific antibodies in patients who met criteria for suspected LF. KGH has been reestablished as a center for LF treatment and research, with over 500 suspected cases now presenting yearly. Higher case fatality rates (CFRs) in LF patients were observed compared to studies conducted prior to the civil conflict. Different criteria for defining LF stages and differences in sensitivity of assays likely account for these differences. The highest incidence of LF in Sierra Leone was observed during the dry season. LF cases were observed in ten of Sierra Leone's thirteen districts, with numerous cases from outside the traditional endemic zone. Deaths in patients presenting with LASV antigenemia were skewed towards individuals less than 29 years of age. Women self-reporting as pregnant were significantly overrepresented among LASV antigenemic patients. The CFR of ribavirin-treated patients presenting early in acute infection was lower than in untreated subjects. Lassa fever remains a major public health threat in Sierra Leone. Outreach activities should expand because LF may be more widespread in Sierra Leone than previously recognized. Enhanced case finding to ensure rapid diagnosis and treatment is imperative to reduce mortality. Even with ribavirin treatment, there was a high rate of fatalities underscoring the need to develop more effective and/or supplemental treatments for LF.

Absence of Nosocomial Transmission of Imported Lassa Fever during Use of Standard Barrier Nursing Methods.

PubMed

Grahn, Anna; Bråve, Andreas; Tolfvenstam, Thomas; Studahl, Marie

2018-06-01

Nosocomial transmission of Lassa virus (LASV) is reported to be low when care for the index patient includes proper barrier nursing methods. We investigated whether asymptomatic LASV infection occurred in healthcare workers who used standard barrier nursing methods during the first 15 days of caring for a patient with Lassa fever in Sweden. Of 76 persons who were defined as having been potentially exposed to LASV, 53 provided blood samples for detection of LASV IgG. These persons also responded to a detailed questionnaire to evaluate exposure to different body fluids from the index patient. LASV-specific IgG was not detected in any of the 53 persons. Five of 53 persons had not been using proper barrier nursing methods. Our results strengthen the argument for a low risk of secondary transmission of LASV in humans when standard barrier nursing methods are used and the patient has only mild symptoms.

Understanding the cryptic nature of Lassa fever in West Africa.

PubMed

Gibb, Rory; Moses, Lina M; Redding, David W; Jones, Kate E

2017-09-01

Lassa fever (LF) is increasingly recognized by global health institutions as an important rodent-borne disease with severe impacts on some of West Africa's poorest communities. However, our knowledge of LF ecology, epidemiology and distribution is limited, which presents barriers to both short-term disease forecasting and prediction of long-term impacts of environmental change on Lassa virus (LASV) zoonotic transmission dynamics. Here, we synthesize current knowledge to show that extrapolations from past research have produced an incomplete picture of the incidence and distribution of LF, with negative consequences for policy planning, medical treatment and management interventions. Although the recent increase in LF case reports is likely due to improved surveillance, recent studies suggest that future socio-ecological changes in West Africa may drive increases in LF burden. Future research should focus on the geographical distribution and disease burden of LF, in order to improve its integration into public policy and disease control strategies.

Conserved residues in Lassa fever virus Z protein modulate viral infectivity at the level of the ribonucleoprotein.

PubMed

Capul, Althea A; de la Torre, Juan Carlos; Buchmeier, Michael J

2011-04-01

Arenaviruses are negative-strand RNA viruses that cause human diseases such as lymphocytic choriomeningitis, Bolivian hemorrhagic fever, and Lassa hemorrhagic fever. No licensed vaccines exist, and current treatment is limited to ribavirin. The prototypic arenavirus, lymphocytic choriomeningitis virus (LCMV), is a model for dissecting virus-host interactions in persistent and acute disease. The RING finger protein Z has been identified as the driving force of arenaviral budding and acts as the viral matrix protein. While residues in Z required for viral budding have been described, residues that govern the Z matrix function(s) have yet to be fully elucidated. Because this matrix function is integral to viral assembly, we reasoned that this would be reflected in sequence conservation. Using sequence alignment, we identified several conserved residues in Z outside the RING and late domains. Nine residues were each mutated to alanine in Lassa fever virus Z. All of the mutations affected the expression of an LCMV minigenome and the infectivity of virus-like particles, but to greatly varying degrees. Interestingly, no mutations appeared to affect Z-mediated budding or association with viral GP. Our findings provide direct experimental evidence supporting a role for Z in the modulation of the activity of the viral ribonucleoprotein (RNP) complex and its packaging into mature infectious viral particles.

Yellow fever 17D-vectored vaccines expressing Lassa virus GP1 and GP2 glycoproteins provide protection against fatal disease in guinea pigs.

PubMed

Jiang, Xiaohong; Dalebout, Tim J; Bredenbeek, Peter J; Carrion, Ricardo; Brasky, Kathleen; Patterson, Jean; Goicochea, Marco; Bryant, Joseph; Salvato, Maria S; Lukashevich, Igor S

2011-02-01

Yellow Fever (YF) and Lassa Fever (LF) are two prevalent hemorrhagic fevers co-circulating in West Africa and responsible for thousands of deaths annually. The YF vaccine 17D has been used as a vector for the Lassa virus glycoprotein precursor (LASV-GPC) or their subunits, GP1 (attachment glycoprotein) and GP2 (fusion glycoprotein). Cloning shorter inserts, LASV-GP1 and -GP2, between YF17D E and NS1 genes enhanced genetic stability of recombinant viruses, YF17D/LASV-GP1 and -GP2, in comparison with YF17D/LASV-GPC recombinant. The recombinant viruses were replication competent and properly processed YF proteins and LASV GP antigens in infected cells. YF17D/LASV-GP1 and -GP2 induced specific CD8+ T cell responses in mice and protected strain 13 guinea pigs against fatal LF. Unlike immunization with live attenuated reassortant vaccine ML29, immunization with YF17D/LASV-GP1 and -GP2 did not provide sterilizing immunity. This study demonstrates the feasibility of YF17D-based vaccine to control LF in West Africa. Copyright © 2010 Elsevier Ltd. All rights reserved.

Lassa virus entry requires a trigger-induced receptor switch

PubMed Central

Jae, Lucas T.; Raaben, Matthijs; Herbert, Andrew S.; Kuehne, Ana I.; Wirchnianski, Ariel S.; Soh, Timothy; Stubbs, Sarah H.; Janssen, Hans; Damme, Markus; Saftig, Paul; Whelan, Sean P.; Dye, John M.; Brummelkamp, Thijn R.

2014-01-01

Lassa virus spreads from rodents to humans and can lead to lethal hemorrhagic fever. Despite its broad tropism, chicken cells were reported to resist infection thirty years ago. We show that Lassa virus readily engaged its cell surface receptor α-dystroglycan in avian cells, but virus entry in susceptible species involved a pH-dependent switch to an intracellular receptor, the lysosome-resident protein LAMP1. Iterative haploid screens revealed that the sialyltransferase ST3GAL4 was required for the interaction of the virus glycoprotein with LAMP1. A single glycosylated residue in LAMP1, present in susceptible species but absent in birds, was essential for interaction with the Lassa virus envelope protein and subsequent infection. The resistance of Lamp1-deficient mice to Lassa virus highlights the relevance of this receptor switch in vivo. PMID:24970085

A DNA vaccine delivered by dermal electroporation fully protects cynomolgus macaques against Lassa fever.

PubMed

Cashman, Kathleen A; Wilkinson, Eric R; Shaia, Carl I; Facemire, Paul R; Bell, Todd M; Bearss, Jeremy J; Shamblin, Joshua D; Wollen, Suzanne E; Broderick, Kate E; Sardesai, Niranjan Y; Schmaljohn, Connie S

2017-12-02

Lassa virus (LASV) is an ambisense RNA virus in the Arenaviridae family and is the etiological agent of Lassa fever, a severe hemorrhagic disease endemic to West and Central Africa. 1,2 There are no US Food and Drug Administration (FDA)-licensed vaccines available to prevent Lassa fever. 1,2 in our previous studies, we developed a gene-optimized DNA vaccine that encodes the glycoprotein precursor gene of LASV (Josiah strain) and demonstrated that 3 vaccinations accompanied by dermal electroporation protected guinea pigs from LASV-associated illness and death. Here, we describe an initial efficacy experiment in cynomolgus macaque nonhuman primates (NHPs) in which we followed an identical 3-dose vaccine schedule that was successful in guinea pigs, and a follow-on experiment in which we used an accelerated vaccination strategy consisting of 2 administrations, spaced 4 weeks apart. In both studies, all of the LASV DNA-vaccinated NHPs survived challenge and none of them had measureable, sustained viremia or displayed weight loss or other disease signs post-exposure. Three of 10 mock-vaccinates survived exposure to LASV, but all of them became acutely ill post-exposure and remained chronically ill to the study end point (45 d post-exposure). Two of the 3 survivors experienced sensorineural hearing loss (described elsewhere). These results clearly demonstrate that the LASV DNA vaccine combined with dermal electroporation is a highly effective candidate for eventual use in humans.

Treatment of Lassa virus infection in outbred guinea pigs with first-in-class human monoclonal antibodies.

PubMed

Cross, Robert W; Mire, Chad E; Branco, Luis M; Geisbert, Joan B; Rowland, Megan M; Heinrich, Megan L; Goba, Augustine; Momoh, Mambu; Grant, Donald S; Fullah, Mohamed; Khan, Sheik Humarr; Robinson, James E; Geisbert, Thomas W; Garry, Robert F

2016-09-01

Lassa fever is a significant health threat to West African human populations with hundreds of thousands of annual cases. There are no approved medical countermeasures currently available. Compassionate use of the antiviral drug ribavirin or transfusion of convalescent serum has resulted in mixed success depending on when administered or the donor source, respectively. We previously identified several recombinant human monoclonal antibodies targeting the glycoprotein of Lassa virus with strong neutralization profiles in vitro. Here, we demonstrate remarkable therapeutic efficacy using first-in-class human antibodies in a guinea pig model of Lassa infection thereby presenting a promising treatment alternative. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Management of a Lassa fever outbreak, Rhineland-Palatinate, Germany, 2016.

PubMed

Ehlkes, Lutz; George, Maja; Samosny, Gerhard; Burckhardt, Florian; Vogt, Manfred; Bent, Stefan; Jahn, Klaus; Zanger, Philipp

2017-09-01

Due to rapid diagnosis and isolation of imported cases, community outbreaks of viral haemorrhagic fevers (VHF) are considered unlikely in industrialised countries. In March 2016, the first documented locally acquired case of Lassa fever (LF) outside Africa occurred, demonstrating the disease's potential as a cross-border health threat. We describe the management surrounding this case of LF in Rhineland-Palatinate - the German federal state where secondary transmission occurred. Twelve days after having been exposed to the corpse of a LF case imported from Togo, a symptomatic undertaker tested positive for Lassa virus RNA. Potential contacts were traced, categorised based on exposure risk, and monitored. Overall, we identified 21 contact persons with legal residency in Rhineland-Palatinate: seven related to the index case, 13 to the secondary case, and one related to both. The secondary case received treatment and recovered. Five contacts were quarantined and one was temporarily banned from work. No further transmission occurred. Based on the experience gained during the outbreak and a review of national and international guidelines, we conclude that exposure risk attributable to corpses may currently be underestimated, and we present suggestions that may help to improve the anti-epidemic response to imported VHF cases in industrialised countries.

The sensitivity and specificity of Lassa virus IgM by ELISA as screening tool at early phase of Lassa fever infection

PubMed Central

Ibekwe, Titus S.; Nwegbu, Maxwell M.; Asogun, Daniel; Adomeh, Donatus I.; Okokhere, Peter O.

2012-01-01

Background: Early diagnosis, prompt treatment, and disease containment are vital measures in the management of Lassa fever (LF), a lethal and contagious arenaviral hemorrhagic disease prevalent in West Africa. Lassa Virus (LAV)-specific Reverse Transcriptase Polymerase Chain Reaction (RT-PCR) test, the gold standard for diagnosis, is unavailable in most centers. Serologic detection of LAV IgM is a more accessible tool and this work was to investigate its adequacy as an early marker for LF. Patients and Methods: A prospective case–control study conducted July 2007-March 2011 in a tertiary referral health center in Nigeria. Blood samples for test and control were evaluated for Lassa specific antigens and IgM using RT-PCR (primers S36+ and LVS 339) and indirect ELISA (Lassa Nucleo-protein (NP)-Antigen) respectively. RT-PCR outcome was used as standard to test for the sensitivity and specificity of IgM. Results: Of the 37 confirmed cases of LF infection by RT-PCR, 21 (57%) were IgM positive. Amongst the 35 confirmed negative cases (control group), eight were IgM positive. The diagnostic sensitivity and specificity of the IgM assay were 57% and 77% respectively. The negative and positive predictive values of the IgM serological assay were 63% and 72%, respectively, while the efficiency of the test was 67%. Conclusion: The specificity and sensitivity of IgM as a screening tool for early detection of LF appear weak and, hence, the need for a reliable LF “rapid screening kit” since RT-PCR is unavailable in most centers. In the interim, “high clinical index of suspicion,” irrespective of IgM status, requires urgent referral to confirmatory centers. PMID:23661877

The sensitivity and specificity of Lassa virus IgM by ELISA as screening tool at early phase of Lassa fever infection.

PubMed

Ibekwe, Titus S; Nwegbu, Maxwell M; Asogun, Daniel; Adomeh, Donatus I; Okokhere, Peter O

2012-10-01

Early diagnosis, prompt treatment, and disease containment are vital measures in the management of Lassa fever (LF), a lethal and contagious arenaviral hemorrhagic disease prevalent in West Africa. Lassa Virus (LAV)-specific Reverse Transcriptase Polymerase Chain Reaction (RT-PCR) test, the gold standard for diagnosis, is unavailable in most centers. Serologic detection of LAV IgM is a more accessible tool and this work was to investigate its adequacy as an early marker for LF. A prospective case-control study conducted July 2007-March 2011 in a tertiary referral health center in Nigeria. Blood samples for test and control were evaluated for Lassa specific antigens and IgM using RT-PCR (primers S36+ and LVS 339) and indirect ELISA (Lassa Nucleo-protein (NP)-Antigen) respectively. RT-PCR outcome was used as standard to test for the sensitivity and specificity of IgM. Of the 37 confirmed cases of LF infection by RT-PCR, 21 (57%) were IgM positive. Amongst the 35 confirmed negative cases (control group), eight were IgM positive. The diagnostic sensitivity and specificity of the IgM assay were 57% and 77% respectively. The negative and positive predictive values of the IgM serological assay were 63% and 72%, respectively, while the efficiency of the test was 67%. The specificity and sensitivity of IgM as a screening tool for early detection of LF appear weak and, hence, the need for a reliable LF "rapid screening kit" since RT-PCR is unavailable in most centers. In the interim, "high clinical index of suspicion," irrespective of IgM status, requires urgent referral to confirmatory centers.

Transcriptome Analysis of Human Peripheral Blood Mononuclear Cells Exposed to Lassa Virus and to the Attenuated Mopeia/Lassa Reassortant 29 (ML29), a Vaccine Candidate

PubMed Central

Zapata, Juan Carlos; Carrion, Ricardo; Patterson, Jean L.; Crasta, Oswald; Zhang, Yan; Mani, Sachin; Jett, Marti; Poonia, Bhawna; Djavani, Mahmoud; White, David M.; Lukashevich, Igor S.; Salvato, Maria S.

2013-01-01

Lassa virus (LASV) is the causative agent of Lassa Fever and is responsible for several hundred thousand infections and thousands of deaths annually in West Africa. LASV and the non-pathogenic Mopeia virus (MOPV) are both rodent-borne African arenaviruses. A live attenuated reassortant of MOPV and LASV, designated ML29, protects rodents and primates from LASV challenge and appears to be more attenuated than MOPV. To gain better insight into LASV-induced pathology and mechanism of attenuation we performed gene expression profiling in human peripheral blood mononuclear cells (PBMC) exposed to LASV and the vaccine candidate ML29. PBMC from healthy human subjects were exposed to either LASV or ML29. Although most PBMC are non-permissive for virus replication, they remain susceptible to signal transduction by virus particles. Total RNA was extracted and global gene expression was evaluated during the first 24 hours using high-density microarrays. Results were validated using RT-PCR, flow cytometry and ELISA. LASV and ML29 elicited differential expression of interferon-stimulated genes (ISG), as well as genes involved in apoptosis, NF-kB signaling and the coagulation pathways. These genes could eventually serve as biomarkers to predict disease outcomes. The remarkable differential expression of thrombomodulin, a key regulator of inflammation and coagulation, suggests its involvement with vascular abnormalities and mortality in Lassa fever disease. PMID:24069471

Prevalence of Lassa Virus Disease (LVD) in Nigerian children with fever or fever and convulsions in an endemic area.

PubMed

Akhuemokhan, Odigie C; Ewah-Odiase, Rosemary O; Akpede, Nosa; Ehimuan, Jacqueline; Adomeh, Donatus I; Odia, Ikpomwonsa; Olomu, Sylvia C; Pahlmann, Meike; Becker-Ziaja, Beate; Happi, Christian T; Asogun, Danny A; Okogbenin, Sylvanus A; Okokhere, Peter O; Dawodu, Osagie S; Omoike, Irekpono U; Sabeti, Pardis C; Günther, Stephan; Akpede, George O

2017-07-01

Convulsions with fever in children are a common neurologic emergency in the tropics, and determining the contribution of endemic viral infections can be challenging. In particular, there is a dearth of data on the prevalence and clinical differentiation of Lassa virus disease (LVD) in febrile children in endemic areas of Nigeria, which has multiple lineages of the virus. The aim of this study was to determine the prevalence and presentation of LVD in febrile children with and without convulsions. This was a prospective study of consecutive febrile children aged ≥1 month- 15 years admitted to the Children's Emergency Room of Irrua Specialist Teaching Hospital over a period of 1 year. Febrile children with convulsions (Cases) were compared with those without convulsions (Controls). LVD was defined by the presence of a positive Lassa virus RT-PCR test. Rates were compared between groups using χ2 or Fisher's exact tests and p <0.05 taken as significant. 373 (40.9%) of 913 admissions had fever. Of these, 108/373 (29%) presented with convulsions. The overall prevalence of LVD was 13/373 (3.5%; 95% CI = 1.9%, 5.7%) in febrile admissions, 3/108 (2.8%) in Cases and 10/265 (3.8%) in Controls [(Odds Ratio (95% Confidence Interval) (OR (95% CI)) of LVD in Cases versus Controls = 0.73 (0.2, 2.7)]. Only vomiting (OR (95% CI) = 0.09 (0.01, 0.70)) and bleeding (OR (95% CI) = 39.56 (8.52, 183.7)) were significantly associated with an increased prevalence of LVD. LVD is an important cause of fever, including undifferentiated fever in children in endemic areas, but it is not significantly associated with convulsions associated with fever. Its prevalence, and lack of clinical differentiation on presentation, underscores the importance of a high index of suspicion in diagnosis. Screening of febrile children with undifferentiated fever in endemic areas for LVD could be an important medical and public health control measure.

Lassa Fever in Post-Conflict Sierra Leone

PubMed Central

Hartnett, Jessica N.; Levy, Danielle C.; Yenni, Rachael E.; Moses, Lina M.; Fullah, Mohammed; Momoh, Mambo; Fonnie, Mbalu; Fonnie, Richard; Kanneh, Lansana; Koroma, Veronica J.; Kargbo, Kandeh; Ottomassathien, Darin; Muncy, Ivana J.; Jones, Abigail B.; Illick, Megan M.; Kulakosky, Peter C.; Haislip, Allyson M.; Bishop, Christopher M.; Elliot, Deborah H.; Brown, Bethany L.; Zhu, Hu; Hastie, Kathryn M.; Andersen, Kristian G.; Gire, Stephen K.; Tabrizi, Shervin; Tariyal, Ridhi; Stremlau, Mathew; Matschiner, Alex; Sampey, Darryl B.; Spence, Jennifer S.; Cross, Robert W.; Geisbert, Joan B.; Folarin, Onikepe A.; Happi, Christian T.; Pitts, Kelly R.; Geske, F. Jon; Geisbert, Thomas W.; Saphire, Erica Ollmann; Robinson, James E.; Wilson, Russell B.; Sabeti, Pardis C.; Henderson, Lee A.; Khan, S. Humarr; Bausch, Daniel G.; Branco, Luis M.; Garry, Robert F.

2014-01-01

Background Lassa fever (LF), an often-fatal hemorrhagic disease caused by Lassa virus (LASV), is a major public health threat in West Africa. When the violent civil conflict in Sierra Leone (1991 to 2002) ended, an international consortium assisted in restoration of the LF program at Kenema Government Hospital (KGH) in an area with the world's highest incidence of the disease. Methodology/Principal Findings Clinical and laboratory records of patients presenting to the KGH Lassa Ward in the post-conflict period were organized electronically. Recombinant antigen-based LF immunoassays were used to assess LASV antigenemia and LASV-specific antibodies in patients who met criteria for suspected LF. KGH has been reestablished as a center for LF treatment and research, with over 500 suspected cases now presenting yearly. Higher case fatality rates (CFRs) in LF patients were observed compared to studies conducted prior to the civil conflict. Different criteria for defining LF stages and differences in sensitivity of assays likely account for these differences. The highest incidence of LF in Sierra Leone was observed during the dry season. LF cases were observed in ten of Sierra Leone's thirteen districts, with numerous cases from outside the traditional endemic zone. Deaths in patients presenting with LASV antigenemia were skewed towards individuals less than 29 years of age. Women self-reporting as pregnant were significantly overrepresented among LASV antigenemic patients. The CFR of ribavirin-treated patients presenting early in acute infection was lower than in untreated subjects. Conclusions/Significance Lassa fever remains a major public health threat in Sierra Leone. Outreach activities should expand because LF may be more widespread in Sierra Leone than previously recognized. Enhanced case finding to ensure rapid diagnosis and treatment is imperative to reduce mortality. Even with ribavirin treatment, there was a high rate of fatalities underscoring the need to develop more effective and/or supplemental treatments for LF. PMID:24651047

[Microbiological surveillance: viral hemorrhagic fever in Central African Republic: current serological data in man].

PubMed

Nakounné, E; Selekon, B; Morvan, J

2000-01-01

An investigation was conducted between 1994 and 1997 in forested areas of the Central African Republic (CAR) to determine the seroprevalence of IgG antibodies against several haemorrhagic fever viruses present in the region. Sera were obtained from 1762 individuals in two groups (Pygmy and Bantu locuted populations) living in 4 forested areas in the south of the country. Sera were tested for IgG antibodies against Ebola, Marburg, Rift Valley fever (RVF), Yellow fever (YF) and Hantaviruses by enzyme immunoassay (EIA), and against Lassa virus by immunofluorescent assay. The prevalence of IgG antibodies was 5.9% for Ebola, 2% for Marburg, 6.9% pour RVF, 6.5% for YF, 2% for Hantaan. No antibodies were detected against Lassa, Seoul, Puumala and Thottapalayam viruses. No IgM antibodies were detected against RVF and YF viruses. The distribution of antibodies appears to be related to tropical rain forest areas. This study indicates that several haemorrhagic fever viruses are endemic in forested areas of the CAR and could emerge due to environmental modification.

Emerging Infections and Bioterrorism

DTIC Science & Technology

2001-09-01

bioterrorism. Some examples of unusual outbreaks that could have been mistaken for bioterrorism are given below: Event/ Disease Location Year Legionnaires ...Geminiviruses) 1 237 Table 2. Viral Hemorrhagic Fevers Family and/or genus Disease ( s ) Arenaviridae Lassa fever, Bolivian HF (Machupo virus), Argentine HF (Junin...bioterrorist agents: these are the organisms or toxins that cause the diseases anthrax, botulism, brucellosis, plague, Q fever, smallpox, staphylococcal

Animal models of viral hemorrhagic fever.

PubMed

Smith, Darci R; Holbrook, Michael R; Gowen, Brian B

2014-12-01

The term "viral hemorrhagic fever" (VHF) designates a syndrome of acute febrile illness, increased vascular permeability and coagulation defects which often progresses to bleeding and shock and may be fatal in a significant percentage of cases. The causative agents are some 20 different RNA viruses in the families Arenaviridae, Bunyaviridae, Filoviridae and Flaviviridae, which are maintained in a variety of animal species and are transferred to humans through direct or indirect contact or by an arthropod vector. Except for dengue, which is transmitted among humans by mosquitoes, the geographic distribution of each type of VHF is determined by the range of its animal reservoir. Treatments are available for Argentine HF and Lassa fever, but no approved countermeasures have been developed against other types of VHF. The development of effective interventions is hindered by the sporadic nature of most infections and their occurrence in geographic regions with limited medical resources. Laboratory animal models that faithfully reproduce human disease are therefore essential for the evaluation of potential vaccines and therapeutics. The goal of this review is to highlight the current status of animal models that can be used to study the pathogenesis of VHF and test new countermeasures. Copyright © 2014 Elsevier B.V. All rights reserved.

Expression and X-Ray Structural Determination of the Nucleoprotein of Lassa Fever Virus.

PubMed

Qi, Xiaoxuan; Wang, Wenjian; Dong, Haohao; Liang, Yuying; Dong, Changjiang; Ly, Hinh

2018-01-01

We describe methods to express the nucleoprotein (NP) of Lassa fever virus (LASV) in E. coli, to purify and crystallize it using the sitting-drop vapor diffusion method. The crystals were screened using Rigaku micro-007 X-ray generator and a dataset was collected at a resolution of 2.36 Å. The crystals belong to space group P3, with the unit cell parameters a = b = 176.35 Å, c = 56.40 Å, α = β = 90°, and γ = 120°. Using the X-ray diffraction method, we constructed a three-dimensional structure of the LASV NP that should aid in the development of novel therapeutic strategies against this virus, for which vaccine and effective treatment modalities are currently unavailable.

Structural basis for antibody-mediated neutralization of Lassa virus.

PubMed

Hastie, Kathryn M; Zandonatti, Michelle A; Kleinfelter, Lara M; Heinrich, Megan L; Rowland, Megan M; Chandran, Kartik; Branco, Luis M; Robinson, James E; Garry, Robert F; Saphire, Erica Ollmann

2017-06-02

The arenavirus Lassa causes severe hemorrhagic fever and a significant disease burden in West Africa every year. The glycoprotein, GPC, is the sole antigen expressed on the viral surface and the critical target for antibody-mediated neutralization. Here we present the crystal structure of the trimeric, prefusion ectodomain of Lassa GP bound to a neutralizing antibody from a human survivor at 3.2-angstrom resolution. The antibody extensively anchors two monomers together at the base of the trimer, and biochemical analysis suggests that it neutralizes by inhibiting conformational changes required for entry. This work illuminates pH-driven conformational changes in both receptor-binding and fusion subunits of Lassa virus, illustrates the unique assembly of the arenavirus glycoprotein spike, and provides a much-needed template for vaccine design against these threats to global health. Copyright © 2017, American Association for the Advancement of Science.

Cutting edge: impairment of dendritic cells and adaptive immunity by Ebola and Lassa viruses.

PubMed

Mahanty, Siddhartha; Hutchinson, Karen; Agarwal, Sudhanshu; McRae, Michael; Rollin, Pierre E; Pulendran, Bali

2003-03-15

Acute infection of humans with Ebola and Lassa viruses, two principal etiologic agents of hemorrhagic fevers, often results in a paradoxical pattern of immune responses: early infection, characterized by an outpouring of inflammatory mediators such as TNF-alpha, IL-1 beta, and IL-6, vs late stage infections, which are associated with poor immune responses. The mechanisms underlying these diverse outcomes are poorly understood. In particular, the role played by cells of the innate immune system, such as dendritic cells (DC), is not known. In this study, we show that Ebola and Lassa viruses infect human monocyte-derived DC and impair their function. Monocyte-derived DC exposed to either virus fail to secrete proinflammatory cytokines, do not up-regulate costimulatory molecules, and are poor stimulators of T cells. These data represent the first evidence for a mechanism by which Ebola and Lassa viruses target DC to impair adaptive immunity.

Development of a Threat Assessment Framework Applicable to Dual Use Biotechnology: Results of a Study to Determine the Feasibility, Applicability and Potential Design of a Threat Assessment Framework Concept

DTIC Science & Technology

2007-04-01

Guanarito virus, Lassa fever • Bunyaviruses. Hantaviruses, Rift Valley fever • Flaviviruses. Dengue • Filoviruses. Ebola, Marburg Category B...Viruses V1. Chikungunya virus V2. Congo-Crimean haemorrhagic fever virus V3. Dengue fever virus...current context and an extensive set of interviews with subject matter experts (SME). After preliminary conversations with experts and scanning initial

Mortality Among Confirmed Lassa Fever Cases During the 2015-2016 Outbreak in Nigeria.

PubMed

Buba, Maryam Ibrahim; Dalhat, Mahmood Muazu; Nguku, Patrick Mboya; Waziri, Ndadilnasiya; Mohammad, Jibreel Omar; Bomoi, Idriss Mohammed; Onyiah, Amaka Pamela; Onwujei, Jude; Balogun, Muhammad Shakir; Bashorun, Adebobola Toluwalashe; Nsubuga, Peter; Nasidi, Abdulsalami

2018-02-01

To determine factors associated with mortality among confirmed Lassa fever cases. We reviewed line lists and clinical records of laboratory-confirmed cases of Lassa fever during the 2016 outbreak in Nigeria to determine factors associated with mortality. We activated an incident command system to coordinate response. We documented 47 cases, 28 of whom died (case fatality rate [CFR] = 59.6%; mean age 31.4 years; SD = ±18.4 years). The youngest and the oldest were the most likely to die, with 100% mortality in those aged 5 years or younger and those aged 55 years or older. Patients who commenced ribavirin were more likely to survive (odds ratio [OR] = 0.1; 95% confidence interval [CI] = 0.03, 0.50). Fatality rates went from 100% (wave 1) through 69% (wave 2) to 31% (wave 3; χ 2 for linear trend: P < .01). Patients admitted to a health care center before incident command system activation were more likely to die (OR = 4.4; 95% CI = 1.1, 17.6). The only pregnant patient in the study died postpartum. Effective, coordinated response reduces mortality from public health events. Attention to vulnerable groups during disasters is essential. Public Health Implications. Activating an incident command system improves the outcome of disasters in resource-constrained settings.

Prevalence of Lassa Virus Disease (LVD) in Nigerian children with fever or fever and convulsions in an endemic area

PubMed Central

Akhuemokhan, Odigie C.; Ewah-Odiase, Rosemary O.; Akpede, Nosa; Ehimuan, Jacqueline; Adomeh, Donatus I.; Odia, Ikpomwonsa; Olomu, Sylvia C.; Pahlmann, Meike; Becker-Ziaja, Beate; Happi, Christian T.; Asogun, Danny A.; Okogbenin, Sylvanus A.; Okokhere, Peter O.; Dawodu, Osagie S.; Omoike, Irekpono U.; Sabeti, Pardis C.; Günther, Stephan; Akpede, George O.

2017-01-01

Background Convulsions with fever in children are a common neurologic emergency in the tropics, and determining the contribution of endemic viral infections can be challenging. In particular, there is a dearth of data on the prevalence and clinical differentiation of Lassa virus disease (LVD) in febrile children in endemic areas of Nigeria, which has multiple lineages of the virus. The aim of this study was to determine the prevalence and presentation of LVD in febrile children with and without convulsions. Methodology/Principal findings This was a prospective study of consecutive febrile children aged ≥1 month– 15 years admitted to the Children’s Emergency Room of Irrua Specialist Teaching Hospital over a period of 1 year. Febrile children with convulsions (Cases) were compared with those without convulsions (Controls). LVD was defined by the presence of a positive Lassa virus RT-PCR test. Rates were compared between groups using χ2 or Fisher’s exact tests and p <0.05 taken as significant. 373 (40.9%) of 913 admissions had fever. Of these, 108/373 (29%) presented with convulsions. The overall prevalence of LVD was 13/373 (3.5%; 95% CI = 1.9%, 5.7%) in febrile admissions, 3/108 (2.8%) in Cases and 10/265 (3.8%) in Controls [(Odds Ratio (95% Confidence Interval) (OR (95% CI)) of LVD in Cases versus Controls = 0.73 (0.2, 2.7)]. Only vomiting (OR (95% CI) = 0.09 (0.01, 0.70)) and bleeding (OR (95% CI) = 39.56 (8.52, 183.7)) were significantly associated with an increased prevalence of LVD. Conclusions/Significance LVD is an important cause of fever, including undifferentiated fever in children in endemic areas, but it is not significantly associated with convulsions associated with fever. Its prevalence, and lack of clinical differentiation on presentation, underscores the importance of a high index of suspicion in diagnosis. Screening of febrile children with undifferentiated fever in endemic areas for LVD could be an important medical and public health control measure. PMID:28671959

Inhibition of Innate Immune Responses Is Key to Pathogenesis by Arenaviruses.

PubMed

Meyer, Bjoern; Ly, Hinh

2016-04-01

Mammalian arenaviruses are zoonotic viruses that cause asymptomatic, persistent infections in their rodent hosts but can lead to severe and lethal hemorrhagic fever with bleeding and multiorgan failure in human patients. Lassa virus (LASV), for example, is endemic in several West African countries, where it is responsible for an estimated 500,000 infections and 5,000 deaths annually. There are currently no FDA-licensed therapeutics or vaccines available to combat arenavirus infection. A hallmark of arenavirus infection (e.g., LASV) is general immunosuppression that contributes to high viremia. Here, we discuss the early host immune responses to arenavirus infection and the recently discovered molecular mechanisms that enable pathogenic viruses to suppress host immune recognition and to contribute to the high degree of virulence. We also directly compare the innate immune evasion mechanisms between arenaviruses and other hemorrhagic fever-causing viruses, such as Ebola, Marburg, Dengue, and hantaviruses. A better understanding of the immunosuppression and immune evasion strategies of these deadly viruses may guide the development of novel preventative and therapeutic options. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Characterization of the Lassa virus matrix protein Z: electron microscopic study of virus-like particles and interaction with the nucleoprotein (NP).

PubMed

Eichler, Robert; Strecker, Thomas; Kolesnikova, Larissa; ter Meulen, Jan; Weissenhorn, Winfried; Becker, Stephan; Klenk, Hans Dieter; Garten, Wolfgang; Lenz, Oliver

2004-03-15

Lassa virus is the causative agent of a hemorrhagic fever endemic in west Africa. The RNA genome of Lassa virus encodes the glycoprotein precursor GP-C, a nucleoprotein (NP), the viral polymerase L and a small protein Z (11 kDa). Here, we analyze the role of Z protein for virus maturation. We have recently shown that expression of Z protein in the absence of other viral proteins is sufficient for the release of enveloped Z-containing particles. In this study, we examined particles secreted into the supernatant of a stably Z protein-expressing CHO cell line by electron microscopy. The observed Z-induced virus-like particles did not significantly differ in their morphology and size from Lassa virus particles. Mutation of two proline-rich domains within Z which are known to drastically reduce the release of virus-like particles, had no effect on the cellular localization of the protein nor on its membrane-association. Furthermore, we present evidence that Z interacts with the NP. We assume that Z recruits NP to cellular membranes where virus assembly takes place. We conclude from our data that Lassa virus Z protein plays an essential role in Lassa virus maturation.

Emerging trends in Lassa fever: redefining the role of immunoglobulin M and inflammation in diagnosing acute infection.

PubMed

Branco, Luis M; Grove, Jessica N; Boisen, Matt L; Shaffer, Jeffrey G; Goba, Augustine; Fullah, Mohammed; Momoh, Mambu; Grant, Donald S; Garry, Robert F

2011-10-24

Lassa fever (LF) is a devastating hemorrhagic viral disease that is endemic to West Africa and responsible for thousands of human deaths each year. Analysis of humoral immune responses (IgM and IgG) by antibody-capture ELISA (Ab-capture ELISA) and Lassa virus (LASV) viremia by antigen-capture ELISA (Ag-capture ELISA) in suspected patients admitted to the Kenema Government Hospital (KGH) Lassa Fever Ward (LFW) in Sierra Leone over the past five years is reshaping our understanding of acute LF. Analyses in LF survivors indicated that LASV-specific IgM persists for months to years after initial infection. Furthermore, exposure to LASV appeared to be more prevalent in historically non-endemic areas of West Africa with significant percentages of reportedly healthy donors IgM and IgG positive in LASV-specific Ab-capture ELISA. We found that LF patients who were Ag positive were more likely to die than suspected cases who were only IgM positive. Analysis of metabolic and immunological parameters in Ag positive LF patients revealed a strong correlation between survival and low levels of IL-6, -8, -10, CD40L, BUN, ALP, ALT, and AST. Despite presenting to the hospital with fever and in some instances other symptoms consistent with LF, the profiles of Ag negative IgM positive individuals were similar to those of normal donors and nonfatal (NF) LF cases, suggesting that IgM status cannot necessarily be considered a diagnostic marker of acute LF in suspected cases living in endemic areas of West Africa. Only LASV viremia assessed by Ag-capture immunoassay, nucleic acid detection or virus isolation should be used to diagnose acute LASV infection in West Africans. LASV-specific IgM serostatus cannot be considered a diagnostic marker of acute LF in suspected cases living in endemic areas of West Africa. By applying these criteria, we identified a dysregulated metabolic and pro-inflammatory response profile conferring a poor prognosis in acute LF. In addition to suggesting that the current diagnostic paradigm for acute LF should be reconsidered, these studies present new opportunities for therapeutic interventions based on potential prognostic markers in LF.

Rat-atouille: A Mixed Method Study to Characterize Rodent Hunting and Consumption in the Context of Lassa Fever.

PubMed

Bonwitt, Jesse; Kelly, Ann H; Ansumana, Rashid; Agbla, Schadrac; Sahr, Foday; Saez, Almudena Mari; Borchert, Matthias; Kock, Richard; Fichet-Calvet, Elisabeth

2016-06-01

Lassa fever is a zoonotic hemorrhagic illness predominant in areas across Nigeria, Sierra Leone, Guinea, Liberia, and southern Mali. The reservoir of Lassa virus is the multimammate mouse (Mastomys natalensis), a highly commensal species in West Africa. Primary transmission to humans occurs through direct or indirect contact with rodent body fluids such as urine, feces, saliva, or blood. Our research draws together qualitative and quantitative methods to provide a fuller and more nuanced perspective on these varied points of human-animal contact. In this article, we focus on the hunting, preparation, and consumption of rodents as possible routes of exposure in Bo, Sierra Leone. We found that the consumption of rodents, including the reservoir species, is widespread and does not neatly tally against generational or gender lines. Further, we found that the reasons for rodent consumption are multifactorial, including taste preferences, food security, and opportunistic behavior. We argue that on certain topics, such as rodent consumption, establishing trust with communities, and using qualitative research methods, is key to investigate sensitive issues and situate them in their wider context. To conclude, we recommend ways to refine sensitization campaigns to account for these socio-cultural contexts.

Mapping transmission risk of Lassa fever in West Africa: the importance of quality control, sampling bias, and error weighting.

PubMed

Peterson, A Townsend; Moses, Lina M; Bausch, Daniel G

2014-01-01

Lassa fever is a disease that has been reported from sites across West Africa; it is caused by an arenavirus that is hosted by the rodent M. natalensis. Although it is confined to West Africa, and has been documented in detail in some well-studied areas, the details of the distribution of risk of Lassa virus infection remain poorly known at the level of the broader region. In this paper, we explored the effects of certainty of diagnosis, oversampling in well-studied region, and error balance on results of mapping exercises. Each of the three factors assessed in this study had clear and consistent influences on model results, overestimating risk in southern, humid zones in West Africa, and underestimating risk in drier and more northern areas. The final, adjusted risk map indicates broad risk areas across much of West Africa. Although risk maps are increasingly easy to develop from disease occurrence data and raster data sets summarizing aspects of environments and landscapes, this process is highly sensitive to issues of data quality, sampling design, and design of analysis, with macrogeographic implications of each of these issues and the potential for misrepresenting real patterns of risk.

Deployable, Field-Sustainable, Reverse Transcription-Polymerase Chain Reaction Assays for Rapid Screening and Serotype Identification of Dengue Virus in Mosquitoes

DTIC Science & Technology

2007-03-01

C, Gottig S, Schiiiing S, et ai: Rapid detection and quantiilcation of RNA of Eboia and Marburg viruses, L.assa virus, Crimean - Congo hemorrhagic fever ...the past two decades, dengue fever (DF) and the poten- tially fatal forms ofthe disease, dengue hemorrhagic fever (DHF) and dengue shock syndrome, have...Viroi 2003; 77: i 1436-47. 5. Gubler DJ: Dengue and dengue hemorrhagic fever . Ciin Microbiol Rev 1998; 11: 480-96. 6. Fonseca BA, Fonseca SN: Dengue virus

VaxCelerate II: Rapid development of a self-assembling vaccine for Lassa fever

PubMed Central

Leblanc, Pierre; Moise, Leonard; Luza, Cybelle; Chantaralawan, Kanawat; Lezeau, Lynchy; Yuan, Jianping; Field, Mary; Richer, Daniel; Boyle, Christine; Martin, William D; Fishman, Jordan B; Berg, Eric A; Baker, David; Zeigler, Brandon; Mais, Dale E; Taylor, William; Coleman, Russell; Warren, H Shaw; Gelfand, Jeffrey A; De Groot, Anne S; Brauns, Timothy; Poznansky, Mark C

2014-01-01

Development of effective vaccines against emerging infectious diseases (EID) can take as much or more than a decade to progress from pathogen isolation/identification to clinical approval. As a result, conventional approaches fail to produce field-ready vaccines before the EID has spread extensively. Lassa is a prototypical emerging infectious disease endemic to West Africa for which no successful vaccine is available. We established the VaxCelerate Consortium to address the need for more rapid vaccine development by creating a platform capable of generating and pre-clinically testing a new vaccine against specific pathogen targets in less than 120 d. A self-assembling vaccine is at the core of the approach. It consists of a fusion protein composed of the immunostimulatory Mycobacterium tuberculosis heat shock protein 70 (MtbHSP70) and the biotin binding protein, avidin. Mixing the resulting protein (MAV) with biotinylated pathogen-specific immunogenic peptides yields a self-assembled vaccine (SAV). To meet the time constraint imposed on this project, we used a distributed R&D model involving experts in the fields of protein engineering and production, bioinformatics, peptide synthesis/design and GMP/GLP manufacturing and testing standards. SAV immunogenicity was first tested using H1N1 influenza specific peptides and the entire VaxCelerate process was then tested in a mock live-fire exercise targeting Lassa fever virus. We demonstrated that the Lassa fever vaccine induced significantly increased class II peptide specific interferon-γ CD4+ T cell responses in HLA-DR3 transgenic mice compared to peptide or MAV alone controls. We thereby demonstrated that our SAV in combination with a distributed development model may facilitate accelerated regulatory review by using an identical design for each vaccine and by applying safety and efficacy assessment tools that are more relevant to human vaccine responses than current animal models. PMID:25483693

VaxCelerate II: rapid development of a self-assembling vaccine for Lassa fever.

PubMed

Leblanc, Pierre; Moise, Leonard; Luza, Cybelle; Chantaralawan, Kanawat; Lezeau, Lynchy; Yuan, Jianping; Field, Mary; Richer, Daniel; Boyle, Christine; Martin, William D; Fishman, Jordan B; Berg, Eric A; Baker, David; Zeigler, Brandon; Mais, Dale E; Taylor, William; Coleman, Russell; Warren, H Shaw; Gelfand, Jeffrey A; De Groot, Anne S; Brauns, Timothy; Poznansky, Mark C

2014-01-01

Development of effective vaccines against emerging infectious diseases (EID) can take as much or more than a decade to progress from pathogen isolation/identification to clinical approval. As a result, conventional approaches fail to produce field-ready vaccines before the EID has spread extensively. Lassa is a prototypical emerging infectious disease endemic to West Africa for which no successful vaccine is available. We established the VaxCelerate Consortium to address the need for more rapid vaccine development by creating a platform capable of generating and pre-clinically testing a new vaccine against specific pathogen targets in less than 120 d A self-assembling vaccine is at the core of the approach. It consists of a fusion protein composed of the immunostimulatory Mycobacterium tuberculosis heat shock protein 70 (MtbHSP70) and the biotin binding protein, avidin. Mixing the resulting protein (MAV) with biotinylated pathogen-specific immunogenic peptides yields a self-assembled vaccine (SAV). To meet the time constraint imposed on this project, we used a distributed R&D model involving experts in the fields of protein engineering and production, bioinformatics, peptide synthesis/design and GMP/GLP manufacturing and testing standards. SAV immunogenicity was first tested using H1N1 influenza specific peptides and the entire VaxCelerate process was then tested in a mock live-fire exercise targeting Lassa fever virus. We demonstrated that the Lassa fever vaccine induced significantly increased class II peptide specific interferon-γ CD4(+) T cell responses in HLA-DR3 transgenic mice compared to peptide or MAV alone controls. We thereby demonstrated that our SAV in combination with a distributed development model may facilitate accelerated regulatory review by using an identical design for each vaccine and by applying safety and efficacy assessment tools that are more relevant to human vaccine responses than current animal models.

Guidance for contact tracing of cases of Lassa fever, Ebola or Marburg haemorrhagic fever on an airplane: results of a European expert consultation.

PubMed

Gilsdorf, Andreas; Morgan, Dilys; Leitmeyer, Katrin

2012-11-21

Travel from countries where viral haemorrhagic fevers (VHF) are endemic has increased significantly over the past decades. In several reported VHF events on airplanes, passenger trace back was initiated but the scale of the trace back differed considerably. The absence of guidance documents to help the decision on necessity and scale of the trace back contributed to this variation.This article outlines the recommendations of an expert panel on Lassa fever, Ebola and Marburg haemorrhagic fever to the wider scientific community in order to advise the relevant stakeholders in the decision and scale of a possible passenger trace back. The evidence was collected through review of published literature and through the views of an expert panel. The guidance was agreed by consensus. Only a few events of VHF cases during air travel are reported in literature, with no documented infection in followed up contacts, so that no evidence of transmission of VHF during air travel exists to date. Based on this and the expert opinion, it was recommended that passenger trace back was undertaken only if: the index case had symptoms during the flight; the flight was within 21 days after detection of the event; and for Lassa fever if exposure of body fluid has been reported. The trace back should only be done after confirmation of the index case. Passengers and crew with direct contact, seat neighbours (+/- 1 seat), crew and cleaning personal of the section of the index case should be included in the trace back. No evidence has been found for the transmission of VHF in airplanes. This information should be taken into account, when a trace back decision has to be taken, because such a measure produces an enormous work load. The procedure suggested by the expert group can guide decisions made in future events, where a patient with suspected VHF infection travelled on a plane. However, the actual decision on start and scale of a trace back always lies in the hands of the responsible people taking all relevant information into account.

Guidance for contact tracing of cases of Lassa fever, Ebola or Marburg haemorrhagic fever on an airplane: results of a European expert consultation

PubMed Central

2012-01-01

Background Travel from countries where viral haemorrhagic fevers (VHF) are endemic has increased significantly over the past decades. In several reported VHF events on airplanes, passenger trace back was initiated but the scale of the trace back differed considerably. The absence of guidance documents to help the decision on necessity and scale of the trace back contributed to this variation. This article outlines the recommendations of an expert panel on Lassa fever, Ebola and Marburg haemorrhagic fever to the wider scientific community in order to advise the relevant stakeholders in the decision and scale of a possible passenger trace back. Method The evidence was collected through review of published literature and through the views of an expert panel. The guidance was agreed by consensus. Results Only a few events of VHF cases during air travel are reported in literature, with no documented infection in followed up contacts, so that no evidence of transmission of VHF during air travel exists to date. Based on this and the expert opinion, it was recommended that passenger trace back was undertaken only if: the index case had symptoms during the flight; the flight was within 21 days after detection of the event; and for Lassa fever if exposure of body fluid has been reported. The trace back should only be done after confirmation of the index case. Passengers and crew with direct contact, seat neighbours (+/− 1 seat), crew and cleaning personal of the section of the index case should be included in the trace back. Conclusion No evidence has been found for the transmission of VHF in airplanes. This information should be taken into account, when a trace back decision has to be taken, because such a measure produces an enormous work load. The procedure suggested by the expert group can guide decisions made in future events, where a patient with suspected VHF infection travelled on a plane. However, the actual decision on start and scale of a trace back always lies in the hands of the responsible people taking all relevant information into account. PMID:23170851

Lassa Fever

MedlinePlus

... in 1969 when two missionary nurses died in Nigeria. The virus is named after the town in Nigeria where the first cases occurred. The virus, a ... west Africa including Sierra Leone, Liberia, Guinea and Nigeria; however, other neighboring countries are also at risk, ...

Arenaviruses. Genes, proteins, and expression

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

Oldstone, M.B.A.

1987-01-01

This book provides a discussion of current knowledge on Arenaviruses. These viruses are the cause of major health problems, such as Lassa fever and Junin virus disease, and have been the Rosetta stone on which many of the major concepts in viral pathogenesis and immunobiology have been built. For example, study of lymphocytic choriomeningitis naturally and experimentally induced infection in the normal mouse host presented the scientific community with the first and definitive work on the following topics: virus induced immune response disease, immunologic tolerance, virus induced immune complex disease, presence and generation of cytotoxic T cells in vitro andmore » in vivo, H-2 restriction and dual recognition phenomena, and viral disease induced by altering physiologic or differential functions of a cell without causing alterations of house keeping or vital functions, i.e. pathology in the absence of cell or tissue lysis.« less

Lassa fever-induced sensorineural hearing loss: A neglected public health and social burden.

PubMed

Mateer, Elizabeth J; Huang, Cheng; Shehu, Nathan Y; Paessler, Slobodan

2018-02-01

Although an association between Lassa fever (LF) and sudden-onset sensorineural hearing loss (SNHL) was confirmed clinically in 1990, the prevalence of LF-induced SNHL in endemic countries is still underestimated. LF, a viral hemorrhagic fever disease caused by Lassa virus (LASV), is endemic in West Africa, causing an estimated 500,000 cases and 5,000 deaths per year. Sudden-onset SNHL, one complication of LF, occurs in approximately one-third of survivors and constitutes a neglected public health and social burden. In the endemic countries, where access to hearing aids is limited, SNHL results in a decline of the quality of life for those affected. In addition, hearing loss costs Nigeria approximately 43 million dollars per year. The epidemiology of LF-induced SNHL has not been characterized well. The complication of LF induced by SNHL is also an important consideration for vaccine development and treatments. However, research into the mechanism has been hindered by the lack of autopsy samples and relevant small animal models. Recently, the first animal model that mimics the symptoms of SNHL associated with LF was developed. Preliminary data from the new animal model as well as the clinical case studies support the mechanism of immune-mediated injury that causes SNHL in LF patients. This article summarizes clinical findings of hearing loss in LF patients highlighting the association between LASV infection and SNHL as well as the potential mechanism(s) for LF-induced SNHL. Further research is necessary to identify the mechanism and the epidemiology of LF-induced SNHL.

Emerging trends in Lassa fever: redefining the role of immunoglobulin M and inflammation in diagnosing acute infection

PubMed Central

2011-01-01

Background Lassa fever (LF) is a devastating hemorrhagic viral disease that is endemic to West Africa and responsible for thousands of human deaths each year. Analysis of humoral immune responses (IgM and IgG) by antibody-capture ELISA (Ab-capture ELISA) and Lassa virus (LASV) viremia by antigen-capture ELISA (Ag-capture ELISA) in suspected patients admitted to the Kenema Government Hospital (KGH) Lassa Fever Ward (LFW) in Sierra Leone over the past five years is reshaping our understanding of acute LF. Results Analyses in LF survivors indicated that LASV-specific IgM persists for months to years after initial infection. Furthermore, exposure to LASV appeared to be more prevalent in historically non-endemic areas of West Africa with significant percentages of reportedly healthy donors IgM and IgG positive in LASV-specific Ab-capture ELISA. We found that LF patients who were Ag positive were more likely to die than suspected cases who were only IgM positive. Analysis of metabolic and immunological parameters in Ag positive LF patients revealed a strong correlation between survival and low levels of IL-6, -8, -10, CD40L, BUN, ALP, ALT, and AST. Despite presenting to the hospital with fever and in some instances other symptoms consistent with LF, the profiles of Ag negative IgM positive individuals were similar to those of normal donors and nonfatal (NF) LF cases, suggesting that IgM status cannot necessarily be considered a diagnostic marker of acute LF in suspected cases living in endemic areas of West Africa. Conclusion Only LASV viremia assessed by Ag-capture immunoassay, nucleic acid detection or virus isolation should be used to diagnose acute LASV infection in West Africans. LASV-specific IgM serostatus cannot be considered a diagnostic marker of acute LF in suspected cases living in endemic areas of West Africa. By applying these criteria, we identified a dysregulated metabolic and pro-inflammatory response profile conferring a poor prognosis in acute LF. In addition to suggesting that the current diagnostic paradigm for acute LF should be reconsidered, these studies present new opportunities for therapeutic interventions based on potential prognostic markers in LF. PMID:22023795

Mechanisms and Consequences of Ebolavirus-Induced Lymphocyte Apoptosis

DTIC Science & Technology

2011-01-31

PROGRAM ELEMENT NUMBER 6. AUTHOR (S) 5d. PROJECT NUMBER 5e. TASK NUMBER 5f. WORK UNIT NUMBER 7. PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES... authors and are not necessarily endorsed by the U.S. Army. Address correspondence and reprint requests to Sina Bavari, U. S. Army Medical Research...common finding in many other hemorrhagic fever viruses, in- cluding Lassa, Marburg, Crimean Congo hemorrhagic fever, and some Hantavirus infections

Lassa serology in natural populations of rodents and horizontal transmission.

PubMed

Fichet-Calvet, Elisabeth; Becker-Ziaja, Beate; Koivogui, Lamine; Günther, Stephan

2014-09-01

Lassa virus causes hemorrhagic fever in West Africa. Previously, we demonstrated by PCR screening that only the multimammate mouse, Mastomys natalensis, hosts Lassa virus in Guinea. In the present study, we used the same specimen collection from 17 villages in Coastal, Upper, and Forest Guinea to investigate the Lassa virus serology in the rodent population. The aim was to determine the dynamics of antibody development in M. natalensis and to detect potential spillover infections in other rodent species. Immunoglobulin G (IgG) antibody screening was performed using the indirect immunofluorescence assay with the Guinean Lassa virus strain Bantou 289 as antigen. The overall seroprevalence was 8% (129/1551) with the following rodents testing positive: 109 M. natalensis, seven Mastomys erythroleucus, four Lemniscomys striatus, four Praomys daltoni, three Mus minutoides, and two Praomys rostratus. Nearly all of them (122/129) originated from Bantou, Tanganya, and Gbetaya, where Lassa virus is highly endemic in M. natalensis. The antibody seroprevalence in M. natalensis from this high-endemic area (27%; 108/396) depended on the village, habitat, host age, and host abundance. A main positive factor was age; the maximum seroprevalence reached 50% in older animals. Our data fit with a model implicating that most M. natalensis rodents become horizontally infected, clear the virus within a period significantly shorter than their life span, and develop antibodies. In addition, the detection of antibodies in other species trapped in the habitats of M. natalensis suggests spillover infections.

Mutational Analysis of Lassa Virus Glycoprotein Highlights Regions Required for Alpha-Dystroglycan Utilization.

PubMed

Acciani, Marissa; Alston, Jacob T; Zhao, Guohui; Reynolds, Hayley; Ali, Afroze M; Xu, Brian; Brindley, Melinda A

2017-09-15

Lassa virus (LASV) is an enveloped RNA virus endemic to West Africa and responsible for severe cases of hemorrhagic fever. Virus entry is mediated by the glycoprotein complex consisting of a stable-signal peptide, a receptor-binding subunit, GP1, and a viral-host membrane fusion subunit, GP2. Several cellular receptors can interact with the GP1 subunit and mediate viral entry, including alpha-dystroglycan (αDG) and lysosome-associated membrane protein 1 (LAMP1). In order to define the regions within GP1 that interact with the cellular receptors, we implemented insertional mutagenesis, carbohydrate shielding, and alanine scanning mutagenesis. Eighty GP constructs were engineered and evaluated for GP1-GP2 processing, surface expression, and the ability to mediate cell-to-cell fusion after low-pH exposure. To examine virus-to-cell entry, 49 constructs were incorporated onto vesicular stomatitis virus (VSV) pseudoparticles and transduction efficiencies were monitored in HAP1 and HAP1-ΔDAG1 cells that differentially produce the αDG cell surface receptor. Seven constructs retained efficient transduction in HAP1-ΔDAG1 cells yet poorly transduced HAP1 cells, suggesting that they are involved in αDG utilization. Residues H141, N146, F147, and Y150 cluster at the predicted central core of the trimeric interface and are important for GP-αDG interaction. Additionally, H92A-H93A, 150HA, 172HA, and 230HA displayed reduced transduction in both HAP1 and HAP1-ΔDAG1 cells, despite efficient cell-to-cell fusion activity. These mutations may interfere with interactions with the endosomal receptor LAMP1 or interfere at another stage in entry that is common to both cell lines. Insight gained from these data can aid in the development of more-effective entry inhibitors by blocking receptor interactions. IMPORTANCE Countries in which Lassa virus is endemic, such as Nigeria, Sierra Leone, Guinea, and Liberia, usually experience a seasonal outbreak of the virus from December to March. Currently, there is neither a preventative vaccine nor a therapeutic available to effectively treat severe Lassa fever. One way to thwart virus infection is to inhibit interaction with cellular receptors. It is known that the GP1 subunit of the Lassa glycoprotein complex plays a critical role in receptor recognition. Our results highlight a region within the Lassa virus GP1 protein that interacts with the cellular receptor alpha-dystroglycan. This information may be used for future development of new Lassa virus antivirals. Copyright © 2017 American Society for Microbiology.

Lamp1 Increases the Efficiency of Lassa Virus Infection by Promoting Fusion in Less Acidic Endosomal Compartments.

PubMed

Hulseberg, Christine E; Fénéant, Lucie; Szymańska, Katarzyna M; White, Judith M

2018-01-02

Lassa virus (LASV) is an arenavirus whose entry into host cells is mediated by a glycoprotein complex (GPC) comprised of a receptor binding subunit, GP1, a fusogenic transmembrane subunit, GP2, and a stable signal peptide. After receptor-mediated internalization, arenaviruses converge in the endocytic pathway, where they are thought to undergo low-pH-triggered, GPC-mediated fusion with a late endosome membrane. A unique feature of LASV entry is a pH-dependent switch from a primary cell surface receptor (α-dystroglycan) to an endosomal receptor, lysosomal-associated membrane protein (Lamp1). Despite evidence that the interaction between LASV GP1 and Lamp1 is critical, the function of Lamp1 in promoting LASV infection remains poorly characterized. Here we used wild-type (WT) and Lamp1 knockout (KO) cells to show that Lamp1 increases the efficiency of, but is not absolutely required for, LASV entry and infection. We then used cell-cell and pseudovirus-cell surface fusion assays to demonstrate that LASV GPC-mediated fusion occurs at a significantly higher pH when Lamp1 is present compared to when Lamp1 is missing. Correspondingly, we found that LASV entry occurs through less acidic endosomes in WT (Lamp1-positive) versus Lamp1 KO cells. We propose that, by elevating the pH threshold for fusion, Lamp1 allows LASV particles to exit the endocytic pathway before they encounter an increasingly acidic and harsh proteolytic environment, which could inactivate a significant percentage of incoming viruses. In this manner Lamp1 increases the overall efficiency of LASV entry and infection. IMPORTANCE Lassa virus is the most clinically important member of the Arenaviridae , a family that includes six additional biosafety level 4 (BSL4) hemorrhagic fever viruses. The lack of specific antiviral therapies for Lassa fever drives an urgent need to identify druggable targets, and interventions that block infection at the entry stage are particularly attractive. Lassa virus is only the second virus known to employ an intracellular receptor, the first being Ebola virus. Here we show that interaction with its intracellular receptor, Lamp1, enhances and upwardly shifts the pH dependence of fusion and consistently permits Lassa virus entry into cells through less acidic endosomes. We propose that in this manner, Lamp1 increases the overall efficiency of Lassa virus infection. Copyright © 2018 Hulseberg et al.

Lessons learnt from the management of a case of Lassa fever and follow-up of nosocomial primary contacts in Nigeria during Ebola virus disease outbreak in West Africa.

PubMed

Iroezindu, Michael O; Unigwe, Uche S; Okwara, Celestine C; Ozoh, Gladys A; Ndu, Anne C; Ohanu, Martin E; Nwoko, Ugochukwu O; Okoroafor, Uwadiegwu W; Ejimudo, Esinulo; Tobin, Ekaete A; Asogun, Danny A

2015-11-01

To describe our experiences in the management of a case of Lassa fever (LF) and follow-up of nosocomial primary contacts during the 2014 Ebola outbreak in West Africa. Clinical management of the index case and infection control/surveillance activities for primary contacts are described. Laboratory confirmation was by Lassa virus-specific reverse-transcriptase PCR. A 28-year-old man with a 10-day history of febrile illness was referred to a major tertiary hospital in south-east Nigeria from a city that previously experienced a LF outbreak and was recently affected by Ebola. On observation of haemorrhagic features, clinicians were at a crossroads. Diagnosis of LF was confirmed at a National Reference Centre. The patient died despite initiation of ribavirin therapy. Response activities identified 121 primary contacts comprising 78 (64.5%) hospital staff/interns, 19 (15.7%) medical students, 18 (14.9%) inpatients and 6 (5.0%) relatives. Their mean age was 32.8 ± 6.6 years, and 65.3% were women. Twenty (16.5%) had high-risk exposure and were offered ribavirin as post-exposure prophylaxis. No secondary case of LF occurred. Fatigue (43.8%) and dizziness (31.3%) were the commonest side effects of ribavirin. Response activities contained nosocomial spread of LF, but challenges were experienced including lack of a purpose-built isolation facility, absence of local Lassa virus laboratory capacity, failure to use appropriate protective equipment and stigmatisation of contacts. A key lesson is that the weak health systems of Africa should be comprehensively strengthened; otherwise, we might win the Ebola battle but lose the one against less virulent infections for which effective treatment exists. © 2015 John Wiley & Sons Ltd.

Therapeutic Efficacy of the Small Molecule GS-5734 against Ebola virus in Rhesus Monkeys

DTIC Science & Technology

2016-03-02

distribution to sanctuary sites for viral 46 replication including testes, eye , and brain. In a rhesus monkey model of EVD, once daily 47...including respiratory syncytial virus (RSV), Junin virus (JUNV), Lassa fever virus 121 (LASV) and Middle East respiratory syndrome virus (MERS), with...yellow fever virus, dengue virus type 2), parainfluenza type 3, and severe 124 acute respiratory syndrome (SARS) associated coronavirus but little or

Lassa hemorrhagic fever in a late term pregnancy from northern sierra leone with a positive maternal outcome: case report

PubMed Central

2011-01-01

Lassa fever (LF) is a devastating viral disease prevalent in West Africa. Efforts to take on this public health crisis have been hindered by lack of infrastructure and rapid field deployable diagnosis in areas where the disease is prevalent. Recent capacity building at the Kenema Government Hospital Lassa Fever Ward (KGH LFW) in Sierra Leone has lead to a major turning point in the diagnosis, treatment and study of LF. Herein we present the first comprehensive rapid diagnosis and real time characterization of an acute hemorrhagic LF case at KGH LFW. This case report focuses on a third trimester pregnant Sierra Leonean woman from the historically non-endemic Northern district of Tonkolili who survived the illness despite fetal demise. Employed in this study were newly developed recombinant LASV Antigen Rapid Test cassettes and dipstick lateral flow immunoassays (LFI) that enabled the diagnosis of LF within twenty minutes of sample collection. Deregulation of overall homeostasis, significant hepatic and renal system involvement, and immunity profiles were extensively characterized during the course of hospitalization. Rapid diagnosis, prompt treatment with a full course of intravenous (IV) ribavirin, IV fluids management, and real time monitoring of clinical parameters resulted in a positive maternal outcome despite admission to the LFW seven days post onset of symptoms, fetal demise, and a natural still birth delivery. These studies solidify the growing rapid diagnostic, treatment, and surveillance capabilities at the KGH LF Laboratory, and the potential to significantly improve the current high mortality rate caused by LF. As a result of the growing capacity, we were also able to isolate Lassa virus (LASV) RNA from the patient and perform Sanger sequencing where we found significant genetic divergence from commonly circulating Sierra Leonean strains, showing potential for the discovery of a newly emerged LASV strain with expanded geographic distribution. Furthermore, recent emergence of LF cases in Northern Sierra Leone highlights the need for superior diagnostics to aid in the monitoring of LASV strain divergence with potentially increased geographic expansion. PMID:21843352

Lassa hemorrhagic fever in a late term pregnancy from northern Sierra Leone with a positive maternal outcome: case report.

PubMed

Branco, Luis M; Boisen, Matt L; Andersen, Kristian G; Grove, Jessica N; Moses, Lina M; Muncy, Ivana J; Henderson, Lee A; Schieffellin, John S; Robinson, James E; Bangura, James J; Grant, Donald S; Raabe, Vanessa N; Fonnie, Mbalu; Zaitsev, Eleina M; Sabeti, Pardis C; Garry, Robert F

2011-08-15

Lassa fever (LF) is a devastating viral disease prevalent in West Africa. Efforts to take on this public health crisis have been hindered by lack of infrastructure and rapid field deployable diagnosis in areas where the disease is prevalent. Recent capacity building at the Kenema Government Hospital Lassa Fever Ward (KGH LFW) in Sierra Leone has lead to a major turning point in the diagnosis, treatment and study of LF. Herein we present the first comprehensive rapid diagnosis and real time characterization of an acute hemorrhagic LF case at KGH LFW. This case report focuses on a third trimester pregnant Sierra Leonean woman from the historically non-endemic Northern district of Tonkolili who survived the illness despite fetal demise. Employed in this study were newly developed recombinant LASV Antigen Rapid Test cassettes and dipstick lateral flow immunoassays (LFI) that enabled the diagnosis of LF within twenty minutes of sample collection. Deregulation of overall homeostasis, significant hepatic and renal system involvement, and immunity profiles were extensively characterized during the course of hospitalization. Rapid diagnosis, prompt treatment with a full course of intravenous (IV) ribavirin, IV fluids management, and real time monitoring of clinical parameters resulted in a positive maternal outcome despite admission to the LFW seven days post onset of symptoms, fetal demise, and a natural still birth delivery. These studies solidify the growing rapid diagnostic, treatment, and surveillance capabilities at the KGH LF Laboratory, and the potential to significantly improve the current high mortality rate caused by LF. As a result of the growing capacity, we were also able to isolate Lassa virus (LASV) RNA from the patient and perform Sanger sequencing where we found significant genetic divergence from commonly circulating Sierra Leonean strains, showing potential for the discovery of a newly emerged LASV strain with expanded geographic distribution. Furthermore, recent emergence of LF cases in Northern Sierra Leone highlights the need for superior diagnostics to aid in the monitoring of LASV strain divergence with potentially increased geographic expansion.

The threat of emerging infections.

PubMed

1996-11-01

A variety of newly discovered pathogens and new forms of older infectious agents threaten to reemerge. Typical symptoms of acute infection are fever, headache, malaise, vomiting, and diarrhea. Some of the better-known emerging viral infections include dengue, filoviruses (Ebola, Marburg), hantaviruses, hepatitis B, hepatitis C, HIV, influenza, lassa fever, measles, rift valley fever, rotavirus, and yellow fever. Emerging bacterial infections include cholera, Escherichia coli 0157:H7, legionnaires disease (Legionella), lyme disease, streptococcus infections (group A), tuberculosis, and typhoid. Emerging parasitic infections include cryptosporidium and other waterborne pathogens and malaria. The causes of many diseases are still shrouded in mystery; thus, treatments and cures for them are as yet unknown.

Geospatial Analysis of Urban Land Use Pattern Analysis for Hemorrhagic Fever Risk - a Review

NASA Astrophysics Data System (ADS)

Izzah, L. N.; Majid, Z.; Ariff, M. A. M.; Fook, C. K.

2016-09-01

Human modification of the natural environment continues to create habitats in which vectors of a wide variety of human and animal pathogens (such as Plasmodium, Aedes aegypti, Arenavirus etc.) thrive if unabated with an enormous potential to negatively affect public health. Typical examples of these modifications include impoundments, dams, irrigation systems, landfills and so on that provide enabled environment for the transmission of Hemorrhagic fever such as malaria, dengue, avian flu, Lassa fever etc. Furthermore, contemporary urban dwelling pattern appears to be associated with the prevalence of Hemorrhagic diseases in recent years. These observations are not peculiar to the developing world, as urban expansion also contributes significantly to mosquito and other vectors habitats. This habitats offer breeding ground to some vector virus populations. The key to disease control is developing an understanding of the contribution of human landscape modification to vector-borne pathogen transmission and how a balance may be achieved between human development, public health, and responsible urban land use. A comprehensive review of urban land use Pattern Analysis for Hemorrhagic fever risk has been conducted in this paper. The study found that most of the available literatures dwell more on the impact of urban land use on malaria and dengue fevers; however, studies are yet to be found discussing the implications of urban land use on the risk of Ebola, Lassa and other non-mosquito borne VHFs. A relational model for investigating the influence of urban land use change pattern on the risk of Hemorrhagic fever has been proposed in this study.

Development and validation of serological assays for viral hemorrhagic fevers and determination of the prevalence of Rift Valley fever in Borno State, Nigeria.

PubMed

Bukbuk, David Nadeba; Fukushi, Shuetsu; Tani, Hideki; Yoshikawa, Tomoki; Taniguchi, Satoshi; Iha, Koichiro; Fukuma, Aiko; Shimojima, Masayuki; Morikawa, Shigeru; Saijo, Masayuki; Kasolo, Francis; Baba, Saka Saheed

2014-12-01

Rift Valley fever (RVF) is endemic to the tropical regions of eastern and southern Africa. The seroprevalence of RVF was investigated among the human population in Borno State, Nigeria to determine the occurrence of the disease in the study area in comparison with that of Lassa fever and Crimean-Congo Hemorrhagic fever. Recombinant nucleoprotein (rNP)-based IgG-ELISAs for the detection of serum antibodies against RVF virus (RVFV), Lassa fever virus (LASV), and Crimean-Congo hemorrhagic fever virus (CCHFV) were used to test human sera in Borno State, Nigeria. The presence of neutralizing antibody against the RVFV-glycoprotein-bearing vesicular stomatitis virus pseudotype (RVFVpv) was also determined in the human sera. Of the 297 serum samples tested, 42 (14.1%) were positive for the presence of RVFV-IgG and 22 (7.4%) and 7 (2.4%) of the serum samples were positive for antibodies against LASV and CCHFV, respectively. There was a positive correlation between the titers of neutralizing antibodies obtained using RVFVpv and those obtained using the conventional neutralization assay with the attenuated RVFV-MP12 strain. The seroprevalence of RVF was significantly higher than that of LASV and CCHF in Borno State, Nigeria. The RVFVpv-based neutralization assay developed in this study has the potential to replace the traditional assays based on live viruses for the diagnosis and seroepidemiological studies of RVF. © The Author 2014. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Crystal Structure of the Oligomeric Form of Lassa Virus Matrix Protein Z.

PubMed

Hastie, Kathryn M; Zandonatti, Michelle; Liu, Tong; Li, Sheng; Woods, Virgil L; Saphire, Erica Ollmann

2016-05-01

The arenavirus matrix protein Z is highly multifunctional and occurs in both monomeric and oligomeric forms. The crystal structure of a dodecamer of Z from Lassa virus, presented here, illustrates a ring-like structure with a highly basic center. Mutagenesis demonstrates that the dimeric interface within the dodecamer and a Lys-Trp-Lys triad at the center of the ring are important for oligomerization. This structure provides an additional template to explore the many functions of Z. The arenavirus Lassa virus causes hundreds of thousands of infections each year, many of which develop into fatal hemorrhagic fever. The arenavirus matrix protein Z is multifunctional, with at least four distinct roles. Z exists in both monomeric and oligomeric forms, each of which likely serves a specific function in the viral life cycle. Here we present the dodecameric form of Lassa virus Z and demonstrate that Z forms a "wreath" with a highly basic center. This structure and that of monomeric Z now provide a pair of critical templates by which the multiple roles of Z in the viral life cycle may be interpreted. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

25-Hydroxycholesterol Inhibition of Lassa Virus Infection through Aberrant GP1 Glycosylation.

PubMed

Shrivastava-Ranjan, Punya; Bergeron, Éric; Chakrabarti, Ayan K; Albariño, César G; Flint, Mike; Nichol, Stuart T; Spiropoulou, Christina F

2016-12-20

Lassa virus (LASV) infection is a major public health concern due to high fatality rates and limited effective treatment. The interferon-stimulated gene cholesterol 25-hydroxylase (CH25H) encodes an enzyme that catalyzes the production of 25-hydroxycholesterol (25HC). 25HC is involved in regulating cholesterol biosynthesis and has recently been identified as a potent antiviral targeting enveloped virus entry. Here, we show a previously unrecognized role of CH25H in inhibiting LASV glycoprotein glycosylation and the production of infectious virus. Overexpression of CH25H or treatment with 25HC decreased LASV G1 glycoprotein N-glycan maturation and reduced the production of infectious LASV. Depletion of endogenous CH25H using small interfering RNA (siRNA) enhanced the levels of fully glycosylated G1 and increased infectious LASV production. Finally, LASV particles produced from 25HC-treated cells were found to be less infectious, to incorporate aberrantly glycosylated GP1 species, and to be defective in binding alpha-dystroglycan, an attachment and entry receptor. Our findings identify a novel role for CH25H in controlling LASV propagation and indicate that manipulation of the expression of CH25H or the administration of 25HC may be a useful anti-LASV therapy. Lassa fever is an acute viral hemorrhagic fever in humans caused by Lassa virus (LASV). No vaccine for LASV is currently available. Treatment is limited to the administration of ribavirin, which is only effective when given early in the course of illness. Cholesterol 25-hydroxylase (CH25H) is a recently identified interferon-stimulated gene (ISG); it encodes an enzyme that catalyzes the production of 25-hydroxycholesterol (25HC), which inhibits several viruses. Here, we identify a novel antiviral mechanism of 25HC that is dependent on inhibiting the glycosylation of Lassa virus (LASV) glycoprotein and reducing the infectivity of LASV as a means of suppressing viral replication. Since N-linked glycosylation is a critical feature of other enveloped-virus glycoproteins, 25HC may be a broad inhibitor of virus infectivity. Copyright © 2016 Shrivastava-Ranjan et al.

Laboratory Diagnosis of Lassa Fever

DTIC Science & Technology

2017-01-30

this type of document. You can upgrade to the latest version of Adobe Reader for Windows®, Mac, or Linux® by visiting http://www.adobe.com/ go ...reader_download. For more assistance with Adobe Reader visit http://www.adobe.com/ go /acrreader. Windows is either a registered trademark or a

Shedding of soluble glycoprotein 1 detected during acute Lassa virus infection in human subjects

PubMed Central

2010-01-01

Background Lassa hemorrhagic fever (LHF) is a neglected tropical disease with significant impact on the health care system, society, and economy of Western and Central African nations where it is endemic. With a high rate of infection that may lead to morbidity and mortality, understanding how the virus interacts with the host's immune system is of great importance for generating vaccines and therapeutics. Previous work by our group identified a soluble isoform of the Lassa virus (LASV) GP1 (sGP1) in vitro resulting from the expression of the glycoprotein complex (GPC) gene [1,2]. Though no work has directly been done to demonstrate the function of this soluble isoform in arenaviral infections, evidence points to immunomodulatory effects against the host's immune system mediated by a secreted glycoprotein component in filoviruses, another class of hemorrhagic fever-causing viruses. A significant fraction of shed glycoprotein isoforms during viral infection and biogenesis may attenuate the host's inflammatory response, thereby enhancing viral replication and tissue damage. Such shed glycoprotein mediated effects were previously reported for Ebola virus (EBOV), a filovirus that also causes hemorrhagic fever with nearly 90% fatality rates [3-5]. The identification of an analogous phenomenon in vivo could establish a new correlate of LHF infection leading to the development of sensitive diagnostics targeting the earliest molecular events of the disease. Additionally, the reversal of potentially untoward immunomodulatory functions mediated by sGP1 could potentiate the development of novel therapeutic intervention. To this end, we investigated the presence of sGP1 in the serum of suspected LASV patients admitted to the Kenema Government Hospital (KGH) Lassa Fever Ward (LFW), in Kenema, Sierra Leone that tested positive for viral antigen or displayed classical signs of Lassa fever. Results It is reasonable to expect that a narrow window exists for detection of sGP1 as the sole protein shed during early arenaviral biogenesis. This phenomenon was clearly distinguishable from virion-associated GP1 only prior to the emergence of de novo viral particles. Despite this restricted time frame, in 2/46 suspected cases in two studies performed in late 2009 and early 2010, soluble glycoprotein component shedding was identified. Differential detection of viral antigens GP1, GP2, and NP by western blot yielded five different scenarios: whole LASV virions (GP1, GP2, NP; i.e. active viremia), different combinations of these three proteins, sGP1 only, NP only, and absence of all three proteins. Four additional samples showed inconclusive evidence for sGP1 shedding due to lack of detection of GP2 and NP by western blot; however, a sensitive LASV NP antigen capture ELISA generated marginally positive signals Conclusions During a narrow window following active infection with LASV, soluble GP1 can be detected in patient sera. This phenomenon parallels other VHF infection profiles, with the actual role of a soluble viral glycoprotein component in vivo remaining largely speculative. The expenditure of energy and cellular resources toward secretion of a critical protein during viral biogenesis without apparent specific function requires further investigation. Future studies will be aimed at systematically identifying the role of LASV sGP1 in the infection process and outcome in vitro and in vivo. PMID:21062490

Shedding of soluble glycoprotein 1 detected during acute Lassa virus infection in human subjects.

PubMed

Branco, Luis M; Grove, Jessica N; Moses, Lina M; Goba, Augustine; Fullah, Mohammed; Momoh, Mambu; Schoepp, Randal J; Bausch, Daniel G; Garry, Robert F

2010-11-09

Lassa hemorrhagic fever (LHF) is a neglected tropical disease with significant impact on the health care system, society, and economy of Western and Central African nations where it is endemic. With a high rate of infection that may lead to morbidity and mortality, understanding how the virus interacts with the host's immune system is of great importance for generating vaccines and therapeutics. Previous work by our group identified a soluble isoform of the Lassa virus (LASV) GP1 (sGP1) in vitro resulting from the expression of the glycoprotein complex (GPC) gene [1, 2]. Though no work has directly been done to demonstrate the function of this soluble isoform in arenaviral infections, evidence points to immunomodulatory effects against the host's immune system mediated by a secreted glycoprotein component in filoviruses, another class of hemorrhagic fever-causing viruses. A significant fraction of shed glycoprotein isoforms during viral infection and biogenesis may attenuate the host's inflammatory response, thereby enhancing viral replication and tissue damage. Such shed glycoprotein mediated effects were previously reported for Ebola virus (EBOV), a filovirus that also causes hemorrhagic fever with nearly 90 percent fatality rates [3 - 5]. The identification of an analogous phenomenon in vivo could establish a new correlate of LHF infection leading to the development of sensitive diagnostics targeting the earliest molecular events of the disease. Additionally, the reversal of potentially untoward immunomodulatory functions mediated by sGP1 could potentiate the development of novel therapeutic intervention. To this end, we investigated the presence of sGP1 in the serum of suspected LASV patients admitted to the Kenema Government Hospital (KGH) Lassa Fever Ward (LFW), in Kenema, Sierra Leone that tested positive for viral antigen or displayed classical signs of Lassa fever. It is reasonable to expect that a narrow window exists for detection of sGP1 as the sole protein shed during early arenaviral biogenesis. This phenomenon was clearly distinguishable from virion-associated GP1 only prior to the emergence of de novo viral particles. Despite this restricted time frame, in 2/46 suspected cases in two studies performed in late 2009 and early 2010, soluble glycoprotein component shedding was identified. Differential detection of viral antigens GP1, GP2, and NP by western blot yielded five different scenarios: whole LASV virions (GP1, GP2, NP; i.e. active viremia), different combinations of these three proteins, sGP1 only, NP only, and absence of all three proteins. Four additional samples showed inconclusive evidence for sGP1 shedding due to lack of detection of GP2 and NP in western blot; however, a sensitive LASV NP antigen capture ELISA generated marginally positive signals. During a narrow window following active infection with LASV, soluble GP1 can be detected in patient sera. This phenomenon parallels other VHF infection profiles, with the actual role of a soluble viral glycoprotein component in vivo remaining largely speculative. The expenditure of energy and cellular resources toward secretion of a critical protein during viral biogenesis without apparent specific function requires further investigation. Future studies will be aimed at systematically identifying the role of LASV sGP1 in the infection process and outcome in vitro and in vivo.

No measurable adverse effects of Lassa, Morogoro and Gairo arenaviruses on their rodent reservoir host in natural conditions.

PubMed

Mariën, Joachim; Borremans, Benny; Gryseels, Sophie; Soropogui, Barré; De Bruyn, Luc; Bongo, Gédéon Ngiala; Becker-Ziaja, Beate; de Bellocq, Joëlle Goüy; Günther, Stephan; Magassouba, N'Faly; Leirs, Herwig; Fichet-Calvet, Elisabeth

2017-04-27

In order to optimize net transmission success, parasites are hypothesized to evolve towards causing minimal damage to their reservoir host while obtaining high shedding rates. For many parasite species however this paradigm has not been tested, and conflicting results have been found regarding the effect of arenaviruses on their rodent host species. The rodent Mastomys natalensis is the natural reservoir host of several arenaviruses, including Lassa virus that is known to cause Lassa haemorrhagic fever in humans. Here, we examined the effect of three arenaviruses (Gairo, Morogoro and Lassa virus) on four parameters of wild-caught Mastomys natalensis: body mass, head-body length, sexual maturity and fertility. After correcting for the effect of age, we compared these parameters between arenavirus-positive (arenavirus RNA or antibody) and negative animals using data from different field studies in Guinea (Lassa virus) and Tanzania (Morogoro and Gairo viruses). Although the sample sizes of our studies (1297, 749 and 259 animals respectively) were large enough to statistically detect small differences in body conditions, we did not observe any adverse effects of these viruses on Mastomys natalensis. We did find that sexual maturity was significantly positively related with Lassa virus antibody presence until a certain age, and with Gairo virus antibody presence in general. Gairo virus antibody-positive animals were also significantly heavier and larger than antibody-free animals. Together, these results suggest that the pathogenicity of arenaviruses is not severe in M. natalensis, which is likely to be an adaptation of these viruses to optimize transmission success. They also suggest that sexual behaviour might increase the probability of M. natalensis to become infected with arenaviruses.

Baseline mapping of Lassa fever virology, epidemiology and vaccine research and development.

PubMed

Hallam, Hoai J; Hallam, Steven; Rodriguez, Sergio E; Barrett, Alan D T; Beasley, David W C; Chua, Arlene; Ksiazek, Thomas G; Milligan, Gregg N; Sathiyamoorthy, Vaseeharan; Reece, Lisa M

2018-01-01

Lassa fever (LF) is a zoonotic disease associated with acute and potentially fatal hemorrhagic illness caused by the Lassa virus (LASV), a member of the family Arenaviridae . It is generally assumed that a single infection with LASV will produce life-long protective immunity. This suggests that protective immunity induced by vaccination is an achievable goal and that cell-mediated immunity may play a more important role in protection, at least following natural infection. Seropositive individuals in endemic regions have been shown to have LASV-specific T cells recognizing epitopes for nucleocapsid protein (NP) and glycoprotein precursor (GPC), suggesting that these will be important vaccine immunogens. The role of neutralizing antibodies in protective immunity is still equivocal as recent studies suggest a role for neutralizing antibodies. There is extensive genetic heterogeneity among LASV strains that is of concern in the development of assays to detect and identify all four LASV lineages. Furthermore, the gene disparity may complicate the synthesis of effective vaccines that will provide protection across multiple lineages. Non-human primate models of LASV infection are considered the gold standard for recapitulation of human LF. The most promising vaccine candidates to date are the ML29 (a live attenuated reassortant of Mopeia and LASV), vesicular stomatitis virus (VSV) and vaccinia-vectored platforms based on their ability to induce protection following single doses, high rates of survival following challenge, and the use of live virus platforms. To date no LASV vaccine candidates have undergone clinical evaluation.

Molecular determinants of Pichinde virus infection of guinea pigs--a small animal model system for arenaviral hemorrhagic fevers.

PubMed

Liang, Yuying; Lan, Shuiyun; Ly, Hinh

2009-09-01

Arenaviruses are enveloped single-strand RNA viruses that mostly have natural hosts in rodents. Upon infection of humans, several arenaviruses can cause severe hemorrhagic fever diseases, including Lassa fever that is endemic in West Africa. The virulence mechanism of these deadly arenaviruses can be studied in a safe and economical small animal model-guinea pigs infected by a nonpathogenic arenavirus Pichinde virus (PICV), a virulent strain of which can cause similar disease syndromes in guinea pigs as arenaviral hemorrhagic fevers in humans. We have recently developed molecular clones for both the virulent and avirulent strains of PICV. Using the available reverse genetics tools, we are characterizing the molecular determinants of virulent arenavirus infections in vivo.

Emerging infectious diseases: Focus on infection control issues for novel coronaviruses (Severe Acute Respiratory Syndrome-CoV and Middle East Respiratory Syndrome-CoV), hemorrhagic fever viruses (Lassa and Ebola), and highly pathogenic avian influenza viruses, A(H5N1) and A(H7N9).

PubMed

Weber, David J; Rutala, William A; Fischer, William A; Kanamori, Hajime; Sickbert-Bennett, Emily E

2016-05-02

Over the past several decades, we have witnessed the emergence of many new infectious agents, some of which are major public threats. New and emerging infectious diseases which are both transmissible from patient-to-patient and virulent with a high mortality include novel coronaviruses (SARS-CoV, MERS-CV), hemorrhagic fever viruses (Lassa, Ebola), and highly pathogenic avian influenza A viruses, A(H5N1) and A(H7N9). All healthcare facilities need to have policies and plans in place for early identification of patients with a highly communicable diseases which are highly virulent, ability to immediately isolate such patients, and provide proper management (e.g., training and availability of personal protective equipment) to prevent transmission to healthcare personnel, other patients and visitors to the healthcare facility. Copyright © 2016 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved.

Multiple Circulating Infections Can Mimic the Early Stages of Viral Hemorrhagic Fevers and Possible Human Exposure to Filoviruses in Sierra Leone Prior to the 2014 Outbreak

PubMed Central

Boisen, Matthew L.; Schieffelin, John S.; Goba, Augustine; Oottamasathien, Darin; Jones, Abigail B.; Shaffer, Jeffrey G.; Hastie, Kathryn M.; Hartnett, Jessica N.; Momoh, Mambu; Fullah, Mohammed; Gabiki, Michael; Safa, Sidiki; Zandonatti, Michelle; Fusco, Marnie; Bornholdt, Zach; Abelson, Dafna; Gire, Stephen K.; Andersen, Kristian G.; Tariyal, Ridhi; Stremlau, Mathew; Cross, Robert W.; Geisbert, Joan B.; Pitts, Kelly R.; Geisbert, Thomas W.; Kulakoski, Peter; Wilson, Russell B.; Henderson, Lee; Sabeti, Pardis C.; Grant, Donald S.; Garry, Robert F.; Saphire, Erica O.; Khan, Sheik Humarr

2015-01-01

Abstract Lassa fever (LF) is a severe viral hemorrhagic fever caused by Lassa virus (LASV). The LF program at the Kenema Government Hospital (KGH) in Eastern Sierra Leone currently provides diagnostic services and clinical care for more than 500 suspected LF cases per year. Nearly two-thirds of suspected LF patients presenting to the LF Ward test negative for either LASV antigen or anti-LASV immunoglobulin M (IgM), and therefore are considered to have a non-Lassa febrile illness (NLFI). The NLFI patients in this study were generally severely ill, which accounts for their high case fatality rate of 36%. The current studies were aimed at determining possible causes of severe febrile illnesses in non-LF cases presenting to the KGH, including possible involvement of filoviruses. A seroprevalence survey employing commercial enzyme-linked immunosorbent assay tests revealed significant IgM and IgG reactivity against dengue virus, chikungunya virus, West Nile virus (WNV), Leptospira, and typhus. A polymerase chain reaction–based survey using sera from subjects with acute LF, evidence of prior LASV exposure, or NLFI revealed widespread infection with Plasmodium falciparum malaria in febrile patients. WNV RNA was detected in a subset of patients, and a 419 nt amplicon specific to filoviral L segment RNA was detected at low levels in a single patient. However, 22% of the patients presenting at the KGH between 2011 and 2014 who were included in this survey registered anti-Ebola virus (EBOV) IgG or IgM, suggesting prior exposure to this agent. The 2014 Ebola virus disease (EVD) outbreak is already the deadliest and most widely dispersed outbreak of its kind on record. Serological evidence reported here for possible human exposure to filoviruses in Sierra Leone prior to the current EVD outbreak supports genetic analysis that EBOV may have been present in West Africa for some time prior to the 2014 outbreak. PMID:25531344

Evaluation of Lassa Antiviral Compound ST-193 in a Guinea Pig Model

PubMed Central

Cashman, Kathleen A.; Smith, Mark A.; Twenhafel, Nancy A.; Larson, Ryan A.; Jones, Kevin F.; Allen, Robert D.; Dai, Dongcheng; Chinsangaram, Jarasvech; Bolken, Tove’ C.; Hruby, Dennis E.; Amberg, Sean M.; Hensley, Lisa E.; Guttieri, Mary C.

2012-01-01

Lassa virus (LASV), a member of the Arenaviridae family, causes a viral hemorrhagic fever endemic to West Africa, where as many as 300,000 infections occur per year. Presently, there are no FDA-approved LASV-specific vaccines or antiviral agents, although the antiviral drug ribavirin has shown some efficacy. A recently identified small-molecule inhibitor of arenavirus entry, ST-193, exhibits submicromolar antiviral activity in vitro. To determine the antiviral utility of ST-193 in vivo, we tested the efficacy of this compound in the LASV guinea pig model. Four groups of strain 13 guinea pigs were administered 25 or 80 mg/kg ST-193, 25 mg/kg of ribavirin, or the vehicle by the intraperitoneal (i.p.) route before infection with a lethal dose of LASV, strain Josiah, and continuing once daily for 14 days. Control animals exhibited severe disease, becoming moribund between days 10 and 15 postinfection. ST-193-treated animals exhibited fewer signs of disease and enhanced survival when compared to the ribavirin or vehicle groups. Body temperatures in all groups were elevated by day 9, but returned to normal by day 19 postinfection in the majority of ST-193-treated animals. ST-193 treatment mediated a 2- to 3-log reduction in viremia relative to vehicle-treated controls. The overall survival rate for the ST-193-treated guinea pigs was 62.5% (10/16) compared with 0% in the ribavirin (0/8) and vehicle (0/7) groups. These data suggest that ST-193 may serve as an improved candidate for the treatment of Lassa fever. PMID:21371508

Immunology and Pathology of Arena Virus Infections.

DTIC Science & Technology

1992-04-15

histopathologic findings; hepatic inflammation, steatosis , lymph node sinus histiocytosis, pneumonitis etc., appeared to be distributed evenly among the two...administration (Tracey, 1988). TNF has been shown to induce hepatic lipogenesis (Feingold, 1987), correlating with the impressive histologic fatty change seen...D. (1990) Lassa Fever. Br. J. Hosp. Med. 43: 186-191. Feingold, K.R., and C. Grunfeld. (1987) Tumor Necrosis Factor Alpha stimulates hepatic

Vaccines for Viral Hemorrhagic Fevers – Progress and Shortcomings

PubMed Central

Falzarano, Darryl; Feldmann, Heinz

2013-01-01

With a few exceptions, vaccines for viruses that cause hemorrhagic fever remain unavailable or lack well-documented efficacy. In the past decade this has not been due to a lack of the ability to develop vaccine platforms against highly pathogenic viruses, but rather the lack of will/interest to invest in platforms that have the potential to become successful vaccines. The two exceptions to this are vaccines against Dengue virus and Rift Valley Fever virus, which recently have seen significant progress in putting forward new and improved vaccines, respectively. Experimental vaccines for filoviruses and Lassa virus do exist but are hindered by a lack of financial interest and only partially or ill-defined correlates/mechanisms of protection that could be assessed in clinical trials. PMID:23773330

The impact of human conflict on the genetics of Mastomys natalensis and Lassa virus in West Africa.

PubMed

Lalis, Aude; Leblois, Raphaël; Lecompte, Emilie; Denys, Christiane; Ter Meulen, Jan; Wirth, Thierry

2012-01-01

Environmental changes have been shown to play an important role in the emergence of new human diseases of zoonotic origin. The contribution of social factors to their spread, especially conflicts followed by mass movement of populations, has not been extensively investigated. Here we reveal the effects of civil war on the phylogeography of a zoonotic emerging infectious disease by concomitantly studying the population structure, evolution and demography of Lassa virus and its natural reservoir, the rodent Mastomys natalensis, in Guinea, West Africa. Analysis of nucleoprotein gene sequences enabled us to reconstruct the evolutionary history of Lassa virus, which appeared 750 to 900 years ago in Nigeria and only recently spread across western Africa (170 years ago). Bayesian demographic inferences revealed that both the host and the virus populations have gone recently through severe genetic bottlenecks. The timing of these events matches civil war-related mass movements of refugees and accompanying environmental degradation. Forest and habitat destruction and human predation of the natural reservoir are likely explanations for the sharp decline observed in the rodent populations, the consequent virus population decline, and the coincident increased incidence of Lassa fever in these regions. Interestingly, we were also able to detect a similar pattern in Nigeria coinciding with the Biafra war. Our findings show that anthropogenic factors may profoundly impact the population genetics of a virus and its reservoir within the context of an emerging infectious disease.

Occupational hazards in hospitals: risk of infection.

PubMed Central

Gestal, J J

1987-01-01

In this review of the risk of infection to hospital staff, attention is drawn to the continuing risk presented by hepatitis B and pulmonary tuberculosis, which are more common than diseases such as typhoid fever, brucellosis, histoplasmosis, whooping cough, infectious gastroenteritis, measles, and parotiditis. Other items considered include the susceptibility of female hospital staff to rubella and the importance of their undergoing screening and vaccination; the risks currently presented by epidemic keratoconjunctivitis and by herpes viruses (herpes simplex, varicella zoster, and cytomegalovirus); and the risk of contracting the new infectious diseases (Legionnaires' disease, Marburg disease, Lassa fever, and the acquired immune deficiency syndrome). PMID:3304395

Categorizing Weapons of Mass Destruction Biological Agents into Postmortem Risk Groups

DTIC Science & Technology

2012-12-20

toxin  •Marburg  • Smallpox  •Brucellosis  •Melioidosis  • Staphylococcal Entertoxin B (SEB)  •Chikungunya  •Mycotoxins  • Tularemia   •Cholera...Marburg, 9.0 Saxitoxin, 6.25   Lassa fever, 8.75 VEE, 6.0   vCJD, 8.75 WEE, 6.0   Smallpox, 8.5 Tularemia , 6.0   Botulinum toxin, 7.75 Junin/Marchupo...WEE, 5.0     VEE, 5.0     Tularemia , 5.0     Junin/Marchupo, 5.0      Ricin, 4.75     Q fever, 4.75     Rift Valley Fever, 4.75      Mycotoxins

[Countermeasure against viral hemorrhagic fever at the border in Japan].

PubMed

Iwasaki, Emiko

2005-12-01

Human have struggled against many infectious diseases such as cholera, plague, dysentery and yellow fever for a long time. And we have spent a lot of energy to control these infectious diseases and developed various tool for them. One of these efforts was Quarantine system that was established in 14th century in Europe. But during recent days, we are suffering from newly emerged diseases. These new infectious diseases are zoonosis and most of them are serious and highly infectious. Viral hemorrhagic fever such as Ebola hemorrhagic fever, Marburg hemorrhagic fever and Lassa fever are typical these emerging serious diseases, and these outbreak always have occurred in Africa and neighboring countries. Fortunately we have never experienced any case, but as these diseases are so serious, we are so nervous diseases entering in Japan. Against these serious diseases, in Japan, Quarantine Station are doing screening examination at airport and port by questionnaire and measuring body temperature, because these viral hemorrhagic fever patients show high fever. If people were suspected viral hemorrhagic fever at Quarantine Station at the border, they will be leaded to hospital for further examination and treatment as soon as possible.

Constraints in the diagnosis and treatment of Lassa Fever and the effect on mortality in hospitalized children and women with obstetric conditions in a rural district hospital in Sierra Leone.

PubMed

Dahmane, A; van Griensven, J; Van Herp, M; Van den Bergh, R; Nzomukunda, Y; Prior, J; Alders, P; Jambai, A; Zachariah, R

2014-03-01

Lassa fever (LF) is an acute viral haemorrhagic infection, endemic in West Africa. Confirmatory diagnosis and treatment (ribavirin) is difficult, expensive, and restricted to specialised hospitals. Among confirmed and suspected LF cases, we report on clinical and laboratory features, timing and administration of ribavirin and the relationship with case fatality. We conducted an audit of patient files of suspected LF cases admitted to a pediatric and obstetric referral hospital in rural Sierra Leone (April 2011 to February 2012). There were 84 suspected LF cases; 36 (43%) were laboratory-confirmed cases, of whom only 20 (56%) received ribavirin after a median duration of eight days (IQR 314 days) of hospital admission. Of 16 patients who did not receive ribavirin, 14 (87%) died before ribavirin treatment could be commenced. Starting ribavirin within six days of admission was associated with a case fatality of 29% (2/7), while starting ribavirin later than six days was associated with a case fatality of 50% (6/12). Among the 48 suspected LF cases without laboratory confirmation, there were 21 (44%) deaths. These findings highlight shortcomings in LF management, including diagnostic and treatment delays. More research and development efforts should be devoted to this 'neglected disease'.

Clinical Sequencing Uncovers Origins and Evolution of Lassa Virus.

PubMed

Andersen, Kristian G; Shapiro, B Jesse; Matranga, Christian B; Sealfon, Rachel; Lin, Aaron E; Moses, Lina M; Folarin, Onikepe A; Goba, Augustine; Odia, Ikponmwonsa; Ehiane, Philomena E; Momoh, Mambu; England, Eleina M; Winnicki, Sarah; Branco, Luis M; Gire, Stephen K; Phelan, Eric; Tariyal, Ridhi; Tewhey, Ryan; Omoniwa, Omowunmi; Fullah, Mohammed; Fonnie, Richard; Fonnie, Mbalu; Kanneh, Lansana; Jalloh, Simbirie; Gbakie, Michael; Saffa, Sidiki; Karbo, Kandeh; Gladden, Adrianne D; Qu, James; Stremlau, Matthew; Nekoui, Mahan; Finucane, Hilary K; Tabrizi, Shervin; Vitti, Joseph J; Birren, Bruce; Fitzgerald, Michael; McCowan, Caryn; Ireland, Andrea; Berlin, Aaron M; Bochicchio, James; Tazon-Vega, Barbara; Lennon, Niall J; Ryan, Elizabeth M; Bjornson, Zach; Milner, Danny A; Lukens, Amanda K; Broodie, Nisha; Rowland, Megan; Heinrich, Megan; Akdag, Marjan; Schieffelin, John S; Levy, Danielle; Akpan, Henry; Bausch, Daniel G; Rubins, Kathleen; McCormick, Joseph B; Lander, Eric S; Günther, Stephan; Hensley, Lisa; Okogbenin, Sylvanus; Schaffner, Stephen F; Okokhere, Peter O; Khan, S Humarr; Grant, Donald S; Akpede, George O; Asogun, Danny A; Gnirke, Andreas; Levin, Joshua Z; Happi, Christian T; Garry, Robert F; Sabeti, Pardis C

2015-08-13

The 2013-2015 West African epidemic of Ebola virus disease (EVD) reminds us of how little is known about biosafety level 4 viruses. Like Ebola virus, Lassa virus (LASV) can cause hemorrhagic fever with high case fatality rates. We generated a genomic catalog of almost 200 LASV sequences from clinical and rodent reservoir samples. We show that whereas the 2013-2015 EVD epidemic is fueled by human-to-human transmissions, LASV infections mainly result from reservoir-to-human infections. We elucidated the spread of LASV across West Africa and show that this migration was accompanied by changes in LASV genome abundance, fatality rates, codon adaptation, and translational efficiency. By investigating intrahost evolution, we found that mutations accumulate in epitopes of viral surface proteins, suggesting selection for immune escape. This catalog will serve as a foundation for the development of vaccines and diagnostics. VIDEO ABSTRACT. Copyright © 2015 Elsevier Inc. All rights reserved.

Clinical sequencing uncovers origins and evolution of Lassa virus

PubMed Central

Andersen, Kristian G.; Shapiro, B. Jesse; Matranga, Christian B.; Sealfon, Rachel; Lin, Aaron E.; Moses, Lina M.; Folarin, Onikepe A.; Goba, Augustine; Odia, Ikponmwonsa; Ehiane, Philomena E.; Momoh, Mambu; England, Eleina M.; Winnicki, Sarah; Branco, Luis M.; Gire, Stephen K.; Phelan, Eric; Tariyal, Ridhi; Tewhey, Ryan; Omoniwa, Omowunmi; Fullah, Mohammed; Fonnie, Richard; Fonnie, Mbalu; Kanneh, Lansana; Jalloh, Simbirie; Gbakie, Michael; Saffa, Sidiki; Karbo, Kandeh; Gladden, Adrianne D.; Qu, James; Stremlau, Matthew; Nekoui, Mahan; Finucane, Hilary K.; Tabrizi, Shervin; Vitti, Joseph J.; Birren, Bruce; Fitzgerald, Michael; McCowan, Caryn; Ireland, Andrea; Berlin, Aaron M.; Bochicchio, James; Tazon-Vega, Barbara; Lennon, Niall J.; Ryan, Elizabeth M.; Bjornson, Zach; Milner, Danny A.; Lukens, Amanda K.; Broodie, Nisha; Rowland, Megan; Heinrich, Megan; Akdag, Marjan; Schieffelin, John S.; Levy, Danielle; Akpan, Henry; Bausch, Daniel G.; Rubins, Kathleen; McCormick, Joseph B.; Lander, Eric S.; Günther, Stephan; Hensley, Lisa; Okogbenin, Sylvanus; Schaffner, Stephen F.; Okokhere, Peter O.; Khan, S. Humarr; Grant, Donald S.; Akpede, George O.; Asogun, Danny A.; Gnirke, Andreas; Levin, Joshua Z.; Happi, Christian T.; Garry, Robert F.; Sabeti, Pardis C.

2015-01-01

Summary The 2013-2015 West African epidemic of Ebola virus disease (EVD) reminds us how little is known about biosafety level-4 viruses. Like Ebola virus, Lassa virus (LASV) can cause hemorrhagic fever with high case fatality rates. We generated a genomic catalog of almost 200 LASV sequences from clinical and rodent reservoir samples. We show that whereas the 2013-2015 EVD epidemic is fueled by human-to-human transmissions, LASV infections mainly result from reservoir-to-human infections. We elucidated the spread of LASV across West Africa and show that this migration was accompanied by changes in LASV genome abundance, fatality rates, codon adaptation, and translational efficiency. By investigating intrahost evolution, we found that mutations accumulate in epitopes of viral surface proteins, suggesting selection for immune escape. This catalog will serve as a foundation for the development of vaccines and diagnostics. PMID:26276630

Sequence Variability and Geographic Distribution of Lassa Virus, Sierra Leone

PubMed Central

Stockelman, Michael G.; Moses, Lina M.; Park, Matthew; Stenger, David A.; Ansumana, Rashid; Bausch, Daniel G.; Lin, Baochuan

2015-01-01

Lassa virus (LASV) is endemic to parts of West Africa and causes highly fatal hemorrhagic fever. The multimammate rat (Mastomys natalensis) is the only known reservoir of LASV. Most human infections result from zoonotic transmission. The very diverse LASV genome has 4 major lineages associated with different geographic locations. We used reverse transcription PCR and resequencing microarrays to detect LASV in 41 of 214 samples from rodents captured at 8 locations in Sierra Leone. Phylogenetic analysis of partial sequences of nucleoprotein (NP), glycoprotein precursor (GPC), and polymerase (L) genes showed 5 separate clades within lineage IV of LASV in this country. The sequence diversity was higher than previously observed; mean diversity was 7.01% for nucleoprotein gene at the nucleotide level. These results may have major implications for designing diagnostic tests and therapeutic agents for LASV infections in Sierra Leone. PMID:25811712

Antibodies to the Glycoprotein GP2 Subunit Cross-React between Old and New World Arenaviruses.

PubMed

Amanat, Fatima; Duehr, James; Oestereich, Lisa; Hastie, Kathryn M; Ollmann Saphire, Erica; Krammer, Florian

2018-01-01

Arenaviruses pose a major public health threat and cause numerous infections in humans each year. Although most viruses belonging to this family do not cause disease in humans, some arenaviruses, such as Lassa virus and Machupo virus, are the etiological agents of lethal hemorrhagic fevers. The absence of a currently licensed vaccine and the highly pathogenic nature of these viruses both make the necessity of developing viable vaccines and therapeutics all the more urgent. Arenaviruses have a single glycoprotein on the surface of virions, the glycoprotein complex (GPC), and this protein can be used as a target for vaccine development. Here, we describe immunization strategies to generate monoclonal antibodies (MAbs) that cross-react between the glycoprotein complexes of both Old World and New World arenaviruses. Several monoclonal antibodies isolated from immunized mice were highly cross-reactive, binding a range of Old World arenavirus glycoproteins, including that of Lassa virus. One such monoclonal antibody, KL-AV-2A1, bound to GPCs of both New World and Old World viruses, including Lassa and Machupo viruses. These cross-reactive antibodies bound to epitopes present on the glycoprotein 2 subunit of the glycoprotein complex, which is relatively conserved among arenaviruses. Monoclonal antibodies binding to these epitopes, however, did not inhibit viral entry as they failed to neutralize a replication-competent vesicular stomatitis virus pseudotyped with the Lassa virus glycoprotein complex in vitro In addition, no protection from virus challenge was observed in in vivo mouse models. Even so, these monoclonal antibodies might still prove to be useful in the development of clinical and diagnostic assays. IMPORTANCE Several viruses in the Arenaviridae family infect humans and cause severe hemorrhagic fevers which lead to high case fatality rates. Due to their pathogenicity and geographic tropisms, these viruses remain very understudied. As a result, an effective vaccine or therapy is urgently needed. Here, we describe efforts to produce cross-reactive monoclonal antibodies that bind to both New and Old World arenaviruses. All of our MAbs seem to be nonneutralizing and nonprotective and target subunit 2 of the glycoprotein. Due to the lack of reagents such as recombinant glycoproteins and antibodies for rapid detection assays, our MAbs could be beneficial as analytic and diagnostic tools. Copyright © 2018 Amanat et al.

Mechanisms and Consequences of Ebolavirus-Induced Lymphocyte Apoptosis

DTIC Science & Technology

2010-01-01

apoptosis. Journal of Immunology 184:327-335 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR (S) Bradfute, SB Swanson, PE...R.S.H.) and 4.10022_08_RD_B (to S.B.). Opinions, interpretations, conclusions, and recommendations are those of the authors and are not necessarily...viruses, in- cluding Lassa, Marburg, Crimean Congo hemorrhagic fever, and some Hantavirus infections. However, no studies to our knowledge have

Vaccine Platforms to Control Arenaviral Hemorrhagic Fevers.

PubMed

Carrion, Ricardo; Bredenbeek, Peter; Jiang, Xiaohong; Tretyakova, Irina; Pushko, Peter; Lukashevich, Igor S

2012-11-20

Arenaviruses are rodent-borne emerging human pathogens. Diseases caused by these viruses, e.g., Lassa fever (LF) in West Africa and South American hemorrhagic fevers (HFs), are serious public health problems in endemic areas. We have employed replication-competent and replication-deficient strategies to design vaccine candidates potentially targeting different groups "at risk". Our leader LF vaccine candidate, the live reassortant vaccine ML29, is safe and efficacious in all tested animal models including non-human primates. In this study we showed that treatment of fatally infected animals with ML29 two days after Lassa virus (LASV) challenge protected 80% of the treated animals. In endemic areas, where most of the target population is poor and many live far from health care facilities, a single-dose vaccination with ML29 would be ideal solution. Once there is an outbreak, a fast-acting vaccine or post-exposure prophylaxis would be best. The 2(nd) vaccine technology is based on Yellow Fever (YF) 17D vaccine. We designed YF17D-based recombinant viruses expressing LASV glycoproteins (GP) and showed protective efficacy of these recombinants. In the current study we developed a novel technology to clone LASV nucleocapsid within YF17D C gene. Low immunogenicity and stability of foreign inserts must be addressed to design successful LASV/YFV bivalent vaccines to control LF and YF in overlapping endemic areas of West Africa. The 3(rd) platform is based on the new generation of alphavirus replicon virus-like-particle vectors (VLPV). Using this technology we designed VLPV expressing LASV GP with enhanced immunogenicity and bivalent VLPV expressing cross-reactive GP of Junin virus (JUNV) and Machupo virus (MACV), causative agents of Argentinian and Bolivian HF, respectively. A prime-boost regimen required for VLPV immunization might be practical for medical providers, military, lab personnel, and visitors in endemic areas.

Rapid Generation and Testing of a Lassa Fever Vaccine Using VaxCelerate Platform

DTIC Science & Technology

2014-08-28

essentially the same way each time but is capable to producing effective vaccine responses to a range of pathogens, and to do this without the use of...this distributed vaccine development consortium to rapidly produce and test a novel vaccine of relevance to public health responses. In parallel...with this effort, the consortium produced and tested a modified version of its self-assembling vaccine protein that used a subunit of the full

IGG Subclass and Isotype Specific Immunoglobulin Responses to Lassa Fever and Venezuelan Equine Encephalomyelitis: Natural Infection and Immunization

DTIC Science & Technology

1990-09-30

EQUINE N ENCEPHALOMYELITIS: NATURAL INFECTION AND IMMUNIZATION , I PRINCIPAL INVESTIGATOR: Renata J. Engler, LTC, MC CONTRACTING ORGANIZATION: Uniformed...Services University of the Health Sciences Department of Medicine Bethesda, MD 20814-4799 REPORT DATE: September 30, 1990 ELECTEO 0CT 3 11990 TYPE OF...Uniformed Services University (If applicable) of Health Sciences I 6c. ADDRESS (City, State, and ZIP Code) 7b. ADDRESS (City, State, and ZIP Code

Constraints in the diagnosis and treatment of Lassa Fever and the effect on mortality in hospitalized children and women with obstetric conditions in a rural district hospital in Sierra Leone

PubMed Central

Dahmane, A.; van Griensven, J.; Van Herp, M.; Van den Bergh, R.; Nzomukunda, Y.; Prior, J.; Alders, P.; Jambai, A.; Zachariah, R.

2014-01-01

Background Lassa fever (LF) is an acute viral haemorrhagic infection, endemic in West Africa. Confirmatory diagnosis and treatment (ribavirin) is difficult, expensive, and restricted to specialised hospitals. Among confirmed and suspected LF cases, we report on clinical and laboratory features, timing and administration of ribavirin and the relationship with case fatality. Methods We conducted an audit of patient files of suspected LF cases admitted to a pediatric and obstetric referral hospital in rural Sierra Leone (April 2011 to February 2012). Results There were 84 suspected LF cases; 36 (43%) were laboratory-confirmed cases, of whom only 20 (56%) received ribavirin after a median duration of eight days (IQR 314 days) of hospital admission. Of 16 patients who did not receive ribavirin, 14 (87%) died before ribavirin treatment could be commenced. Starting ribavirin within six days of admission was associated with a case fatality of 29% (2/7), while starting ribavirin later than six days was associated with a case fatality of 50% (6/12). Among the 48 suspected LF cases without laboratory confirmation, there were 21 (44%) deaths. Conclusions These findings highlight shortcomings in LF management, including diagnostic and treatment delays. More research and development efforts should be devoted to this ‘neglected disease’. PMID:24535150

Postexposure prophylaxis for Lassa fever: Experience from a recent outbreak in Nigeria.

PubMed

Isa, Samson E; Okwute, Attah; Iraoyah, Kelly O; Nathan, Shehu Y; Simji, Gomerep S; Okolo, Mark O; Anejo-Okopi, Joseph; Spicola, Daria; Isa, Daisy E

2016-01-01

Secondary transmission of Lassa fever (LF) occurs in the community and in health-care facilities, and is associated with high fatality in Nigeria. We investigated the role of oral ribavirin postexposure prophylaxis (orPEP) in preventing LF among the primary contacts of confirmed cases from December 2015 to March 2016. Epidemiological and clinical data of LF contacts were prospectively collected. However, information regarding ribavirin adverse effects (AEs) were collected retrospectively through a telephone interview. High-risk contacts were clinically monitored ΁ orPEP. Thirty-five (94.6%) out of the 37 individuals enrolled in the study were contacts of confirmed LF cases, and friends and family members (54%) constituted the largest group. However, only 29 (83%) individuals were classified as high-risk contacts. Twenty-one (60%) of contacts were prescribed ribavirin with 6 (28.6%) of them reporting AEs. Body weakness (33%) was the most frequent AE, but there was no incidence of treatment discontinuation due to AE. Furthermore, there were no reported cases of LF among all respondents (0%), whether they had orPEP or not. Secondary transmission of LF seems uncommon and the benefit of orPEP is uncertain. Although AEs of ribavirin may not be uncommon, they are rarely serious enough to cause treatment interruption. More emphasis should be on supporting persons looking after LF cases adopt measures that minimize the risks of exposure.

Integrative modelling for One Health: pattern, process and participation

PubMed Central

Redding, D. W.; Wood, J. L. N.

2017-01-01

This paper argues for an integrative modelling approach for understanding zoonoses disease dynamics, combining process, pattern and participatory models. Each type of modelling provides important insights, but all are limited. Combining these in a ‘3P’ approach offers the opportunity for a productive conversation between modelling efforts, contributing to a ‘One Health’ agenda. The aim is not to come up with a composite model, but seek synergies between perspectives, encouraging cross-disciplinary interactions. We illustrate our argument with cases from Africa, and in particular from our work on Ebola virus and Lassa fever virus. Combining process-based compartmental models with macroecological data offers a spatial perspective on potential disease impacts. However, without insights from the ground, the ‘black box’ of transmission dynamics, so crucial to model assumptions, may not be fully understood. We show how participatory modelling and ethnographic research of Ebola and Lassa fever can reveal social roles, unsafe practices, mobility and movement and temporal changes in livelihoods. Together with longer-term dynamics of change in societies and ecologies, all can be important in explaining disease transmission, and provide important complementary insights to other modelling efforts. An integrative modelling approach therefore can offer help to improve disease control efforts and public health responses. This article is part of the themed issue ‘One Health for a changing world: zoonoses, ecosystems and human well-being’. PMID:28584172

The challenges of detecting and responding to a Lassa fever outbreak in an Ebola-affected setting.

PubMed

Hamblion, E L; Raftery, P; Wendland, A; Dweh, E; Williams, G S; George, R N C; Soro, L; Katawera, V; Clement, P; Gasasira, A N; Musa, E; Nagbe, T K

2018-01-01

Lassa fever (LF), a priority emerging pathogen likely to cause major epidemics, is endemic in much of West Africa and is difficult to distinguish from other viral hemorrhagic fevers, including Ebola virus disease (EVD). Definitive diagnosis requires laboratory confirmation, which is not widely available in affected settings. The public health action to contain a LF outbreak and the challenges encountered in an EVD-affected setting are reported herein. In February 2016, a rapid response team was deployed in Liberia in response to a cluster of LF cases. Active case finding, case investigation, contact tracing, laboratory testing, environmental investigation, risk communication, and community awareness raising were undertaken. From January to June 2016, 53 suspected LF cases were reported through the Integrated Disease Surveillance and Response system (IDSR). Fourteen cases (26%) were confirmed for LF, 14 (26%) did not have a sample tested, and 25 (47%) were classified as not a case following laboratory analysis. The case fatality rate in the confirmed cases was 29%. One case of international exportation was reported from Sweden. Difficulties were identified in timely specimen collection, packaging, and transportation (in confirmed cases, the time from sample collection to sample result ranged from 2 to 64 days) and a lack of response interventions for early cases. The delay in response to this outbreak could have been related to a number of challenges in this EVD-affected setting: a need to strengthen the IDSR system, develop preparedness plans, train rapid response teams, and build laboratory capacity. Prioritizing these actions will aid in the timely response to future outbreaks. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Material Proximities and Hotspots: Toward an Anthropology of Viral Hemorrhagic Fevers

PubMed Central

Brown, Hannah; Kelly, Ann H

2014-01-01

This article outlines a research program for an anthropology of viral hemorrhagic fevers (collectively known as VHFs). It begins by reviewing the social science literature on Ebola, Marburg, and Lassa fevers and charting areas for future ethnographic attention. We theoretically elaborate the hotspot as a way of integrating analysis of the two routes of VHF infection: from animal reservoirs to humans and between humans. Drawing together recent anthropological investigations of human–animal entanglements with an ethnographic interest in the social production of space, we seek to enrich conceptualizations of viral movement by elaborating the circumstances through which viruses, humans, objects, and animals come into contact. We suggest that attention to the material proximities—between animals, humans, and objects—that constitute the hotspot opens a frontier site for critical and methodological development in medical anthropology and for future collaborations in VHF management and control. PMID:24752909

Material proximities and hotspots: toward an anthropology of viral hemorrhagic fevers.

PubMed

Brown, Hannah; Kelly, Ann H

2014-06-01

This article outlines a research program for an anthropology of viral hemorrhagic fevers (collectively known as VHFs). It begins by reviewing the social science literature on Ebola, Marburg, and Lassa fevers and charting areas for future ethnographic attention. We theoretically elaborate the hotspot as a way of integrating analysis of the two routes of VHF infection: from animal reservoirs to humans and between humans. Drawing together recent anthropological investigations of human-animal entanglements with an ethnographic interest in the social production of space, we seek to enrich conceptualizations of viral movement by elaborating the circumstances through which viruses, humans, objects, and animals come into contact. We suggest that attention to the material proximities-between animals, humans, and objects-that constitute the hotspot opens a frontier site for critical and methodological development in medical anthropology and for future collaborations in VHF management and control. © 2014 by the American Anthropological Association.

Hemorrhagic Fever Virus Budding Studies.

PubMed

Harty, Ronald N

2018-01-01

Independent expression of the VP40 or Z matrix proteins of filoviruses (marburgviruses and ebolaviruses) and arenaviruses (Lassa fever and Junín), respectively, gives rise to the production and release of virus-like particles (VLPs) that are morphologically identical to infectious virions. We can detect and quantify VLP production and egress in mammalian cells by transient transfection, SDS-PAGE, Western blotting, and live cell imaging techniques such as total internal reflection fluorescence (TIRF) microscopy. Since the VLP budding assay accurately mimics budding of infectious virus, this BSL-2 assay is safe and useful for the interrogation of both viral and host determinants required for budding and can be used as an initial screen to identify and validate small molecule inhibitors of virus release and spread.

Lassa and Marburg viruses elicit distinct host transcriptional responses early after infection.

PubMed

Caballero, Ignacio S; Yen, Judy Y; Hensley, Lisa E; Honko, Anna N; Goff, Arthur J; Connor, John H

2014-11-06

Lassa virus and Marburg virus are two causative agents of viral hemorrhagic fever. Their diagnosis is difficult because patients infected with either pathogen present similar nonspecific symptoms early after infection. Current diagnostic tests are based on detecting viral proteins or nucleic acids in the blood, but these cannot be found during the early stages of disease, before the virus starts replicating in the blood. Using the transcriptional response of the host during infection can lead to earlier diagnoses compared to those of traditional methods. In this study, we use RNA sequencing to obtain a high-resolution view of the in vivo transcriptional dynamics of peripheral blood mononuclear cells (PBMCs) throughout both types of infection. We report a subset of host mRNAs, including heat-shock proteins like HSPA1B, immunoglobulins like IGJ, and cell adhesion molecules like SIGLEC1, whose differences in expression are strong enough to distinguish Lassa infection from Marburg infection in non-human primates. We have validated these infection-specific expression differences by using microarrays on a larger set of samples, and by quantifying the expression of individual genes using RT-PCR. These results suggest that host transcriptional signatures are correlated with specific viral infections, and that they can be used to identify highly pathogenic viruses during the early stages of disease, before standard detection methods become effective.

IGG Subclass and Isotype Specific Immunoglobulin Responses to LASSA fever and Venezuelan Equine Encephalomyelitis: Natural Infection and Immunication

DTIC Science & Technology

1989-03-01

VENEZUELAN EQUINE ENCEPHALOMYELITIS: NATURAL INFECTION AND IMMUNIZATION PRINCIPAL INVESTIGATOR: Renata J. Engler CONTRACTING ORGANIZATION: Uniformed Services...University of Health Sciences 4301 Jones Bridges Road Bethesda, MD 20814-4799 DTIC REPORT DATE: March 1, 1989 E T E MAR0 6 1990 TYPE OF REPORT...University (if applicable) of Health Sciences I 6c. ADDRESS (City, State, and ZIP Code) 7b. ADDRESS (City, State, and ZIP Code) 4301 Jones Bridges Road

TRAINING PROGRAM FOR NURSING STAFF REGARDING VIRAL HEMORRHAGIC FEVERS IN A MILITARY HOSPITAL.

PubMed

El-Bahnasawy, Mamdouh M; Megahed, Laila Abdel-Mawla; Saleh, Halla Ahmed Abdullah; Abdelfattah, Magda Abdelhamid; Morsy, Tosson Aly

2015-08-01

Viral hemorrhagic fevers (VHFs) refer to a group of illnesses caused by several distinct families of viruses. In general, the term "viral hemorrhagic fever" is used to describe a severe multisystem syndrome (multisystem in that multiple organ systems in the bpdy are affected). Characteristically, the overall vascular system is damaged, and the body's ability to regulate itself is impaired. These symptoms are often accompanied by hemorrhage (bleeding); however, the bleeding is it rarely life-threatening. While some types of hemorrhagic fever viruses can cause relatively mild illnesses, many of these viruses cause severe, life-threatening disease. The selected disaster diseases for this study included: 1-Crimean-Congo hemorrhagic Fever, 2-Dengue Fever, 3-Ebola Fever, 4-Hem-orrhagic Fever with renal syndrome (HFRS), 5-Hantavirus Pulmonary Syndrome, 6-Lassa Fever, 7-Marburg Fever, 8-Rift Valley Fever and 9-Yellow Fever. The educational training program was given over ten sessions to a group of Staff Nurses. The results showed that the program succeeded in enhancing nurse' knowledge, awareness, responsibility, and obligations toward patients with the Viral Hemorrhagic Fevers The results showed a significant impact of training sessions illuminated in the follow-up test on the knowledge score of nurses in all types of diseases except for the Congo hemorrhagic fever, while, statistical significance varied in some diseases in the study when it comes to the comparison between pretest and post-test. All results confirmed on the positive impact of the training program in enhancing the knowledge of nurses toward VHFs patients and their relevant. There was a significant positive impact of the training sessions on changing the attitude of nurses toward patients with VHFs. This result was confirmed on the collective level since the total scores on tests revealed significant positive impact of the study on changing the attitude of nurses toward relevant patients. The relationship included personal data (age, sex, level of education, & years of experiences) and main variables (knowledge scores & attitude change to patients) with the disease in question. This part revealed a significant relationship between all personal data and total knowledge score among nurses except for the level of education, while all results were insignificant for the relationship between the personal data and the nurses' attitude. Difference between the total nurses' attitude change and the total knowledge scores was significant on the three tests' levels; pre, post, and the follow-up. The overall evaluation showed that six criteria were adopted, regarding the educator, the length of presentations, the evaluation of the studied groups regarding the training facilities, the subject matters, the overall training program, and the importance of diseases in question to their practical working environment. The frequency distribution showed that the educator met nurses' expectations; the material tools were plausible enough to satisfy trainees and presentations were fairly short. But, the training facilities were just excellent by the vast majority of trainees. The entire material met specific needs of relevant health care organizations, but about 43% reported that it was difficult. The vast majority of trainees favored the program under almost all criteria studied in the final questionnaire. Above 50% of trainees were not confident enough toward their ability in applying their knowledge acquired practically. The final evaluation showed that the most important were Rift Valley fever, Ebola fever, Hanta virus pulmonary syndrome, Crimean Congo fever and lastly Dengue fever. Lassa and Marburg fevers were of less interest to nurses.

Development of a time-trend model for analyzing and predicting case-pattern of Lassa fever epidemics in Liberia, 2013-2017.

PubMed

Olugasa, Babasola O; Odigie, Eugene A; Lawani, Mike; Ojo, Johnson F

2015-01-01

The objective was to develop a case-pattern model for Lassa fever (LF) among humans and derive predictors of time-trend point distribution of LF cases in Liberia in view of the prevailing under-reporting and public health challenge posed by the disease in the country. A retrospective 5 years data of LF distribution countrywide among humans were used to train a time-trend model of the disease in Liberia. A time-trend quadratic model was selected due to its goodness-of-fit (R2 = 0.89, and P < 0.05) and best performance compared to linear and exponential models. Parameter predictors were run on least square method to predict LF cases for a prospective 5 years period, covering 2013-2017. The two-stage predictive model of LF case-pattern between 2013 and 2017 was characterized by a prospective decline within the South-coast County of Grand Bassa over the forecast period and an upward case-trend within the Northern County of Nimba. Case specific exponential increase was predicted for the first 2 years (2013-2014) with a geometric increase over the next 3 years (2015-2017) in Nimba County. This paper describes a translational application of the space-time distribution pattern of LF epidemics, 2008-2012 reported in Liberia, on which a predictive model was developed. We proposed a computationally feasible two-stage space-time permutation approach to estimate the time-trend parameters and conduct predictive inference on LF in Liberia.

Containing a Lassa fever epidemic in a resource-limited setting: outbreak description and lessons learned from Abakaliki, Nigeria (January-March 2012).

PubMed

Ajayi, Nnennaya A; Nwigwe, Chinedu G; Azuogu, Ben N; Onyire, Benson N; Nwonwu, Elizabeth U; Ogbonnaya, Lawrence U; Onwe, Francis I; Ekaete, Tobin; Günther, Stephan; Ukwaja, Kingsley N

2013-11-01

Despite the epidemic nature of Lassa fever (LF), details of outbreaks and response strategies have not been well documented in resource-poor settings. We describe the course of a LF outbreak in Ebonyi State, Nigeria, during January to March 2012. We analyzed clinical, epidemiological, and laboratory data from surveillance records and hospital statistics during the outbreak. Fisher's exact tests were used to compare proportions and t-tests to compare differences in means. The outbreak response consisted of effective coordination, laboratory testing, active surveillance, community mobilization, contact and suspected case evaluation, and case management. Twenty LF cases (10 confirmed and 10 suspected) were recorded during the outbreak. Nosocomial transmission to six health workers occurred through the index case. Only 1/110 contacts had an asymptomatic infection. Overall, there was high case fatality rate among all cases (6/20; 30%). Patients who received ribavirin were less likely to die than those who did not (p=0.003). The mean delay to presentation for patients who died was 11 ± 3.5 days, while for those who survived was 6 ± 2.6 days (p<0.001). The response strategies contained the epidemic. Challenges to control efforts included poor local laboratory capacity, inadequate/poor quality of protective materials, fear among health workers, and inadequate emergency preparedness. Copyright © 2013 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

[Chikungunya fever - A new global threat].

PubMed

Montero, Antonio

2015-08-07

The recent onset of epidemics caused by viruses such as Ebola, Marburg, Nipah, Lassa, coronavirus, West-Nile encephalitis, Saint Louis encephalitis, human immunodeficiency virus, dengue, yellow fever and Venezuelan hemorrhagic fever alerts about the risk these agents represent for the global health. Chikungunya virus represents a new threat. Surged from remote African regions, this virus has become endemic in the Indic ocean basin, the Indian subcontinent and the southeast of Asia, causing serious epidemics in Africa, Indic Ocean Islands, Asia and Europe. Due to their epidemiological and biological features and the global presence of their vectors, chikungunya represents a serious menace and could become endemic in the Americas. Although chikungunya infection has a low mortality rate, its high attack ratio may collapse the health system during epidemics affecting a sensitive population. In this paper, we review the clinical and epidemiological features of chikungunya fever as well as the risk of its introduction into the Americas. We remark the importance of the epidemiological control and mosquitoes fighting in order to prevent this disease from being introduced into the Americas. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.

Alphavirus vector-based replicon particles expressing multivalent cross-protective Lassa virus glycoproteins

PubMed Central

Wang, Min; Jokinen, Jenny; Tretyakova, Irina; Pushko, Peter; Lukashevich, Igor S.

2018-01-01

Lassa virus (LASV) is the most prevalent rodent-borne arenavirus circulated in West Africa. With population at risk from Senegal to Nigeria, LASV causes Lassa fever and is responsible for thousands of deaths annually. High genetic diversity of LASV is one of the challenges for vaccine R&D. We developed multivalent virus-like particle vectors (VLPVs) derived from the human Venezuelan equine encephalitis TC-83 IND vaccine (VEEV) as the next generation of alphavirus-based bicistronic RNA replicon particles. The genes encoding VEEV structural proteins were replaced with LASV glycoproteins (GPC) from distantly related clades I and IV with individual 26S promoters. Bicistronic RNA replicons encoding wild-type LASV GPC (GPCwt) and C-terminally deleted, non-cleavable modified glycoprotein (ΔGPfib), were encapsidated into VLPV particles using VEEV capsid and glycoproteins provided in trans. In transduced cells, VLPVs induced simultaneous expression of LASV GPCwt and ΔGPfib from 26S alphavirus promoters. LASV ΔGPfib was predominantly expressed as trimers, accumulated in the endoplasmic reticulum, induced ER stress and apoptosis promoting antigen cross-priming. VLPV vaccines were immunogenic and protective in mice and upregulated CD11c+/CD8+ dendritic cells playing the major role in cross-presentation. Notably, VLPV vaccination resulted in induction of cross-reactive multifunctional T cell responses after stimulation of immune splenocytes with peptide cocktails derived from LASV from clades I-IV. Multivalent RNA replicon-based LASV vaccines can be applicable for first responders, international travelers visiting endemic areas, military and lab personnel. PMID:29287681

A STAT-1 Knockout Mouse Model for Machupo Virus Pathogenesis

DTIC Science & Technology

2011-06-14

hemorrhagic fever viruses, including Ebola, Marburg, Junín, and Crimean - Congo Hemorrhagic Fever viruses [11-14...Akerstrom S, Klingstrom J, Mirazimi A: Crimean - Congo hemorrhagic fever virus infection is lethal for adult type I interferon receptor-knockout mice. J...Shieh WJ, Camus G, Stroher U, Zaki S, Jones SM: Pathogenesis and immune response of Crimean - Congo hemorrhagic fever virus in a STAT-1 knockout

Using Modelling to Disentangle the Relative Contributions of Zoonotic and Anthroponotic Transmission: The Case of Lassa Fever

PubMed Central

Lo Iacono, Giovanni; Cunningham, Andrew A.; Fichet-Calvet, Elisabeth; Garry, Robert F.; Grant, Donald S.; Khan, Sheik Humarr; Leach, Melissa; Moses, Lina M.; Schieffelin, John S.; Shaffer, Jeffrey G.; Webb, Colleen T.; Wood, James L. N.

2015-01-01

Background Zoonotic infections, which transmit from animals to humans, form the majority of new human pathogens. Following zoonotic transmission, the pathogen may already have, or may acquire, the ability to transmit from human to human. With infections such as Lassa fever (LF), an often fatal, rodent-borne, hemorrhagic fever common in areas of West Africa, rodent-to-rodent, rodent-to-human, human-to-human and even human-to-rodent transmission patterns are possible. Indeed, large hospital-related outbreaks have been reported. Estimating the proportion of transmission due to human-to-human routes and related patterns (e.g. existence of super-spreaders), in these scenarios is challenging, but essential for planned interventions. Methodology/Principal Findings Here, we make use of an innovative modeling approach to analyze data from published outbreaks and the number of LF hospitalized patients to Kenema Government Hospital in Sierra Leone to estimate the likely contribution of human-to-human transmission. The analyses show that almost of the cases at KGH are secondary cases arising from human-to-human transmission. However, we found much of this transmission is associated with a disproportionally large impact of a few individuals (‘super-spreaders’), as we found only of human cases result in an effective reproduction number (i.e. the average number of secondary cases per infectious case) , with a maximum value up to . Conclusions/Significance This work explains the discrepancy between the sizes of reported LF outbreaks and a clinical perception that human-to-human transmission is low. Future assessment of risks of LF and infection control guidelines should take into account the potentially large impact of super-spreaders in human-to-human transmission. Our work highlights several neglected topics in LF research, the occurrence and nature of super-spreading events and aspects of social behavior in transmission and detection. PMID:25569707

Using modelling to disentangle the relative contributions of zoonotic and anthroponotic transmission: the case of lassa fever.

PubMed

Lo Iacono, Giovanni; Cunningham, Andrew A; Fichet-Calvet, Elisabeth; Garry, Robert F; Grant, Donald S; Khan, Sheik Humarr; Leach, Melissa; Moses, Lina M; Schieffelin, John S; Shaffer, Jeffrey G; Webb, Colleen T; Wood, James L N

2015-01-01

Zoonotic infections, which transmit from animals to humans, form the majority of new human pathogens. Following zoonotic transmission, the pathogen may already have, or may acquire, the ability to transmit from human to human. With infections such as Lassa fever (LF), an often fatal, rodent-borne, hemorrhagic fever common in areas of West Africa, rodent-to-rodent, rodent-to-human, human-to-human and even human-to-rodent transmission patterns are possible. Indeed, large hospital-related outbreaks have been reported. Estimating the proportion of transmission due to human-to-human routes and related patterns (e.g. existence of super-spreaders), in these scenarios is challenging, but essential for planned interventions. Here, we make use of an innovative modeling approach to analyze data from published outbreaks and the number of LF hospitalized patients to Kenema Government Hospital in Sierra Leone to estimate the likely contribution of human-to-human transmission. The analyses show that almost [Formula: see text] of the cases at KGH are secondary cases arising from human-to-human transmission. However, we found much of this transmission is associated with a disproportionally large impact of a few individuals ('super-spreaders'), as we found only [Formula: see text] of human cases result in an effective reproduction number (i.e. the average number of secondary cases per infectious case) [Formula: see text], with a maximum value up to [Formula: see text]. This work explains the discrepancy between the sizes of reported LF outbreaks and a clinical perception that human-to-human transmission is low. Future assessment of risks of LF and infection control guidelines should take into account the potentially large impact of super-spreaders in human-to-human transmission. Our work highlights several neglected topics in LF research, the occurrence and nature of super-spreading events and aspects of social behavior in transmission and detection.

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

Cellular Factors Required for Lassa Virus Budding

PubMed Central

Urata, Shuzo; Noda, Takeshi; Kawaoka, Yoshihiro; Yokosawa, Hideyoshi; Yasuda, Jiro

2006-01-01

It is known that Lassa virus Z protein is sufficient for the release of virus-like particles (VLPs) and that it has two L domains, PTAP and PPPY, in its C terminus. However, little is known about the cellular factor for Lassa virus budding. We examined which cellular factors are used in Lassa virus Z budding. We demonstrated that Lassa Z protein efficiently produces VLPs and uses cellular factors, Vps4A, Vps4B, and Tsg101, in budding, suggesting that Lassa virus budding uses the multivesicular body pathway functionally. Our data may provide a clue to develop an effective antiviral strategy for Lassa virus. PMID:16571837

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

Bacterial-based systems for expression and purification of recombinant Lassa virus proteins of immunological relevance

PubMed Central

Branco, Luis M; Matschiner, Alex; Fair, Joseph N; Goba, Augustine; Sampey, Darryl B; Ferro, Philip J; Cashman, Kathleen A; Schoepp, Randal J; Tesh, Robert B; Bausch, Daniel G; Garry, Robert F; Guttieri, Mary C

2008-01-01

Background There is a significant requirement for the development and acquisition of reagents that will facilitate effective diagnosis, treatment, and prevention of Lassa fever. In this regard, recombinant Lassa virus (LASV) proteins may serve as valuable tools in diverse antiviral applications. Bacterial-based systems were engineered for expression and purification of recombinant LASV nucleoprotein (NP), glycoprotein 1 (GP1), and glycoprotein 2 (GP2). Results Full-length NP and the ectodomains of GP1 and GP2 were generated as maltose-binding protein (MBP) fusions in the Rosetta strains of Escherichia coli (E. coli) using pMAL-c2x vectors. Average fusion protein yields per liter of culture for MBP-NP, MBP-GP1, and MBP-GP2 were 10 mg, 9 mg, and 9 mg, respectively. Each protein was captured from cell lysates using amylose resin, cleaved with Factor Xa, and purified using size-exclusion chromatography (SEC). Fermentation cultures resulted in average yields per liter of 1.6 mg, 1.5 mg, and 0.7 mg of purified NP, GP1 and GP2, respectively. LASV-specific antibodies in human convalescent sera specifically detected each of the purified recombinant LASV proteins, highlighting their utility in diagnostic applications. In addition, mouse hyperimmune ascitic fluids (MHAF) against a panel of Old and New World arenaviruses demonstrated selective cross reactivity with LASV proteins in Western blot and enzyme-linked immunosorbent assay (ELISA). Conclusion These results demonstrate the potential for developing broadly reactive immunological assays that employ all three arenaviral proteins individually and in combination. PMID:18538016

At Home with Mastomys and Rattus: Human-Rodent Interactions and Potential for Primary Transmission of Lassa Virus in Domestic Spaces

PubMed Central

Bonwitt, Jesse; Sáez, Almudena Mari; Lamin, Joseph; Ansumana, Rashid; Dawson, Michael; Buanie, Jacob; Lamin, Joyce; Sondufu, Diana; Borchert, Matthias; Sahr, Foday; Fichet-Calvet, Elisabeth; Brown, Hannah

2017-01-01

The multimammate mouse (Mastomys natalensis) is the reservoir for Lassa virus (LASV). Zoonotic transmission occurs when humans are directly or indirectly exposed to fluids of the multimammate mouse, such as urine, saliva, and blood. Housing characteristics and domestic organization affect rodent density in and around households and villages, and are likely to be a risk factor for Lassa fever in humans where the reservoir exists. We use semi-structured interviews (N = 51), a quantitative survey (N = 429), direct observations, and a rodent ecology study to provide new insights into how the organization of domestic spaces brings together humans and rodents and creates pathways for infection in rural settlements in Bo District, Sierra Leone. Rodents were frequently reported inside houses (92.4% of respondents), in which we predominantly trapped M. natalensis (57% of trapped rodents) and Rattus rattus (38% of trapped rodents). Building design and materials provide hiding and nesting places for rodents and lead to close proximity with humans. Patterns of contact are both unintentional and intentional and research participants reported high levels of contact with rodents (34.2% of respondents) and rodent fluids (52.8% of respondents). Rodents are also perceived as a serious threat to food security. These results present detailed knowledge about how humans live with and come into contact with rodents, including the LASV reservoir. Our results argue for further collaborative research in housing and environmental modification such as ceiling construction, food storage, and sanitation as prevention against zoonotic LASV transmission. PMID:28167603

Protection of Lassa Virus-Infected Guinea Pigs with Lassa-Immune Plasma of Guinea Pig, Primate, and Human Origin

DTIC Science & Technology

1983-01-01

DTICCS OCT 19 1983ora o ek Viroly 12-93-102 (1963) Protection of Lassa Virus-infected Guinea Pigs With Lassa-Immune Plasma of Guinea Pig , Primate...siotrain 13 guinea pigs were infected with a lethal dose of Lassa virus and treated with various Lassa-immune plasmas obtained from guinea pigs , primates...plaque-forming units (PFU) neutralization index (LNI). All guinea pigs treated with immune plasma 6 mI/kg/treatment on days 0, 3, and 6 after virus

[Highly contagious diseases with human-to-human transmission].

PubMed

Rybka, Aleš; Szanyi, Juraj; Kapla, Jaroslav; Plíšek, Stanislav

2012-12-01

Highly contagious diseases are caused by various biological agents that pose a risk to individuals and may have a potential for public health impact. They result in high mortality and morbidity rates, might cause public panic and therefore require special measures. The pathogens that can be easily disseminated or transmitted from person to person are the riskiest for clinicians (Ebola virus, Marburg virus, Lassa virus, Crimean-Congo hemorrhagic fever virus, Variola major, SARS virus and Yersinia pestis). Human-to-human transmission has not been confirmed for the other biological agents and therefore they pose a very low risk for population.

Studies on the pathogenesis of fever. VIII. Further observations on the role of endogenous pyrogen in endotoxin fever.

PubMed

GILLMAN, S M; BORNSTEIN, D L; WOOD, W B

1961-11-01

Rabbits made granulocytopenic with nitrogen mustard have been shown to generate serum endogenous pyrogen when given a fever-producing dose of bacterial endotoxin. This finding is in accord with the hypothesis that endogenous pyrogen plays a central role in the pathogenesis of endotoxin fever. The fact that leucopenic animals produce less serum-endogenous pyrogen than normal animals given the same dose of endotoxin has also been confirmed and suggests that polymorphonuclear leucocytes constitute a major source of the endogenous pyrogen which is demonstrable in the circulation during endotoxin fever.

Serological assays based on recombinant viral proteins for the diagnosis of arenavirus hemorrhagic fevers.

PubMed

Fukushi, Shuetsu; Tani, Hideki; Yoshikawa, Tomoki; Saijo, Masayuki; Morikawa, Shigeru

2012-10-12

The family Arenaviridae, genus Arenavirus, consists of two phylogenetically independent groups: Old World (OW) and New World (NW) complexes. The Lassa and Lujo viruses in the OW complex and the Guanarito, Junin, Machupo, Sabia, and Chapare viruses in the NW complex cause viral hemorrhagic fever (VHF) in humans, leading to serious public health concerns. These viruses are also considered potential bioterrorism agents. Therefore, it is of great importance to detect these pathogens rapidly and specifically in order to minimize the risk and scale of arenavirus outbreaks. However, these arenaviruses are classified as BSL-4 pathogens, thus making it difficult to develop diagnostic techniques for these virus infections in institutes without BSL-4 facilities. To overcome these difficulties, antibody detection systems in the form of an enzyme-linked immunosorbent assay (ELISA) and an indirect immunofluorescence assay were developed using recombinant nucleoproteins (rNPs) derived from these viruses. Furthermore, several antigen-detection assays were developed. For example, novel monoclonal antibodies (mAbs) to the rNPs of Lassa and Junin viruses were generated. Sandwich antigen-capture (Ag-capture) ELISAs using these mAbs as capture antibodies were developed and confirmed to be sensitive and specific for detecting the respective arenavirus NPs. These rNP-based assays were proposed to be useful not only for an etiological diagnosis of VHFs, but also for seroepidemiological studies on VHFs. We recently developed arenavirus neutralization assays using vesicular stomatitis virus (VSV)-based pseudotypes bearing arenavirus recombinant glycoproteins. The goal of this article is to review the recent advances in developing laboratory diagnostic assays based on recombinant viral proteins for the diagnosis of VHFs and epidemiological studies on the VHFs caused by arenaviruses.

Studies on the pathogenesis of fever. V. The relation of circulating endogenous pyrogen to the fever of acute bacterial infections.

PubMed

KING, M K; WOOD, W B

1958-02-01

An endogenous pyrogen, which is indistinguishable from leucocytic pyrogen, has been demonstrated in the blood streams of rabbits with fevers caused by experimental pneumococcal and streptococcal infections. Like the endogenous pyrogen previously detected in the serum of animals with fever produced by the intravenous injection of typhoid vaccine, the newly discovered circulating factor acts directly upon the thermoregulatory centers of the brain. Its origin from polymorphonuclear leucocytes at the site of infection appears to have been established. The possible relationship of this circulating endogenous pyrogen to the pathogenesis of other forms of fever is discussed.

Pathogenesis of Cell Injury by Rickettsia conorii

DTIC Science & Technology

1985-05-17

Rocky Mountain spotted fever ), R...can assume a more severe course similar to the picture of Rocky Mountain spotted fever . Severe disease has been associated with G6PD deficiency...boutonneuse fever have been investigated to a far less degree than typhus fever and Rocky Mountain spotted fever . In particular, pathogenic

COMMISSION ON EPIDEMIOLOGICAL SURVEY

DTIC Science & Technology

Ribonucleic Acid Metabolism during Infection; Mechanisms of Endotoxin Tolerance; Typhoid Fever: Pathogenesis and Prevention; Studies on Rocky Mountain Spotted Fever : Serologic...Response in Man to Vaccination with Combined Epidemic Typhus, Rocky Mountain Spotted Fever and Q Fever Vaccine; and Influence of Tularemia on Insulin Secretion.

[Epidemiological risk of introduction of dangerous and exotic infectious diseases on the territory of the XXII Olympic Winter Games and XI Paralympic Winter Games 2014 in Sochi].

PubMed

Kuz'kin, B P; Ezhlova, E B; Kulichenko, A N; Maletskaia, O V; Demina, Iu V; Taran, T V; Pakskina, N D; Kharchenko, T V; Grizhebovskiĭ, G M; Savel'ev, V N; Orobeĭ, V G; Klindukhov, V P; Grechanaia, T V; Tesheva, S Ch; Brukhanova, G D

2015-01-01

To assess the epidemiological risk of introduction of serious infectious diseases in the pre-Olympic period defined list of dangerous and exotic infections and held assessment of potential danger threatening. Initial external information to assess the potential risk of skidding were reports, forecasts, posted on the official websites. The risk of skidding and epidemiological complications conditionally designated as high, moderate and minimal risk importation of measles virus-Rate was considered as high. In confirmation of the forecast for the period of the Olympic Games in Sochi have been registered about 100 cases of measles. Moderate risk of importation was determined for poliomyelitis due to wild poliovirus, Lassa fever, cholera, plague, and the minimal--for Dengue fever, yellow fever, the Middle East and respiratory syndrome, diseases caused by viruses Marburg and Ebola. Based on of analysis of previous Olympic Games and subsequent co-events related to the activity of the infectious diseases in the world, mate-cluded that even a slight risk of importation of infectious diseases requires maximum alertness and readiness to conduct adequate epidemiological issues incorporated.

The etiology of Ebola virus disease-like illnesses in Ebola virusnegative patients from Sierra Leone.

PubMed

Li, Wen-Gang; Chen, Wei-Wei; Li, Lei; Ji, Dong; Ji, Ying-Jie; Li, Chen; Gao, Xu-Dong; Wang, Li-Fu; Zhao, Min; Duan, Xue-Zhang; Duan, Hui-Juan

2016-05-10

During the 2014 Ebola virus disease (EVD) outbreak, less than half of EVD-suspected cases were laboratory tested as Ebola virus (EBOV)-negative, but disease identity remained unknown. In this study we investigated the etiology of EVD-like illnesses in EBOV-negative cases. From November 13, 2014 to March 16, 2015, EVD-suspected patients were admitted to Jui Government Hospital and assessed for EBOV infection by real-time PCR. Of 278 EBOV negative patients, 223 (80.21%), 142 (51.08%), 123 (44.24%), 114 (41.01%), 59 (21.22%), 35 (12.59%), and 12 (4.32%) reported fever, headache, joint pain, fatigue, nausea/vomiting, diarrhea, hemorrhage, respectively. Furthermore, 121 (43.52%), 44 (15.83%), 36 (12.95%), 33 (11.87%), 23 (8.27%), 10 (3.60%) patients were diagnosed as infection with malaria, HIV, Lassa fever, tuberculosis, yellow fever, and pneumonia, respectively. No significant differences in clinical features and symptoms were found between non-EVD and EVD patients. To the best of our knowledge, the present study is the first to explore the etiology of EVD-like illnesses in uninfected patients in Sierra Leone, highlighting the importance of accurate diagnosis to EVD confirmation.

COMMISSION ON EPIDEMIOLOGICAL SURVEY

DTIC Science & Technology

Ribonucleic Acid Metabolism during Infection; Mechanisms of Endotoxin Tolerance; Typhoid Fever: Pathogenesis and Prevention; Studies on Rocky Mountain Spotted Fever : Serologic...Response in Man to Vaccination with Combined Epidemic Typhus, Rocky Mountain Spotted Fever and Q Fever Vaccine; and Influence of Tularemia on Tularemia on Insulin Secretion.

Comparative analysis of disease pathogenesis and molecular mechanisms of New World and Old World arenavirus infections

PubMed Central

McLay, Lisa; Liang, Yuying

2014-01-01

Arenaviruses can cause fatal human haemorrhagic fever (HF) diseases for which vaccines and therapies are extremely limited. Both the New World (NW) and Old World (OW) groups of arenaviruses contain HF-causing pathogens. Although these two groups share many similarities, important differences with regard to pathogenicity and molecular mechanisms of virus infection exist. These closely related pathogens share many characteristics, including genome structure, viral assembly, natural host selection and the ability to interfere with innate immune signalling. However, members of the NW and OW viruses appear to use different receptors for cellular entry, as well as different mechanisms of virus internalization. General differences in disease signs and symptoms and pathological lesions in patients infected with either NW or OW arenaviruses are also noted and discussed herein. Whilst both the OW Lassa virus (LASV) and the NW Junin virus (JUNV) can cause disruption of the vascular endothelium, which is an important pathological feature of HF, the immune responses to these related pathogens seem to be quite distinct. Whereas LASV infection results in an overall generalized immune suppression, patients infected with JUNV seem to develop a cytokine storm. Additionally, the type of immune response required for recovery and clearance of the virus is different between NW and OW infections. These differences may be important to allow the viruses to evade host immune detection. Understanding these differences will aid the development of new vaccines and treatment strategies against deadly HF viral infections. PMID:24068704

Comparative analysis of disease pathogenesis and molecular mechanisms of New World and Old World arenavirus infections.

PubMed

McLay, Lisa; Liang, Yuying; Ly, Hinh

2014-01-01

Arenaviruses can cause fatal human haemorrhagic fever (HF) diseases for which vaccines and therapies are extremely limited. Both the New World (NW) and Old World (OW) groups of arenaviruses contain HF-causing pathogens. Although these two groups share many similarities, important differences with regard to pathogenicity and molecular mechanisms of virus infection exist. These closely related pathogens share many characteristics, including genome structure, viral assembly, natural host selection and the ability to interfere with innate immune signalling. However, members of the NW and OW viruses appear to use different receptors for cellular entry, as well as different mechanisms of virus internalization. General differences in disease signs and symptoms and pathological lesions in patients infected with either NW or OW arenaviruses are also noted and discussed herein. Whilst both the OW Lassa virus (LASV) and the NW Junin virus (JUNV) can cause disruption of the vascular endothelium, which is an important pathological feature of HF, the immune responses to these related pathogens seem to be quite distinct. Whereas LASV infection results in an overall generalized immune suppression, patients infected with JUNV seem to develop a cytokine storm. Additionally, the type of immune response required for recovery and clearance of the virus is different between NW and OW infections. These differences may be important to allow the viruses to evade host immune detection. Understanding these differences will aid the development of new vaccines and treatment strategies against deadly HF viral infections.

A Multiplex PCR/LDR Assay for the Simultaneous Identification of Category A Infectious Pathogens: Agents of Viral Hemorrhagic Fever and Variola Virus

PubMed Central

Das, Sanchita; Rundell, Mark S.; Mirza, Aashiq H.; Pingle, Maneesh R.; Shigyo, Kristi; Garrison, Aura R.; Paragas, Jason; Smith, Scott K.; Olson, Victoria A.; Larone, Davise H.; Spitzer, Eric D.; Barany, Francis; Golightly, Linnie M.

2015-01-01

CDC designated category A infectious agents pose a major risk to national security and require special action for public health preparedness. They include viruses that cause viral hemorrhagic fever (VHF) syndrome as well as variola virus, the agent of smallpox. VHF is characterized by hemorrhage and fever with multi-organ failure leading to high morbidity and mortality. Smallpox, a prior scourge, has been eradicated for decades, making it a particularly serious threat if released nefariously in the essentially non-immune world population. Early detection of the causative agents, and the ability to distinguish them from other pathogens, is essential to contain outbreaks, implement proper control measures, and prevent morbidity and mortality. We have developed a multiplex detection assay that uses several species-specific PCR primers to generate amplicons from multiple pathogens; these are then targeted in a ligase detection reaction (LDR). The resultant fluorescently-labeled ligation products are detected on a universal array enabling simultaneous identification of the pathogens. The assay was evaluated on 32 different isolates associated with VHF (ebolavirus, marburgvirus, Crimean Congo hemorrhagic fever virus, Lassa fever virus, Rift Valley fever virus, Dengue virus, and Yellow fever virus) as well as variola virus and vaccinia virus (the agent of smallpox and its vaccine strain, respectively). The assay was able to detect all viruses tested, including 8 sequences representative of different variola virus strains from the CDC repository. It does not cross react with other emerging zoonoses such as monkeypox virus or cowpox virus, or six flaviviruses tested (St. Louis encephalitis virus, Murray Valley encephalitis virus, Powassan virus, Tick-borne encephalitis virus, West Nile virus and Japanese encephalitis virus). PMID:26381398

A Multiplex PCR/LDR Assay for the Simultaneous Identification of Category A Infectious Pathogens: Agents of Viral Hemorrhagic Fever and Variola Virus.

PubMed

Das, Sanchita; Rundell, Mark S; Mirza, Aashiq H; Pingle, Maneesh R; Shigyo, Kristi; Garrison, Aura R; Paragas, Jason; Smith, Scott K; Olson, Victoria A; Larone, Davise H; Spitzer, Eric D; Barany, Francis; Golightly, Linnie M

2015-01-01

CDC designated category A infectious agents pose a major risk to national security and require special action for public health preparedness. They include viruses that cause viral hemorrhagic fever (VHF) syndrome as well as variola virus, the agent of smallpox. VHF is characterized by hemorrhage and fever with multi-organ failure leading to high morbidity and mortality. Smallpox, a prior scourge, has been eradicated for decades, making it a particularly serious threat if released nefariously in the essentially non-immune world population. Early detection of the causative agents, and the ability to distinguish them from other pathogens, is essential to contain outbreaks, implement proper control measures, and prevent morbidity and mortality. We have developed a multiplex detection assay that uses several species-specific PCR primers to generate amplicons from multiple pathogens; these are then targeted in a ligase detection reaction (LDR). The resultant fluorescently-labeled ligation products are detected on a universal array enabling simultaneous identification of the pathogens. The assay was evaluated on 32 different isolates associated with VHF (ebolavirus, marburgvirus, Crimean Congo hemorrhagic fever virus, Lassa fever virus, Rift Valley fever virus, Dengue virus, and Yellow fever virus) as well as variola virus and vaccinia virus (the agent of smallpox and its vaccine strain, respectively). The assay was able to detect all viruses tested, including 8 sequences representative of different variola virus strains from the CDC repository. It does not cross react with other emerging zoonoses such as monkeypox virus or cowpox virus, or six flaviviruses tested (St. Louis encephalitis virus, Murray Valley encephalitis virus, Powassan virus, Tick-borne encephalitis virus, West Nile virus and Japanese encephalitis virus).

STUDIES ON THE PATHOGENESIS OF FEVER

PubMed Central

Atkins, Elisha; Wood, W. Barry

1955-01-01

Further studies have been made of a pyrogenic substance which appears in the circulation of rabbits during the course of experimental fever induced by injection of typhoid vaccine. With the use of a passive transfer method and pyrogen-tolerant recipients, the biological properties of this substance have been differentiated from those of the uncleared vaccine in the circulation. The newly identified factor resembles leucocytic pyrogen in the rapidity with which it produces fever and in its failure to exhibit cross-tolerance with bacterial pyrogen. This striking similarity of properties suggests that the circulating factor is of endogenous origin and may arise from cell injury. A close correlation between its presence in the circulation and the existence of fever has been demonstrated. The possible relationship of these findings to the pathogenesis of fever is evident. PMID:13271667

Pathogenesis of Cell Injury by Rickettsia conorii.

DTIC Science & Technology

1984-06-15

Rocky Mountain spotted fever . Vasculitis...The lesions where similar to other rickettsioses such as typhus fever and Rocky Mountain spotted fever . Vasculitis was more prominent than vascular...pathogenic mechanism of cell injury by R. conorii. The failure of killed rickettsial and bacterial vaccines, e.g., Rocky Mountain spotted fever ,

The Pathogenesis of Rift Valley Fever

PubMed Central

Ikegami, Tetsuro; Makino, Shinji

2011-01-01

Rift Valley fever (RVF) is an emerging zoonotic disease distributed in sub-Saharan African countries and the Arabian Peninsula. The disease is caused by the Rift Valley fever virus (RVFV) of the family Bunyaviridae and the genus Phlebovirus. The virus is transmitted by mosquitoes, and virus replication in domestic ruminant results in high rates of mortality and abortion. RVFV infection in humans usually causes a self-limiting, acute and febrile illness; however, a small number of cases progress to neurological disorders, partial or complete blindness, hemorrhagic fever, or thrombosis. This review describes the pathology of RVF in human patients and several animal models, and summarizes the role of viral virulence factors and host factors that affect RVFV pathogenesis. PMID:21666766

Connaissances et attitudes des relais communautaires sur les fièvres hémorragiques à virus Lassa et Ebola dans le département de la Donga (Nord Bénin)

PubMed Central

Attinsounon, Cossi Angelo; Hounnankan, Cossi Athanase; Dovonou, Comlan Albert; Alassani, Cossi Adébayo; Salifou, Sourakatou

2017-01-01

Introduction L’objectif de cette étude était d’évaluer les connaissances et attitudes des relais communautaires vis-à-vis des fièvres hémorragiques à virus Ebola et Lassa et leur implication dans la mise œuvre des activités de prévention de ces maladies. Méthodes Une enquête transversale descriptive a été menée auprès des relais communautaires recrutés par tirage au sort dans 40 villages du département de la Donga. Ces relais faisaient la prise en charge à domicile des maladies respiratoires, diarrhéiques et du paludisme chez les enfants de moins de cinq ans. Un questionnaire anonyme a été administré par interview directe. Les données ont été analysées à l’aide du logiciel Epi-info 3.5.1. Résultats Au total 58 relais communautaires (RC) ont participé à cette enquête sur les 60 attendus. L’âge moyen était de 38,7±10,6 ans avec un sex-ratio de 3,5. Il y avait majoritairement trente cinq cultivateurs (60,3%) et treize revendeuses (22,4%). Quarante huit enquêtés (82,8%) reconnaissaient les deux maladies comme étant graves, mortelles et transmissibles. Les trois principales voies de transmission citées étaient le contact ou la consommation de gibiers (87,9%), le contact direct avec les personnes infectées (74,1%) ou leurs cadavres (46,6%). Les principaux moyens préventifs énumérés étaient en lien avec les voies de transmission. La fièvre (81,0%), les vomissements (81,0%) et la diarrhée (60,3%) venaient en tête des symptômes cités. Seulement vingt-deux RC (37,9%) disposaient de gants mais les utilisaient rarement pour examiner les enfants malades. Quant à la conduite à tenir devant un cas suspect de fièvre hémorragique virale Lassa ou Ebola, quarante-et-un relais communautaires (70,7%) feraient recours aux agents de santé sans toucher au malade, neuf (15,5%) feraient appel à l’ambulance et huit (13,8%) transporteraient le cas sur leur propre moto ou sur un taxi-moto vers le centre de santé le plus proche. Conclusion Le renforcement des capacités des relais communautaires sur les fièvres hémorragiques virales contribuerait à l’amélioration de leurs connaissances sur ces épidémies mortelles et à la qualité de leurs interventions dans la population. Introduction This study aimed to evaluate the knowledges and attitudes of community volunteers on Lassa and Ebola viral haemorrhagic fevers and their role in the implementation of activities for the prevention of these diseases. Methods We conducted a cross-sectional descriptive survey among community volunteers chosen by lot in 40 villages in the Donga Department. Children under five years of age with respiratory and diarrheal diseases and malaria were treated by these community volunteers in their home. An anonymous questionnaire was administered by direct interview. Data were analyzed using Epi-Info 3.5.1. Results Out of 60 community volunteers potentially participating in this survey a total of 58 effectively participated. The average age of community volunteers was 38.7 ± 10.6 years with a sex-ratio of 3.5. The majority of the community volunteers were farmers (thirty-five, 60.3%) and resellers (thirteen, 22.4%). Forty-eight respondents (82.8%) recognized the two diseases as being serious, life-threatening and transmissible. The three main routes of transmission cited were the contact with or the consumption of bushmeat (87.9%), the direct contact with infected people (74.1%) or with their corpses (46.6%). The main preventive measures listed were related to the routes of transmission. Fever (81.0%), vomiting (81.0%) and diarrhea (60.3%) were at the top of the cited symptoms. Only twenty-two community volunteers (37.9%) had gloves but they rarely used them to examine sick children. As regards the procedure to follow in case of suspected Lassa or Ebola viral haemorrhagic fever , forty-one community volunteers (70.7%) would make use of community-based health workers without touching the patient, nine (15.5%) would call for the ambulance and eight (13.8%) would take the patient to the nearest health center using their own motorcycle or a motorcycle-taxi. Conclusion Strengthening community volunteers’ capacity to manage viral hemorrhagic fevers would contribute to the improvement of their knowledge of these life-threatening epidemics and to the quality of population health interventions. PMID:28690743

Animal health care seeking behavior of pets or livestock owners and knowledge and awareness on zoonoses in a university community.

PubMed

Awosanya, Emmanuel J; Akande, H O

2015-07-01

We investigated the attitude of pets or livestock owning households in a university community to animal health care services and assessed the knowledge and awareness level of the residents on zoonoses. Structured questionnaire was used to obtain information on demography, pet or livestock ownership, animal health care seeking behavior, awareness and knowledge of zoonoses from 246 households. We did descriptive statistics and bivariate analysis to determine the level of association in discrete variables between owners and non-owners of pets or livestock at a significant level of p<0.05. Of the 246 respondents, 80 (32.5%) were either pet or livestock owners. The animal health care seeking behavior of the 80 pets or livestock owners in terms of treatment and vaccination was 70%. Of the 56 (70%) who provided health care services for their animals, about 48 (85.7%) engaged the services of a veterinarian. Dog owning households (42) had the highest frequency of treating their pets against endoparasites (97.6%); ectoparasites (81%) and vaccination against diseases (73.8%). Of the 246 respondents, only 47 (19.1%) have heard of the term zoonoses. Of the considered zoonoses; their awareness of rabies (79.3%) was the highest, followed by Lassa fever (66.3%), the least was pasteurellosis with 18.7%. Having pets or livestock was significantly associated (p=0.04) with rabies awareness. However, there is no significant difference in the level of awareness of zoonoses; knowledge of zoonoses, knowledge of prevention of zoonoses and knowledge of risk of zoonoses between owners and non-owners of pets or livestock. The animal health care seeking behavior of households with pets or livestock is good and should be encouraged. Public education should be created for other zoonoses aside from rabies, Lassa fever, and avian influenza.

Animal health care seeking behavior of pets or livestock owners and knowledge and awareness on zoonoses in a university community

PubMed Central

Awosanya, Emmanuel J.; Akande, H. O.

2015-01-01

Aim: We investigated the attitude of pets or livestock owning households in a university community to animal health care services and assessed the knowledge and awareness level of the residents on zoonoses. Materials and Methods: Structured questionnaire was used to obtain information on demography, pet or livestock ownership, animal health care seeking behavior, awareness and knowledge of zoonoses from 246 households. We did descriptive statistics and bivariate analysis to determine the level of association in discrete variables between owners and non-owners of pets or livestock at a significant level of p<0.05. Results: Of the 246 respondents, 80 (32.5%) were either pet or livestock owners. The animal health care seeking behavior of the 80 pets or livestock owners in terms of treatment and vaccination was 70%. Of the 56 (70%) who provided health care services for their animals, about 48 (85.7%) engaged the services of a veterinarian. Dog owning households (42) had the highest frequency of treating their pets against endoparasites (97.6%); ectoparasites (81%) and vaccination against diseases (73.8%). Of the 246 respondents, only 47 (19.1%) have heard of the term zoonoses. Of the considered zoonoses; their awareness of rabies (79.3%) was the highest, followed by Lassa fever (66.3%), the least was pasteurellosis with 18.7%. Having pets or livestock was significantly associated (p=0.04) with rabies awareness. However, there is no significant difference in the level of awareness of zoonoses; knowledge of zoonoses, knowledge of prevention of zoonoses and knowledge of risk of zoonoses between owners and non-owners of pets or livestock. Conclusion: The animal health care seeking behavior of households with pets or livestock is good and should be encouraged. Public education should be created for other zoonoses aside from rabies, Lassa fever, and avian influenza. PMID:27047163

Potential for autoimmune pathogenesis of Rift Valley Fever virus retinitis.

PubMed

Newman-Gerhardt, Shoshana; Muiruri, Samuel; Muchiri, Eric; Peters, Clarence J; Morrill, John; Lucas, Alexander H; King, Charles H; Kazura, James; LaBeaud, Angelle Desiree

2013-09-01

Rift Valley Fever (RVF) is a significant threat to human health because it can progress to retinitis, encephalitis, and hemorrhagic fever. The timing of onset of Rift Valley Fever virus (RVFV) retinitis suggests an autoimmune origin. To determine whether RVFV retinitis is associated with increased levels of IgG against retinal tissue, we measured and compared levels of IgG against healthy human eye tissue by immunohistochemical analysis. We found that serum samples from RVFV-exposed Kenyans with retinitis (n = 8) were slightly more likely to have antibodies against retinal tissue than control populations, but the correlation was not statistically significant. Further investigation into the possible immune pathogenesis of RVFV retinitis could lead to improved therapies to prevent or treat this severe complication.

Potential for Autoimmune Pathogenesis of Rift Valley Fever Virus Retinitis

PubMed Central

Newman-Gerhardt, Shoshana; Muiruri, Samuel; Muchiri, Eric; Peters, Clarence J.; Morrill, John; Lucas, Alexander H.; King, Charles H.; Kazura, James; LaBeaud, Angelle Desiree

2013-01-01

Rift Valley Fever (RVF) is a significant threat to human health because it can progress to retinitis, encephalitis, and hemorrhagic fever. The timing of onset of Rift Valley Fever virus (RVFV) retinitis suggests an autoimmune origin. To determine whether RVFV retinitis is associated with increased levels of IgG against retinal tissue, we measured and compared levels of IgG against healthy human eye tissue by immunohistochemical analysis. We found that serum samples from RVFV-exposed Kenyans with retinitis (n = 8) were slightly more likely to have antibodies against retinal tissue than control populations, but the correlation was not statistically significant. Further investigation into the possible immune pathogenesis of RVFV retinitis could lead to improved therapies to prevent or treat this severe complication. PMID:23918215

Mapping of the Lassa virus LAMP1 binding site reveals unique determinants not shared by other old world arenaviruses.

PubMed

Israeli, Hadar; Cohen-Dvashi, Hadas; Shulman, Anastasiya; Shimon, Amir; Diskin, Ron

2017-04-01

Cell entry of many enveloped viruses occurs by engagement with cellular receptors, followed by internalization into endocytic compartments and pH-induced membrane fusion. A previously unnoticed step of receptor switching was found to be critical during cell entry of two devastating human pathogens: Ebola and Lassa viruses. Our recent studies revealed the functional role of receptor switching to LAMP1 for triggering membrane fusion by Lassa virus and showed the involvement of conserved histidines in this switching, suggesting that other viruses from this family may also switch to LAMP1. However, when we investigated viruses that are genetically close to Lassa virus, we discovered that they cannot bind LAMP1. A crystal structure of the receptor-binding module from Morogoro virus revealed structural differences that allowed mapping of the LAMP1 binding site to a unique set of Lassa residues not shared by other viruses in its family, illustrating a key difference in the cell-entry mechanism of Lassa virus that may contribute to its pathogenicity.

Comprehensive Panel of Real-Time TaqMan™ Polymerase Chain Reaction Assays for Detection and Absolute Quantification of Filoviruses, Arenaviruses, and New World Hantaviruses

PubMed Central

Trombley, Adrienne R.; Wachter, Leslie; Garrison, Jeffrey; Buckley-Beason, Valerie A.; Jahrling, Jordan; Hensley, Lisa E.; Schoepp, Randal J.; Norwood, David A.; Goba, Augustine; Fair, Joseph N.; Kulesh, David A.

2010-01-01

Viral hemorrhagic fever is caused by a diverse group of single-stranded, negative-sense or positive-sense RNA viruses belonging to the families Filoviridae (Ebola and Marburg), Arenaviridae (Lassa, Junin, Machupo, Sabia, and Guanarito), and Bunyaviridae (hantavirus). Disease characteristics in these families mark each with the potential to be used as a biological threat agent. Because other diseases have similar clinical symptoms, specific laboratory diagnostic tests are necessary to provide the differential diagnosis during outbreaks and for instituting acceptable quarantine procedures. We designed 48 TaqMan™-based polymerase chain reaction (PCR) assays for specific and absolute quantitative detection of multiple hemorrhagic fever viruses. Forty-six assays were determined to be virus-specific, and two were designated as pan assays for Marburg virus. The limit of detection for the assays ranged from 10 to 0.001 plaque-forming units (PFU)/PCR. Although these real-time hemorrhagic fever virus assays are qualitative (presence of target), they are also quantitative (measure a single DNA/RNA target sequence in an unknown sample and express the final results as an absolute value (e.g., viral load, PFUs, or copies/mL) on the basis of concentration of standard samples and can be used in viral load, vaccine, and antiviral drug studies. PMID:20439981

Studies on the pathogenesis of fever. II. Identification of an endogenous pyrogen in the blood stream following the injection of typhoid vaccine.

PubMed

ATKINS, E; WOOD, W B

1955-11-01

Further studies have been made of a pyrogenic substance which appears in the circulation of rabbits during the course of experimental fever induced by injection of typhoid vaccine. With the use of a passive transfer method and pyrogen-tolerant recipients, the biological properties of this substance have been differentiated from those of the uncleared vaccine in the circulation. The newly identified factor resembles leucocytic pyrogen in the rapidity with which it produces fever and in its failure to exhibit cross-tolerance with bacterial pyrogen. This striking similarity of properties suggests that the circulating factor is of endogenous origin and may arise from cell injury. A close correlation between its presence in the circulation and the existence of fever has been demonstrated. The possible relationship of these findings to the pathogenesis of fever is evident.

Differential Immune Responses to New World and Old World Mammalian Arenaviruses

PubMed Central

Ly, Hinh

2017-01-01

Some New World (NW) and Old World (OW) mammalian arenaviruses are emerging, zoonotic viruses that can cause lethal hemorrhagic fever (HF) infections in humans. While these are closely related RNA viruses, the infected hosts appear to mount different types of immune responses against them. Lassa virus (LASV) infection, for example, results in suppressed immune function in progressive disease stage, whereas patients infected with Junín virus (JUNV) develop overt pro-inflammatory cytokine production. These viruses have also evolved different molecular strategies to evade host immune recognition and activation. This paper summarizes current progress in understanding the differential immune responses to pathogenic arenaviruses and how the information can be exploited toward the development of vaccines against them. PMID:28498311

Structural drivers of vulnerability to zoonotic disease in Africa.

PubMed

Dzingirai, Vupenyu; Bukachi, Salome; Leach, Melissa; Mangwanya, Lindiwe; Scoones, Ian; Wilkinson, Annie

2017-07-19

This paper argues that addressing the underlying structural drivers of disease vulnerability is essential for a 'One Health' approach to tackling zoonotic diseases in Africa. Through three case studies-trypanosomiasis in Zimbabwe, Ebola and Lassa fever in Sierra Leone and Rift Valley fever in Kenya-we show how political interests, commercial investments and conflict and securitization all generate patterns of vulnerability, reshaping the political ecology of disease landscapes, influencing traditional coping mechanisms and affecting health service provision and outbreak responses. A historical, political economy approach reveals patterns of 'structural violence' that reinforce inequalities and marginalization of certain groups, increasing disease risks. Addressing the politics of One Health requires analysing trade-offs and conflicts between interests and visions of the future. For all zoonotic diseases economic and political dimensions are ultimately critical and One Health approaches must engage with these factors, and not just end with an 'anti-political' focus on institutional and disciplinary collaboration.This article is part of the themed issue 'One Health for a changing world: zoonoses, ecosystems and human well-being'. © 2017 The Authors.

Structural drivers of vulnerability to zoonotic disease in Africa

PubMed Central

Bukachi, Salome; Mangwanya, Lindiwe; Scoones, Ian

2017-01-01

This paper argues that addressing the underlying structural drivers of disease vulnerability is essential for a ‘One Health’ approach to tackling zoonotic diseases in Africa. Through three case studies—trypanosomiasis in Zimbabwe, Ebola and Lassa fever in Sierra Leone and Rift Valley fever in Kenya—we show how political interests, commercial investments and conflict and securitization all generate patterns of vulnerability, reshaping the political ecology of disease landscapes, influencing traditional coping mechanisms and affecting health service provision and outbreak responses. A historical, political economy approach reveals patterns of ‘structural violence’ that reinforce inequalities and marginalization of certain groups, increasing disease risks. Addressing the politics of One Health requires analysing trade-offs and conflicts between interests and visions of the future. For all zoonotic diseases economic and political dimensions are ultimately critical and One Health approaches must engage with these factors, and not just end with an ‘anti-political’ focus on institutional and disciplinary collaboration. This article is part of the themed issue ‘One Health for a changing world: zoonoses, ecosystems and human well-being’. PMID:28584177

Viral haemorrhagic fevers imported into non-endemic countries: risk assessment and management.

PubMed

Bannister, Barbara

2010-01-01

Viral haemorrhagic fevers (VHFs) are severe infections capable of causing haemorrhagic disease and fatal multi-organ failure. Crimean-Congo, Marburg, Ebola and Lassa viruses cause both sporadic cases and large epidemics over wide endemic areas. Original articles and reviews identified by PubMed search and personal reading; European and United States national guidance and legislation. World Health Organization information, documents and reports. VHFs cause significant morbidity and mortality in their endemic areas; they can cause healthcare-related infections, and their broad diversity and range are increasingly recognized. There is uncertainty about the risks presented by VHFs in non-endemic countries, particularly in healthcare environments. Consensus on the best modes of care and infection control are only slowly emerging. With increasing commerce in rural and low-income areas, VHF outbreaks increasingly expand, causing social and economic damage. New ecologies, viral strains and clinical syndromes are being discovered. There is a great need for rapid diagnostic tests and effective antiviral treatments. Vaccine development programmes are challenged by multiple viral strains and the need for trials in rural communities.

Host genetic diversity enables Ebola hemorrhagic fever pathogenesis and resistance.

PubMed

Rasmussen, Angela L; Okumura, Atsushi; Ferris, Martin T; Green, Richard; Feldmann, Friederike; Kelly, Sara M; Scott, Dana P; Safronetz, David; Haddock, Elaine; LaCasse, Rachel; Thomas, Matthew J; Sova, Pavel; Carter, Victoria S; Weiss, Jeffrey M; Miller, Darla R; Shaw, Ginger D; Korth, Marcus J; Heise, Mark T; Baric, Ralph S; de Villena, Fernando Pardo-Manuel; Feldmann, Heinz; Katze, Michael G

2014-11-21

Existing mouse models of lethal Ebola virus infection do not reproduce hallmark symptoms of Ebola hemorrhagic fever, neither delayed blood coagulation and disseminated intravascular coagulation nor death from shock, thus restricting pathogenesis studies to nonhuman primates. Here we show that mice from the Collaborative Cross panel of recombinant inbred mice exhibit distinct disease phenotypes after mouse-adapted Ebola virus infection. Phenotypes range from complete resistance to lethal disease to severe hemorrhagic fever characterized by prolonged coagulation times and 100% mortality. Inflammatory signaling was associated with vascular permeability and endothelial activation, and resistance to lethal infection arose by induction of lymphocyte differentiation and cellular adhesion, probably mediated by the susceptibility allele Tek. These data indicate that genetic background determines susceptibility to Ebola hemorrhagic fever. Copyright © 2014, American Association for the Advancement of Science.

Hemorrhagic Fever with Renal Syndrome: Pathogenesis and Clinical Picture.

PubMed

Jiang, Hong; Du, Hong; Wang, Li M; Wang, Ping Z; Bai, Xue F

2016-01-01

Hantaan virus (HTNV) causes hemorrhagic fever with renal syndrome (HFRS), which is a zoonosis endemic in eastern Asia, especially in China. The reservoir host of HTNV is field mouse (Apodemus agraricus). The main manifestation of HFRS, including acute kidney injury, increases vascular permeability, and coagulation abnormalities. In this paper, we review the current knowledge of the pathogenesis of HFRS including virus factor, immunity factor and host genetic factors. Furthermore, the treatment and prevention will be discussed.

Hemorrhagic Fever with Renal Syndrome: Pathogenesis and Clinical Picture

PubMed Central

Jiang, Hong; Du, Hong; Wang, Li M.; Wang, Ping Z.; Bai, Xue F.

2016-01-01

Hantaan virus (HTNV) causes hemorrhagic fever with renal syndrome (HFRS), which is a zoonosis endemic in eastern Asia, especially in China. The reservoir host of HTNV is field mouse (Apodemus agraricus). The main manifestation of HFRS, including acute kidney injury, increases vascular permeability, and coagulation abnormalities. In this paper, we review the current knowledge of the pathogenesis of HFRS including virus factor, immunity factor and host genetic factors. Furthermore, the treatment and prevention will be discussed. PMID:26870699

Lassa virus Z protein is a matrix protein and sufficient for the release of virus-like particles [corrected].

PubMed

Strecker, Thomas; Eichler, Robert; Meulen, Jan ter; Weissenhorn, Winfried; Dieter Klenk, Hans; Garten, Wolfgang; Lenz, Oliver

2003-10-01

Lassa virus is an enveloped virus with glycoprotein spikes on its surface. It contains an RNA ambisense genome that encodes the glycoprotein precursor GP-C, the nucleoprotein NP, the polymerase L, and the Z protein. Here we demonstrate that the Lassa virus Z protein (i). is abundant in viral particles, (ii). is strongly membrane associated, (iii). is sufficient in the absence of all other viral proteins to release enveloped particles, and (iv). contains two late domains, PTAP and PPXY, necessary for the release of virus-like particles. Our data provide evidence that Z is the Lassa virus matrix protein that is the driving force for virus particle release.

Taking forward a 'One Health' approach for turning the tide against the Middle East respiratory syndrome coronavirus and other zoonotic pathogens with epidemic potential.

PubMed

Zumla, Alimuddin; Dar, Osman; Kock, Richard; Muturi, Matthew; Ntoumi, Francine; Kaleebu, Pontiano; Eusebio, Macete; Mfinanga, Sayoki; Bates, Matthew; Mwaba, Peter; Ansumana, Rashid; Khan, Mishal; Alagaili, Abdulaziz N; Cotten, Matthew; Azhar, Esam I; Maeurer, Markus; Ippolito, Giuseppe; Petersen, Eskild

2016-06-01

The appearance of novel pathogens of humans with epidemic potential and high mortality rates have threatened global health security for centuries. Over the past few decades new zoonotic infectious diseases of humans caused by pathogens arising from animal reservoirs have included West Nile virus, Yellow fever virus, Ebola virus, Nipah virus, Lassa Fever virus, Hanta virus, Dengue fever virus, Rift Valley fever virus, Crimean-Congo haemorrhagic fever virus, severe acute respiratory syndrome coronavirus, highly pathogenic avian influenza viruses, Middle East Respiratory Syndrome Coronavirus, and Zika virus. The recent Ebola Virus Disease epidemic in West Africa and the ongoing Zika Virus outbreak in South America highlight the urgent need for local, regional and international public health systems to be be more coordinated and better prepared. The One Health concept focuses on the relationship and interconnectedness between Humans, Animals and the Environment, and recognizes that the health and wellbeing of humans is intimately connected to the health of animals and their environment (and vice versa). Critical to the establishment of a One Health platform is the creation of a multidisciplinary team with a range of expertise including public health officers, physicians, veterinarians, animal husbandry specialists, agriculturalists, ecologists, vector biologists, viral phylogeneticists, and researchers to co-operate, collaborate to learn more about zoonotic spread between animals, humans and the environment and to monitor, respond to and prevent major outbreaks. We discuss the unique opportunities for Middle Eastern and African stakeholders to take leadership in building equitable and effective partnerships with all stakeholders involved in human and health systems to take forward a 'One Health' approach to control such zoonotic pathogens with epidemic potential. Copyright © 2016 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Development and Characterization of a Mouse Model for Marburg Hemorrhagic Fever

DTIC Science & Technology

2009-07-01

Microbiology. All Rights Reserved. Development and Characterization of a Mouse Model for Marburg Hemorrhagic Fever Kelly L. Warfield,* Steven B...mouse model has hampered an understanding of the pathogenesis and immunity of Marburg hemorrhagic fever (MHF), the disease caused by marburgvirus (MARV...cause severe hemorrhagic fevers in humans and non- human primates (27). The incubation time is estimated to be 3 to 21 days, with human case fatality

Problems associated with the control of rodents in tropical Africa

PubMed Central

Gratz, N. G.; Arata, A. A.

1975-01-01

As elsewhere in the world, rodents are responsible for very considerable economic losses in tropical Africa because of their depredations on both growing crops and stored food products. Unfortunately, few accurate data are available on the extent of these losses but there is evidence that they are considerable. The public health importance of rodents, both as reservoirs and vectors of disease in tropical Africa, is also great; plague, leptospirosis, murine typhus, and Lassa fever are among the diseases associated with rodent hosts. Scientifically based rodent control programmes have been carried out in very few areas of Africa and there is urgent need for studies and demonstrations on rodent control in both urban and rural areas. The problems likely to be encountered are reviewed and methods of control proposed. PMID:1085224

Far East Scarlet-Like Fever: A Review of the Epidemiology, Symptomatology, and Role of Superantigenic Toxin: Yersinia pseudotuberculosis-Derived Mitogen A

PubMed Central

Amphlett, A.

2016-01-01

Far East scarlet-like fever (FESLF) is a severe inflammatory disease that occurs sporadically and in outbreaks in Russia and Japan. Far East scarlet-like fever is caused by Yersinia pseudotubuclosis infection, an organism that typically causes self-limiting gastroenteritis in Europe. Studies suggest the ability of Far Eastern strains to produce superantigen toxin Y pseudotuberculosis-derived mitogen A is integral to FESLF pathogenesis. In Europe, human Y pseudotuberculosis infection typically occurs sporadically, in the form of a self-limiting gastroenteritis. In Russia and Japan, outbreaks of Y pseudotuberculosis infection cause severe systemic inflammatory symptoms. This disease variant is called FESLF. Geographical heterogeneity exists between virulence factors produced by European and Far Eastern Y pseudotuberculosis strains, implicating superantigen Y pseudotuberculosis-derived mitogen A (YPMa) in the pathogenesis of FESLF. This article describes the epidemiology and clinical features of FESLF, and it presents the evidence for the role of YPMa in FESLF pathogenesis. PMID:26819960

Far East Scarlet-Like Fever: A Review of the Epidemiology, Symptomatology, and Role of Superantigenic Toxin: Yersinia pseudotuberculosis-Derived Mitogen A.

PubMed

Amphlett, A

2016-01-01

Far East scarlet-like fever (FESLF) is a severe inflammatory disease that occurs sporadically and in outbreaks in Russia and Japan. Far East scarlet-like fever is caused by Yersinia pseudotubuclosis infection, an organism that typically causes self-limiting gastroenteritis in Europe. Studies suggest the ability of Far Eastern strains to produce superantigen toxin Y pseudotuberculosis-derived mitogen A is integral to FESLF pathogenesis. In Europe, human Y pseudotuberculosis infection typically occurs sporadically, in the form of a self-limiting gastroenteritis. In Russia and Japan, outbreaks of Y pseudotuberculosis infection cause severe systemic inflammatory symptoms. This disease variant is called FESLF. Geographical heterogeneity exists between virulence factors produced by European and Far Eastern Y pseudotuberculosis strains, implicating superantigen Y pseudotuberculosis-derived mitogen A (YPMa) in the pathogenesis of FESLF. This article describes the epidemiology and clinical features of FESLF, and it presents the evidence for the role of YPMa in FESLF pathogenesis.

Updates in diagnosis and management of Ebola hemorrhagic fever

PubMed Central

El Sayed, Salah Mohamed; Abdelrahman, Ali A.; Ozbak, Hani Adnan; Hemeg, Hassan Abdullah; Kheyami, Ali Mohammed; Rezk, Nasser; El-Ghoul, Mohamed Baioumy; Nabo, Manal Mohamed Helmy; Fathy, Yasser Mohamed

2016-01-01

Ebola hemorrhagic fever is a lethal viral disease transmitted by contact with infected people and animals. Ebola infection represents a worldwide health threat causing enormous mortality rates and fatal epidemics. Major concern is pilgrimage seasons with possible transmission to Middle East populations. In this review, we aim to shed light on Ebola hemorrhagic fever as regard: virology, transmission, biology, pathogenesis, clinical picture, and complications to get the best results for prevention and management. We also aim to guide future research to new therapeutic perspectives to precise targets. Our methodology was to review the literature extensively to make an overall view of the biology of Ebola virus infection, its serious health effects and possible therapeutic benefits using currently available remedies and future perspectives. Key findings in Ebola patients are fever, hepatic impairment, hepatocellular necrosis, lymphopenia (for T-lymphocyte and natural killer cells) with lymphocyte apoptosis, hemorrhagic manifestations, and complications. Pathogenesis in Ebola infection includes oxidative stress, immune suppression of both cell-mediated and humoral immunities, hepatic and adrenal impairment and failure, hemorrhagic fever, activation of deleterious inflammatory pathways, for example, tumor necrosis factor-related apoptosis-inducing ligand, and factor of apoptotic signal death receptor pathways causing lymphocyte depletion. Several inflammatory mediators and cytokines are involved in pathogenesis, for example, interleukin-2, 6, 8, and 10 and others. In conclusion, Ebola hemorrhagic fever is a serious fatal viral infection that can be prevented using strict health measures and can be treated to some extent using some currently available remedies. Newer treatment lines, for example, prophetic medicine remedies as nigella sativa may be promising. PMID:28163730

Updates in diagnosis and management of Ebola hemorrhagic fever.

PubMed

El Sayed, Salah Mohamed; Abdelrahman, Ali A; Ozbak, Hani Adnan; Hemeg, Hassan Abdullah; Kheyami, Ali Mohammed; Rezk, Nasser; El-Ghoul, Mohamed Baioumy; Nabo, Manal Mohamed Helmy; Fathy, Yasser Mohamed

2016-01-01

Ebola hemorrhagic fever is a lethal viral disease transmitted by contact with infected people and animals. Ebola infection represents a worldwide health threat causing enormous mortality rates and fatal epidemics. Major concern is pilgrimage seasons with possible transmission to Middle East populations. In this review, we aim to shed light on Ebola hemorrhagic fever as regard: virology, transmission, biology, pathogenesis, clinical picture, and complications to get the best results for prevention and management. We also aim to guide future research to new therapeutic perspectives to precise targets. Our methodology was to review the literature extensively to make an overall view of the biology of Ebola virus infection, its serious health effects and possible therapeutic benefits using currently available remedies and future perspectives. Key findings in Ebola patients are fever, hepatic impairment, hepatocellular necrosis, lymphopenia (for T-lymphocyte and natural killer cells) with lymphocyte apoptosis, hemorrhagic manifestations, and complications. Pathogenesis in Ebola infection includes oxidative stress, immune suppression of both cell-mediated and humoral immunities, hepatic and adrenal impairment and failure, hemorrhagic fever, activation of deleterious inflammatory pathways, for example, tumor necrosis factor-related apoptosis-inducing ligand, and factor of apoptotic signal death receptor pathways causing lymphocyte depletion. Several inflammatory mediators and cytokines are involved in pathogenesis, for example, interleukin-2, 6, 8, and 10 and others. In conclusion, Ebola hemorrhagic fever is a serious fatal viral infection that can be prevented using strict health measures and can be treated to some extent using some currently available remedies. Newer treatment lines, for example, prophetic medicine remedies as nigella sativa may be promising.

The Jeremiah Metzger Lecture. The pathogenesis of fever in human subjects.

PubMed Central

Wolff, S. M.; Dinarello, C. A.

1980-01-01

The pathogenesis of fever in man begins with the production of endogenous pyrogen by phagocytic leukocytes in response to exogenous pyrogens (toxic, immunologic or infectious agents). Endogenous pyrogen, a protein, is released from a variety of phagocytic leukocytes and enters the circulation after new messenger RNA and protein are synthesized. Fever is caused by an interaction of endogenous pyrogen with specialized receptors on or near thermosensitive neurons in the thermoregulatory center of the anterior hypothalamus. This interaction may cause local hypothalamic production of prostaglandins, monoamines and, possibly, cyclic AMP. From the anterior hypothalamus, information is transmitted through the posterior hypothalamus to the vasomotor center, which directs sympathetic-nerve fibers to constrict peripheral vessels and decrease heat dissipation. PMID:552177

Pathogenesis of Cell Injury by Rickettsia conorii

DTIC Science & Technology

1986-11-26

patients with boutonneuse fever who consented to liver biopsy had hepatic lesions. This suggests that R. conorli is fre- quently viscerotropic and in...patients with particular risk factors poses a serious threat. Cl inlcoepidemlologic studies with European collaborators depict boutonneuse fever as...Statement of Problem Spotted fever group rickettsiae including Rickettsia conorli, R. sibirica, and R. akari are important potential causes of military

Fever: Its History, Cause, and Function

PubMed Central

Atkins, Elisha

1982-01-01

Concepts of fever from Hippocrates to the present are briefly outlined and compared with current ideas of the pathogenesis of fever. Evidence is presented that endogenous pyrogen, the hormone that elevates body temperature, is identical with lymphocyte-activating factor, a monokine that stimulates lymphocyte proliferation and function. It now appears that inflammation and fever are closely interrelated phenomena that are modulated by a single hormone and that have been selected by evolution to protect the host against infection. PMID:6758374

A tribute to Sheik Humarr Khan and all the healthcare workers in West Africa who have sacrificed in the fight against Ebola virus disease: Mae we hush.

PubMed

Bausch, Daniel G; Bangura, James; Garry, Robert F; Goba, Augustine; Grant, Donald S; Jacquerioz, Frederique A; McLellan, Susan L; Jalloh, Simbirie; Moses, Lina M; Schieffelin, John S

2014-11-01

The Kenema Government Hospital Lassa Fever Ward in Sierra Leone, directed since 2005 by Dr. Sheikh Humarr Khan, is the only medical unit in the world devoted exclusively to patient care and research of a viral hemorrhagic fever. When Ebola virus disease unexpectedly appeared in West Africa in late 2013 and eventually spread to Kenema, Khan and his fellow healthcare workers remained at their posts, providing care to patients with this devastating illness. Khan and the chief nurse, Mbalu Fonnie, became infected and died at the end of July, a fate that they have sadly shared with more than ten other healthcare workers in Kenema and hundreds across the region. This article pays tribute to Sheik Humarr Khan, Mbalu Fonnie and all the healthcare workers who have acquired Ebola virus disease while fighting the epidemic in West Africa. Besides the emotional losses, the death of so many skilled and experienced healthcare workers will severely impair health care and research in affected regions, which can only be restored through dedicated, long-term programs. Copyright © 2014. Published by Elsevier B.V.

Interferon-driven alterations of the host's amino acid metabolism in the pathogenesis of typhoid fever.

PubMed

Blohmke, Christoph J; Darton, Thomas C; Jones, Claire; Suarez, Nicolas M; Waddington, Claire S; Angus, Brian; Zhou, Liqing; Hill, Jennifer; Clare, Simon; Kane, Leanne; Mukhopadhyay, Subhankar; Schreiber, Fernanda; Duque-Correa, Maria A; Wright, James C; Roumeliotis, Theodoros I; Yu, Lu; Choudhary, Jyoti S; Mejias, Asuncion; Ramilo, Octavio; Shanyinde, Milensu; Sztein, Marcelo B; Kingsley, Robert A; Lockhart, Stephen; Levine, Myron M; Lynn, David J; Dougan, Gordon; Pollard, Andrew J

2016-05-30

Enteric fever, caused by Salmonella enterica serovar Typhi, is an important public health problem in resource-limited settings and, despite decades of research, human responses to the infection are poorly understood. In 41 healthy adults experimentally infected with wild-type S. Typhi, we detected significant cytokine responses within 12 h of bacterial ingestion. These early responses did not correlate with subsequent clinical disease outcomes and likely indicate initial host-pathogen interactions in the gut mucosa. In participants developing enteric fever after oral infection, marked transcriptional and cytokine responses during acute disease reflected dominant type I/II interferon signatures, which were significantly associated with bacteremia. Using a murine and macrophage infection model, we validated the pivotal role of this response in the expression of proteins of the host tryptophan metabolism during Salmonella infection. Corresponding alterations in tryptophan catabolites with immunomodulatory properties in serum of participants with typhoid fever confirmed the activity of this pathway, and implicate a central role of host tryptophan metabolism in the pathogenesis of typhoid fever. © 2016 Blohmke et al.

Interferon-driven alterations of the host’s amino acid metabolism in the pathogenesis of typhoid fever

PubMed Central

Jones, Claire; Waddington, Claire S.; Zhou, Liqing; Hill, Jennifer; Clare, Simon; Mukhopadhyay, Subhankar; Schreiber, Fernanda; Roumeliotis, Theodoros I.; Yu, Lu; Ramilo, Octavio; Sztein, Marcelo B.; Kingsley, Robert A.; Levine, Myron M.

2016-01-01

Enteric fever, caused by Salmonella enterica serovar Typhi, is an important public health problem in resource-limited settings and, despite decades of research, human responses to the infection are poorly understood. In 41 healthy adults experimentally infected with wild-type S. Typhi, we detected significant cytokine responses within 12 h of bacterial ingestion. These early responses did not correlate with subsequent clinical disease outcomes and likely indicate initial host–pathogen interactions in the gut mucosa. In participants developing enteric fever after oral infection, marked transcriptional and cytokine responses during acute disease reflected dominant type I/II interferon signatures, which were significantly associated with bacteremia. Using a murine and macrophage infection model, we validated the pivotal role of this response in the expression of proteins of the host tryptophan metabolism during Salmonella infection. Corresponding alterations in tryptophan catabolites with immunomodulatory properties in serum of participants with typhoid fever confirmed the activity of this pathway, and implicate a central role of host tryptophan metabolism in the pathogenesis of typhoid fever. PMID:27217537

Malignant catarrhal fever: understanding molecular diagnostics in context of epidemiology

USDA-ARS?s Scientific Manuscript database

Malignant catarrhal fever (MCF) is a frequently fatal disease, primarily of ruminants, caused by a group of gammaherpesviruses. Due to complexities of pathogenesis and epidemiology in various species which are either clinically-susceptible or reservoir hosts, veterinary clinicians face significant ...

Pathogenesis of highly-pathogenic Asian PRRSV in pigs

USDA-ARS?s Scientific Manuscript database

In 2006, Chinese investigators reported a unique syndrome in growing swine that was highlighted by clinical signs of high fever, anorexia, listlessness, red discoloration of skin, respiratory distress and very high morbidity and mortality rates. Originally known as porcine high fever disease (PHFD),...

Role of Endotoxin in the Pathogenesis of Louse-borne Relapsing Fever and in the Mechanism of the Jarisch-Herxheimer Reaction Following Treatment of Louse-borne Relapsing Fever

DTIC Science & Technology

1977-12-01

therapy and during the Jarisch-Herxheimer-like reaction. Further similarities between relapsing fever and Gram-negative bacteremic diseases were sought by...activated during Gram- negative bacterial infections (11-17). The aims of therapy should be to clear the blood of circulating spirochetes without relapse and...more slowly with more prolonged fever. Single dose therapy with intravenous tetracycline [1,2] and oral doxycycline [18] has been shown effective, but

Investigations of Pro- and Anti-Apoptotic Factors Affecting African Swine Fever Virus Replication and Pathogenesis.

PubMed

Dixon, Linda K; Sánchez-Cordón, Pedro J; Galindo, Inmaculada; Alonso, Covadonga

2017-08-25

African swine fever virus (ASFV) is a large DNA virus that replicates predominantly in the cell cytoplasm and is the only member of the Asfarviridae family. The virus causes an acute haemorrhagic fever, African swine fever (ASF), in domestic pigs and wild boar resulting in the death of most infected animals. Apoptosis is induced at an early stage during virus entry or uncoating. However, ASFV encodes anti-apoptotic proteins which facilitate production of progeny virions. These anti-apoptotic proteins include A179L, a Bcl-2 family member; A224L, an inhibitor of apoptosis proteins (IAP) family member; EP153R a C-type lectin; and DP71L. The latter acts by inhibiting activation of the stress activated pro-apoptotic pathways pro-apoptotic pathways. The mechanisms by which these proteins act is summarised. ASF disease is characterised by massive apoptosis of uninfected lymphocytes which reduces the effectiveness of the immune response, contributing to virus pathogenesis. Mechanisms by which this apoptosis is induced are discussed.

Investigations of Pro- and Anti-Apoptotic Factors Affecting African Swine Fever Virus Replication and Pathogenesis

PubMed Central

Dixon, Linda K.; Sánchez-Cordón, Pedro J.; Galindo, Inmaculada

2017-01-01

African swine fever virus (ASFV) is a large DNA virus that replicates predominantly in the cell cytoplasm and is the only member of the Asfarviridae family. The virus causes an acute haemorrhagic fever, African swine fever (ASF), in domestic pigs and wild boar resulting in the death of most infected animals. Apoptosis is induced at an early stage during virus entry or uncoating. However, ASFV encodes anti-apoptotic proteins which facilitate production of progeny virions. These anti-apoptotic proteins include A179L, a Bcl-2 family member; A224L, an inhibitor of apoptosis proteins (IAP) family member; EP153R a C-type lectin; and DP71L. The latter acts by inhibiting activation of the stress activated pro-apoptotic pathways pro-apoptotic pathways. The mechanisms by which these proteins act is summarised. ASF disease is characterised by massive apoptosis of uninfected lymphocytes which reduces the effectiveness of the immune response, contributing to virus pathogenesis. Mechanisms by which this apoptosis is induced are discussed. PMID:28841179

The model of response to viral haemorrhagic fevers of the National Institute for Infectious Diseases "Lazzaro Spallanzani".

PubMed

Armignacco, O; Lauria, F N; Puro, V; Macrì, G; Petrecchia, A; Ippolito, G

2001-01-01

Viral haemorrhagic fevers (VHF) are severe and life-threatening diseases caused by a range of viruses. However, only four agents of VHF are known to be readily capable of person-to-person spread: Lassa virus, Crimean/Congo haemorrhagic fever virus, Ebola and Marburg viruses. Diseases caused by these viruses are endemic only in few areas in the world, most notably Africa and some rural parts of the Middle East and Eastern Europe. Nonetheless, the increasing volume of international travel presents a greater likelihood for the importation of these infections or of suspected cases in non endemic countries. Four conditions can lead to the importation and to the subsequent recognition of VHF within Europe: 1) patients arriving as a result of a planned medical evacuation; 2) persons who became sick on route to their destination; 3) persons discovered ill when entering a country, for example during routine clinical examination at the airport; 4) persons becoming sick after their arrival. Public health implications and the risk of secondary spread of pathogens in the above reported circumstances are very different. Similarly, preparedness and response should vary. This paper summarizes the present knowledge on the four VHF capable of person-to-person spread, describes the high isolation area constructed at the Italian National Institute for Infectious Diseases Lazzaro Spallanzani in Rome to respond to the occurrence of VHF. A brief overview of procedures and equipment adopted is provided.

PATHOGENESIS OF FEVER: EFFECTS OF VARIOUS ENDOGENOUS PYROGENS UPON THE LEVEL OF CIRCULATING GRANULOCYTES IN NORMAL RABBITS

PubMed Central

King, M. K.

1960-01-01

The endogenous pyrogen in the serum or plasma of rabbits 2 hours after the intravenous injection of typhoid vaccine had a marked effect on the circulating leucocytes of normal rabbits. Immediately following intravenous injection there was a brief, but marked, granulocytopenia which was quickly followed by a granulocytosis. Under the same circumstances pooled heterologous serum or plasma from normal rabbits produced no fever or significant change in the level of circulating leucocytes. The cell-free fluid of sterile peritoneal exudates produced a marked leucocytosis without a preceding leucopenia when injected intravenously into normal rabbits. When comparably pyrogenic doses of typhoid vaccine were injected in the same manner no significant change in the level of circulating leucocytes occurred. The relevance of these findings to the pathogenesis of fever is discussed. PMID:13756095

Pathogenesis of fever: effects of various endogenous pyrogens upon the level of circulating granulocytes in normal rabbits.

PubMed

KING, M K

1960-11-01

The endogenous pyrogen in the serum or plasma of rabbits 2 hours after the intravenous injection of typhoid vaccine had a marked effect on the circulating leucocytes of normal rabbits. Immediately following intravenous injection there was a brief, but marked, granulocytopenia which was quickly followed by a granulocytosis. Under the same circumstances pooled heterologous serum or plasma from normal rabbits produced no fever or significant change in the level of circulating leucocytes. The cell-free fluid of sterile peritoneal exudates produced a marked leucocytosis without a preceding leucopenia when injected intravenously into normal rabbits. When comparably pyrogenic doses of typhoid vaccine were injected in the same manner no significant change in the level of circulating leucocytes occurred. The relevance of these findings to the pathogenesis of fever is discussed.

Yellow fever.

PubMed

Monath, Thomas P; Vasconcelos, Pedro F C

2015-03-01

Yellow fever, a mosquito-borne flavivirus disease occurs in tropical areas of South America and Africa. It is a disease of major historical importance, but remains a threat to travelers to and residents of endemic areas despite the availability of an effective vaccine for nearly 70 years. An important aspect is the receptivity of many non-endemic areas to introduction and spread of yellow fever. This paper reviews the clinical aspects, pathogenesis, and epidemiology of yellow fever, with an emphasis on recent changes in the distribution and incidence of the disease. Recent knowledge about yellow fever 17D vaccine mechanism of action and safety are discussed. Copyright © 2014 Elsevier B.V. All rights reserved.

Role of LAMP1 Binding and pH Sensing by the Spike Complex of Lassa Virus.

PubMed

Cohen-Dvashi, Hadas; Israeli, Hadar; Shani, Orly; Katz, Aliza; Diskin, Ron

2016-11-15

To effectively infect cells, Lassa virus needs to switch in an endosomal compartment from its primary receptor, α-dystroglycan, to a protein termed LAMP1. A unique histidine triad on the surface of the receptor-binding domain from the glycoprotein spike complex of Lassa virus is important for LAMP1 binding. Here we investigate mutated spikes that have an impaired ability to interact with LAMP1 and show that although LAMP1 is important for efficient infectivity, it is not required for spike-mediated membrane fusion per se Our studies reveal important regulatory roles for histidines from the triad in sensing acidic pH and preventing premature spike triggering. We further show that LAMP1 requires a positively charged His230 residue to engage with the spike complex and that LAMP1 binding promotes membrane fusion. These results elucidate the molecular role of LAMP1 binding during Lassa virus cell entry and provide new insights into how pH is sensed by the spike. Lassa virus is a devastating disease-causing agent in West Africa, with a significant yearly death toll and severe long-term complications associated with its infection in survivors. In recent years, we learned that Lassa virus needs to switch receptors in a pH-dependent manner to efficiently infect cells, but neither the molecular mechanisms that allow switching nor the actual effects of switching were known. Here we investigate the activity of the viral spike complex after abrogation of its ability to switch receptors. These studies inform us about the role of switching receptors and provide new insights into how the spike senses acidic pH. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Intrahypothalamic Injection of the HIV-1 Envelope Glycoprotein Induces Fever via Interaction with the Chemokine System

PubMed Central

Addou, Saad; Yondorf, Menachem; Geller, Ellen B.; Eisenstein, Toby K.; Adler, Martin W.

2010-01-01

Wasting syndrome is a common complication of HIV infection and is marked by progressive weight loss and weakness, often associated with fever. The mechanisms involved in the pathogenesis of these syndromes are not well defined, and neither are the brain areas involved. The present study tests a new hypothesis: that the preoptic anterior hypothalamus (POAH), the main brain area for thermoregulation and fever, has a role in the pathogenesis of fever induced by glycoprotein 120 (gp120), the surface envelope protein used by the HIV to gain access into immune cells, and that the CXC chemokine receptors (CXCR4) that serve as a coreceptor for HIV entry mediate the effect. A sterilized stainless steel C313G cannula guide was implanted into the POAH, and a biotelemetry system was used to monitor the body temperature (Tb) changes. The administration of gp120 into the POAH induced fever in a dose-dependent manner. To demonstrate possible links between the gp120 and CXCR4 in generating the fever, we pretreated the rats with 1,1′-[1,4-phenylenebis(methylene)]bis[1,4,8,11-tetraazacyclotetradecane] octohydrobromide dihydrate (AMD 3100), an antagonist of stromal cell-derived growth factor (SDF)-1α/CXCL12, acting at its receptor, CXCR4, 30 min before administration of gp120. AMD 3100 significantly reduced the gp120-induced fever. The present studies show that the presence of HIV-1 envelope glycoprotein gp120 in the POAH provokes fever via interaction CXCR4 pathway. PMID:19906780

Chimpanzee adenoviral vectors as vaccines for outbreak pathogens

PubMed Central

2017-01-01

ABSTRACT The 2014–15 Ebola outbreak in West Africa highlighted the potential for large disease outbreaks caused by emerging pathogens and has generated considerable focus on preparedness for future epidemics. Here we discuss drivers, strategies and practical considerations for developing vaccines against outbreak pathogens. Chimpanzee adenoviral (ChAd) vectors have been developed as vaccine candidates for multiple infectious diseases and prostate cancer. ChAd vectors are safe and induce antigen-specific cellular and humoral immunity in all age groups, as well as circumventing the problem of pre-existing immunity encountered with human Ad vectors. For these reasons, such viral vectors provide an attractive platform for stockpiling vaccines for emergency deployment in response to a threatened outbreak of an emerging pathogen. Work is already underway to develop vaccines against a number of other outbreak pathogens and we will also review progress on these approaches here, particularly for Lassa fever, Nipah and MERS. PMID:29083948

Mammarenaviruses deleted from their Z gene are replicative and produce an infectious progeny in BHK-21 cells.

PubMed

Zaza, Amélie D; Herbreteau, Cécile H; Peyrefitte, Christophe N; Emonet, Sébastien F

2018-05-01

Mammarenaviruses bud out of infected cells via the recruitment of the endosomal sorting complex required for transport through late domain motifs localized into their Z protein. Here, we demonstrated that mammarenaviruses lacking this protein can be rescued and are replicative, despite a 3-log reduction in virion production, in BHK-21 cells, but not in five other cell lines. Mutations of putative late domain motifs identified into the viral nucleoprotein resulted in the almost complete abolition of infectious virion production by Z-deleted mammarenaviruses. This result strongly suggested that the nucleoprotein may compensate for the deletion of Z. These observations were primarily obtained using the Lymphocytic choriomeningitis virus, and further confirmed using the Old World Lassa and New World Machupo viruses, responsible of human hemorrhagic fevers. Z-deleted viruses should prove very useful tools to investigate the biology of Mammarenaviruses. Copyright © 2018 Elsevier Inc. All rights reserved.

Studies on the pathogenesis of fever. III. The leucocytic origin of endogenous pyrogen in acute inflammatory exudates.

PubMed

KING, M K; WOOD, W B

1958-02-01

The evolution of an acute inflammatory exudate produced in rabbits by the intraperitoneal injection of saline has been described. Evidence has been presented that polymorphonuclear leucocytes release endogenous pyrogen into the cell-free fluid of the exudate. Leucocytes from such exudates have also been shown to release pyrogen into the surrounding medium during incubation in vitro at 37 degrees C. The results of parallel cytological studies have provided evidence which suggests that the leucocytes give up their pyrogen while functionally intact. These observations add further support to the hypothesis that polymorphonuclear leucocytes play a significant role in the pathogenesis of fever.

STUDIES ON THE PATHOGENESIS OF FEVER

PubMed Central

King, M. Kenton; Wood, W. Barry

1958-01-01

By means of a method designed to compare the febrile responses produced by intracarotid and intravenous injections, the endogenous pyrogen, which is contained in leucocytic exudates and is present in the serum of rabbits 2 hours after intravenous injections of typhoid vaccine, has been shown to act directly upon the thermoregulatory centers of the brain. In contrast, the exogenous bacterial pyrogen present in serum obtained 5 minutes after vaccine injections was found to act by a different and less direct mechanism. These observations add strong support to the original hypothesis that endogenous pyrogen, presumably derived from polymorphonuclear leucocytes, is an essential factor in the pathogenesis of endotoxin fever. PMID:13491763

The role of endothelial activation in dengue hemorrhagic fever and hantavirus pulmonary syndrome

PubMed Central

Spiropoulou, Christina F; Srikiatkhachorn, Anon

2013-01-01

The loss of the endothelium barrier and vascular leakage play a central role in the pathogenesis of hemorrhagic fever viruses. This can be caused either directly by the viral infection and damage of the vascular endothelium, or indirectly by a dysregulated immune response resulting in an excessive activation of the endothelium. This article briefly reviews our knowledge of the importance of the disruption of the vascular endothelial barrier in two severe disease syndromes, dengue hemorrhagic fever and hantavirus pulmonary syndrome. Both viruses cause changes in vascular permeability without damaging the endothelium. Here we focus on our understanding of the virus interaction with the endothelium, the role of the endothelium in the induced pathogenesis, and the possible mechanisms by which each virus causes vascular leakage. Understanding the dynamics between viral infection and the dysregulation of the endothelial cell barrier will help us to define potential therapeutic targets for reducing disease severity. PMID:23841977

The role of endothelial activation in dengue hemorrhagic fever and hantavirus pulmonary syndrome.

PubMed

Spiropoulou, Christina F; Srikiatkhachorn, Anon

2013-08-15

The loss of the endothelium barrier and vascular leakage play a central role in the pathogenesis of hemorrhagic fever viruses. This can be caused either directly by the viral infection and damage of the vascular endothelium, or indirectly by a dysregulated immune response resulting in an excessive activation of the endothelium. This article briefly reviews our knowledge of the importance of the disruption of the vascular endothelial barrier in two severe disease syndromes, dengue hemorrhagic fever and hantavirus pulmonary syndrome. Both viruses cause changes in vascular permeability without damaging the endothelium. Here we focus on our understanding of the virus interaction with the endothelium, the role of the endothelium in the induced pathogenesis, and the possible mechanisms by which each virus causes vascular leakage. Understanding the dynamics between viral infection and the dysregulation of the endothelial cell barrier will help us to define potential therapeutic targets for reducing disease severity.

STUDIES ON THE PATHOGENESIS OF FEVER WITH INFLUENZAL VIRUSES

PubMed Central

Atkins, Elisha; Huang, Wei Cheng

1958-01-01

A substance with pyrogenic properties appears in the blood streams of rabbits made febrile by the intravenous inoculation of the PR8 strain of influenza A and Newcastle disease viruses (NDV). By means of a technique involving passive transfer of sera from animals given virus to recipient rabbits, the titer of circulating pyrogen was found to be closely correlated with the course of fever produced by virus. Certain properties of the pyrogen are described which differentiate it from the originally injected virus and suggest that the induced pyrogen is of endogenous origin. These properties resemble those of endogenous pyrogens occurring in other forms of experimental fever. The source of virus-induced pyrogen is unknown. In vitro incubation of virus with various constituents of the circulation did not result in the appearance of endogenous pyrogen. Granulocytopenia induced by HN2 failed to influence either fever or the production of endogenous pyrogen in rabbits injected with NDV. Similarly, the intraperitoneal inoculation of NDV into prepared exudates did not modify the febrile response. These findings do not lend support to the possibility that the polymorphonuclear leukocyte is a significant source of endogenous pyrogen in virus-induced fever. It is concluded that the liberation of an endogenous pyrogen from some as yet undefined source is an essential step in the pathogenesis of fever caused by the influenza group of viruses. PMID:13513908

Local disease–ecosystem–livelihood dynamics: reflections from comparative case studies in Africa

PubMed Central

Bett, Bernard; Said, M.; Bukachi, Salome; Sang, Rosemary; Anderson, Neil; Machila, Noreen; Kuleszo, Joanna; Schaten, Kathryn; Mangwanya, Lindiwe; Ntiamoa-Baidu, Yaa; Lawson, Elaine; Amponsah-Mensah, Kofi; Moses, Lina M.; Grant, Donald S.; Koninga, James

2017-01-01

This article explores the implications for human health of local interactions between disease, ecosystems and livelihoods. Five interdisciplinary case studies addressed zoonotic diseases in African settings: Rift Valley fever (RVF) in Kenya, human African trypanosomiasis in Zambia and Zimbabwe, Lassa fever in Sierra Leone and henipaviruses in Ghana. Each explored how ecological changes and human–ecosystem interactions affect pathogen dynamics and hence the likelihood of zoonotic spillover and transmission, and how socially differentiated peoples’ interactions with ecosystems and animals affect their exposure to disease. Cross-case analysis highlights how these dynamics vary by ecosystem type, across a range from humid forest to semi-arid savannah; the significance of interacting temporal and spatial scales; and the importance of mosaic and patch dynamics. Ecosystem interactions and services central to different people's livelihoods and well-being include pastoralism and agro-pastoralism, commercial and subsistence crop farming, hunting, collecting food, fuelwood and medicines, and cultural practices. There are synergies, but also tensions and trade-offs, between ecosystem changes that benefit livelihoods and affect disease. Understanding these can inform ‘One Health’ approaches towards managing ecosystems in ways that reduce disease risks and burdens. This article is part of the themed issue ‘One Health for a changing world: zoonoses, ecosystems and human well-being’. PMID:28584171

Local disease-ecosystem-livelihood dynamics: reflections from comparative case studies in Africa.

PubMed

Leach, Melissa; Bett, Bernard; Said, M; Bukachi, Salome; Sang, Rosemary; Anderson, Neil; Machila, Noreen; Kuleszo, Joanna; Schaten, Kathryn; Dzingirai, Vupenyu; Mangwanya, Lindiwe; Ntiamoa-Baidu, Yaa; Lawson, Elaine; Amponsah-Mensah, Kofi; Moses, Lina M; Wilkinson, Annie; Grant, Donald S; Koninga, James

2017-07-19

This article explores the implications for human health of local interactions between disease, ecosystems and livelihoods. Five interdisciplinary case studies addressed zoonotic diseases in African settings: Rift Valley fever (RVF) in Kenya, human African trypanosomiasis in Zambia and Zimbabwe, Lassa fever in Sierra Leone and henipaviruses in Ghana. Each explored how ecological changes and human-ecosystem interactions affect pathogen dynamics and hence the likelihood of zoonotic spillover and transmission, and how socially differentiated peoples' interactions with ecosystems and animals affect their exposure to disease. Cross-case analysis highlights how these dynamics vary by ecosystem type, across a range from humid forest to semi-arid savannah; the significance of interacting temporal and spatial scales; and the importance of mosaic and patch dynamics. Ecosystem interactions and services central to different people's livelihoods and well-being include pastoralism and agro-pastoralism, commercial and subsistence crop farming, hunting, collecting food, fuelwood and medicines, and cultural practices. There are synergies, but also tensions and trade-offs, between ecosystem changes that benefit livelihoods and affect disease. Understanding these can inform 'One Health' approaches towards managing ecosystems in ways that reduce disease risks and burdens.This article is part of the themed issue 'One Health for a changing world: zoonoses, ecosystems and human well-being'. © 2017 The Authors.

Experimental respiratory Marburg virus haemorrhagic fever infection in the common marmoset (Callithrix jacchus)

PubMed Central

Smither, Sophie J; Nelson, Michelle; Eastaugh, Lin; Laws, Thomas R; Taylor, Christopher; Smith, Simon A; Salguero, Francisco J; Lever, Mark S

2013-01-01

Marburg virus causes a highly infectious and lethal haemorrhagic fever in primates and may be exploited as a potential biothreat pathogen. To combat the infection and threat of Marburg haemorrhagic fever, there is a need to develop and license appropriate medical countermeasures. To determine whether the common marmoset (Callithrix jacchus) would be an appropriate model to assess therapies against Marburg haemorrhagic fever, initial susceptibility, lethality and pathogenesis studies were performed. Low doses of virus, between 4 and 28 TCID50, were sufficient to cause a lethal, reproducible infection. Animals became febrile between days 5 and 6, maintaining a high fever before succumbing to disease between 8 and 11 days postchallenge. Typical signs of Marburg virus infection were observed including haemorrhaging and a transient rash. In pathogenesis studies, virus was isolated from the animals’ lungs from day 3 postchallenge and from the liver, spleen and blood from day 5 postchallenge. Early signs of histopathology were apparent in the kidney and liver from day 3. The most striking features were observed in animals exhibiting severe clinical signs, which included high viral titres in all organs, with the highest levels in the blood, increased levels in liver function enzymes and blood clotting times, decreased levels in platelets, multifocal moderate-to-severe hepatitis and perivascular oedema. PMID:23441639

Changes in Body Fluid Compartments, Tissue Water and Electrolyte Distribution, and Lipid Concentrations in Rhesus Macaques with Yellow Fever

DTIC Science & Technology

1982-11-01

When these techniques were used for the changes are reported to be caused by the invasion of virus study of pathogenesis of Rocky Mountain spotted fever in...37. Beisel WR: Zinc metabolism in infection, in Brewer AJ, Prasad monkeys with Rocky Mountain spotted fever . JInfect Dis 138-42-48,1978. VTISGR13oI K1TA just’ ’ jnd/Or 2018AmJetRVo4ion/1

Fever in Children: Should it be Treated?

PubMed Central

Habbick, Brian F.

1988-01-01

Fever, which is the regulation of body temperature at an elevated level, must be differentiated from hyperthermia. The pathogenesis of fever involves exogenous pyrogens acting on macrophages/monocytes to produce the endogenous pyrogen, interleukin-1, which acts on the thermoregulatory centre and also has important effects on the body's immune responses to infection. Fever by itself is rarely harmful, and there is no evidence that febrile seizures produce long-term sequelae. On the other hand, fever may be part of the body's innate protection against infection. The main reason for treating a fever in a child is to relieve discomfort. Acetaminophen should be the drug of first choice in treatment, and sponging, if used at all, should be employed only after acetaminophen has been given first. Education of parents about fever management can be helpful. PMID:21253180

The pathogenesis of highly virulent African Swine Fever virus in domestic pigs exposed via intraoropharyngeal, intranasopharyngeal, and intramuscular inoculation, and by direct contact with infected pigs

USDA-ARS?s Scientific Manuscript database

In order to optimize novel systems for African Swine Fever Virus (ASFV) vaccine development, domestic pigs were challenged with the highly virulent ASFV-Malawi strain via intraoropharyngeal (IOP), intranasopharyngeal (INP), intramuscular (IM), and direct contact (DC) routes. Direct challenge doses ...

A Unified Framework for the Infection Dynamics of Zoonotic Spillover and Spread.

PubMed

Lo Iacono, Giovanni; Cunningham, Andrew A; Fichet-Calvet, Elisabeth; Garry, Robert F; Grant, Donald S; Leach, Melissa; Moses, Lina M; Nichols, Gordon; Schieffelin, John S; Shaffer, Jeffrey G; Webb, Colleen T; Wood, James L N

2016-09-01

A considerable amount of disease is transmitted from animals to humans and many of these zoonoses are neglected tropical diseases. As outbreaks of SARS, avian influenza and Ebola have demonstrated, however, zoonotic diseases are serious threats to global public health and are not just problems confined to remote regions. There are two fundamental, and poorly studied, stages of zoonotic disease emergence: 'spillover', i.e. transmission of pathogens from animals to humans, and 'stuttering transmission', i.e. when limited human-to-human infections occur, leading to self-limiting chains of transmission. We developed a transparent, theoretical framework, based on a generalization of Poisson processes with memory of past human infections, that unifies these stages. Once we have quantified pathogen dynamics in the reservoir, with some knowledge of the mechanism of contact, the approach provides a tool to estimate the likelihood of spillover events. Comparisons with independent agent-based models demonstrates the ability of the framework to correctly estimate the relative contributions of human-to-human vs animal transmission. As an illustrative example, we applied our model to Lassa fever, a rodent-borne, viral haemorrhagic disease common in West Africa, for which data on human outbreaks were available. The approach developed here is general and applicable to a range of zoonoses. This kind of methodology is of crucial importance for the scientific, medical and public health communities working at the interface between animal and human diseases to assess the risk associated with the disease and to plan intervention and appropriate control measures. The Lassa case study revealed important knowledge gaps, and opportunities, arising from limited knowledge of the temporal patterns in reporting, abundance of and infection prevalence in, the host reservoir.

A Unified Framework for the Infection Dynamics of Zoonotic Spillover and Spread

PubMed Central

Cunningham, Andrew A.; Fichet-Calvet, Elisabeth; Garry, Robert F.; Grant, Donald S.; Leach, Melissa; Moses, Lina M.; Nichols, Gordon; Schieffelin, John S.; Shaffer, Jeffrey G.; Webb, Colleen T.; Wood, James L. N.

2016-01-01

A considerable amount of disease is transmitted from animals to humans and many of these zoonoses are neglected tropical diseases. As outbreaks of SARS, avian influenza and Ebola have demonstrated, however, zoonotic diseases are serious threats to global public health and are not just problems confined to remote regions. There are two fundamental, and poorly studied, stages of zoonotic disease emergence: ‘spillover’, i.e. transmission of pathogens from animals to humans, and ‘stuttering transmission’, i.e. when limited human-to-human infections occur, leading to self-limiting chains of transmission. We developed a transparent, theoretical framework, based on a generalization of Poisson processes with memory of past human infections, that unifies these stages. Once we have quantified pathogen dynamics in the reservoir, with some knowledge of the mechanism of contact, the approach provides a tool to estimate the likelihood of spillover events. Comparisons with independent agent-based models demonstrates the ability of the framework to correctly estimate the relative contributions of human-to-human vs animal transmission. As an illustrative example, we applied our model to Lassa fever, a rodent-borne, viral haemorrhagic disease common in West Africa, for which data on human outbreaks were available. The approach developed here is general and applicable to a range of zoonoses. This kind of methodology is of crucial importance for the scientific, medical and public health communities working at the interface between animal and human diseases to assess the risk associated with the disease and to plan intervention and appropriate control measures. The Lassa case study revealed important knowledge gaps, and opportunities, arising from limited knowledge of the temporal patterns in reporting, abundance of and infection prevalence in, the host reservoir. PMID:27588425

Insight into the binding modes of Lassa nucleoprotein complexed with ssRNA by molecular dynamic simulations and free energy calculations.

PubMed

Zhang, Ying; Chen, Hang; Han, Ju-Guang

2015-01-01

Lassa virus (LASV), an arenavirus known to be responsible for a severe hemorrhagic fever, causes thousands of deaths annually and there is no effective vaccine for it so far. The nucleoprotein (NP) of LASV plays an essential role in the replication and transcription of the viral genome. Recent research shows that viral RNA binds in a deep crevice located within the N-terminal domain of NP and suggests a gating mechanism in which NP transforms from a "closed" position to an "open" position to bind RNA. To characterize the molecular mechanisms of how RNA binds to N-terminal domain of NP, two molecular dynamic (MD) simulations of RNA-binding structure and RNA-free structure have been performed. The simulation results show that an important helix α6 interacts with RNA in the "open" conformation, while helix α6 rotates toward the binding crevice and reduces the space of RNA-binding pocket in the "closed" conformation; it appears that helix α6 would clash with RNA while NP is in a "closed" state. In addition, to characterize the role of residues involved in the binding of RNA, the MD simulations of the double-mutant (W164A/F176A) and the single-mutant (G243P) RNA-binding NP complexes have been performed. Our MD simulations and molecular mechanics-generalized born surface area (MM-GBSA) energy calculations exhibit that the three mutant residues increase the binding affinity. Furthermore, we infer that the defect of the replication and transcription of viral genome is possibly due to the change of structural integrity rather than the reduction of RNA-binding affinity.

A Case of Human Lassa Virus Infection With Robust Acute T-Cell Activation and Long-Term Virus-Specific T-Cell Responses.

PubMed

McElroy, Anita K; Akondy, Rama S; Harmon, Jessica R; Ellebedy, Ali H; Cannon, Deborah; Klena, John D; Sidney, John; Sette, Alessandro; Mehta, Aneesh K; Kraft, Colleen S; Lyon, Marshall G; Varkey, Jay B; Ribner, Bruce S; Nichol, Stuart T; Spiropoulou, Christina F

2017-06-15

A nurse who acquired Lassa virus infection in Togo in the spring of 2016 was repatriated to the United States for care at Emory University Hospital. Serial sampling from this patient permitted the characterization of several aspects of the innate and cellular immune responses to Lassa virus. Although most of the immune responses correlated with the kinetics of viremia resolution, the CD8 T-cell response was of surprisingly high magnitude and prolonged duration, implying prolonged presentation of viral antigens. Indeed, long after viremia resolution, there was persistent viral RNA detected in the semen of the patient, accompanied by epididymitis, suggesting the male reproductive tract as 1 site of antigen persistence. Consistent with the magnitude of acute T-cell responses, the patient ultimately developed long-term, polyfunctional memory T-cell responses to Lassa virus. Published by Oxford University Press for the Infectious Diseases Society of America 2017. This work is written by (a) US Government employee(s) and is in the public domain in the US.

Epidemiology and Pathogenesis of Bolivian Hemorrhagic Fever

PubMed Central

Patterson, Michael; Grant, Ashley; Paessler, Slobodan

2014-01-01

The etiologic agent of Bolivian hemorrhagic fever (BHF), Machupo virus (MACV) is reported to have a mortality rate of 25 to 35%. First identified in 1959, BHF was the cause of a localized outbreak in San Joaquin until rodent population controls were implemented in 1964. The rodent Calomys collosus was identified as the primary vector and reservoir for the virus. Multiple animal models were considered during the 1970’s with the most human-like disease identified in Rhesus macaques but minimal characterization of the pathogenesis has been published since. A reemergence of reported BHF cases has been reported in recent years, which necessitates the further study and development of a vaccine to prevent future outbreaks. PMID:24636947

Ebolavirus: An Overview of Molecular and Clinical Pathogenesis.

PubMed

Vine, Veronica; Scott, Dana P; Feldmann, Heinz

2017-01-01

Ebolaviruses cause severe, often fatal hemorrhagic fever in Central, East, and West Africa. Until recently, they have been viewed as rare but highly pathogenic infections with regional, but limited, global public health impact. This view has changed with the emergence of the first epidemic of Ebola hemorrhagic fever in West Africa. In this chapter we provide an introduction of the pathogenesis of ebolaviruses as well as a description of clinical disease features. We also describe the current animal models used in ebolavirus research, detailing each model's unique strengths and weaknesses. We focus on Ebola virus representing the type species Zaire ebolavirus of the genus Ebolavirus, as most work relates to this pathogen.

Studies on the pathogenesis of fever. IV. The site of action of leucocytic and circulating endogenous pyrogen.

PubMed

KING, M K; WOOD, W B

1958-02-01

By means of a method designed to compare the febrile responses produced by intracarotid and intravenous injections, the endogenous pyrogen, which is contained in leucocytic exudates and is present in the serum of rabbits 2 hours after intravenous injections of typhoid vaccine, has been shown to act directly upon the thermoregulatory centers of the brain. In contrast, the exogenous bacterial pyrogen present in serum obtained 5 minutes after vaccine injections was found to act by a different and less direct mechanism. These observations add strong support to the original hypothesis that endogenous pyrogen, presumably derived from polymorphonuclear leucocytes, is an essential factor in the pathogenesis of endotoxin fever.

Studies on the pathogenesis of fever with influenzal viruses. I. The appearance of an endogenous pyrogen in the blood following intravenous injection of virus.

PubMed

ATKINS, E; HUANG, W C

1958-03-01

A substance with pyrogenic properties appears in the blood streams of rabbits made febrile by the intravenous inoculation of the PR8 strain of influenza A and Newcastle disease viruses (NDV). By means of a technique involving passive transfer of sera from animals given virus to recipient rabbits, the titer of circulating pyrogen was found to be closely correlated with the course of fever produced by virus. Certain properties of the pyrogen are described which differentiate it from the originally injected virus and suggest that the induced pyrogen is of endogenous origin. These properties resemble those of endogenous pyrogens occurring in other forms of experimental fever. The source of virus-induced pyrogen is unknown. In vitro incubation of virus with various constituents of the circulation did not result in the appearance of endogenous pyrogen. Granulocytopenia induced by HN(2) failed to influence either fever or the production of endogenous pyrogen in rabbits injected with NDV. Similarly, the intraperitoneal inoculation of NDV into prepared exudates did not modify the febrile response. These findings do not lend support to the possibility that the polymorphonuclear leukocyte is a significant source of endogenous pyrogen in virus-induced fever. It is concluded that the liberation of an endogenous pyrogen from some as yet undefined source is an essential step in the pathogenesis of fever caused by the influenza group of viruses.

Pathogenesis of Crimean-Congo hemorrhagic fever.

PubMed

Akıncı, Esragül; Bodur, Hürrem; Leblebicioglu, Hakan

2013-07-01

Although Crimean-Congo hemorrhagic fever (CCHF) is a widespread tick-borne disease, little is known about its pathogenesis. The interaction of the virus with host cells is most likely responsible for the pathogenesis of CCHF. The main contributors are endothelial cells (ECs) and immune cells. There are 2 theories underlying the CCHF pathogenesis: One is that the virus interacts with the ECs directly and the other that it interacts indirectly via immune cells with subsequent release of soluble mediators. ECs are activated upon infection by the upregulation of soluble molecules and proinflammatory cytokines. Probably, in severe cases, deregulation and excessive release of the cytokines accompanied by endothelial activation have toxic effects, leading to increased vascular permeability, vasodilatation, and subsequently hypotension, multiple organ failure, shock, and death. Studies indicate that CCHF virus (CCHFV) also can impair the innate immune system and cause a delay in adaptive immune response, which is critical for the clearance of CCHFV. The virus has many different ways to block the immune response, leading to uncontrolled viral replication followed by systemic spread of the virus throughout the body. Partial activation of dendritic cells and macrophages, delayed induction of interferons, weak antibody response, apoptosis of lymphocytes, and hemophagocytosis are some of these tactics. However, there are many points waiting for clarification about the pathogenesis of CCHF. Although the high risk of contagiousness limits research, we need more studies to understand the CCHF pathogenesis better. Here we review the main characteristics of the pathogenesis of CCHF.

Tick-Borne Relapsing Fever Spirochetes in the Americas

PubMed Central

Lopez, Job E.; Krishnavahjala, Aparna; Garcia, Melissa N.; Bermudez, Sergio

2016-01-01

Relapsing fever spirochetes are tick- and louse-borne pathogens that primarily afflict those in impoverished countries. Historically the pathogens have had a significant impact on public health, yet currently they are often overlooked because of the nonspecific display of disease. In this review, we discuss aspects of relapsing fever (RF) spirochete pathogenesis including the: (1) clinical manifestation of disease; (2) ability to diagnose pathogen exposure; (3) the pathogen’s life cycle in the tick and mammal; and (4) ecological factors contributing to the maintenance of RF spirochetes in nature. PMID:28959690

Experimental respiratory Marburg virus haemorrhagic fever infection in the common marmoset (Callithrix jacchus).

PubMed

Smither, Sophie J; Nelson, Michelle; Eastaugh, Lin; Laws, Thomas R; Taylor, Christopher; Smith, Simon A; Salguero, Francisco J; Lever, Mark S

2013-04-01

Marburg virus causes a highly infectious and lethal haemorrhagic fever in primates and may be exploited as a potential biothreat pathogen. To combat the infection and threat of Marburg haemorrhagic fever, there is a need to develop and license appropriate medical countermeasures. To determine whether the common marmoset (Callithrix jacchus) would be an appropriate model to assess therapies against Marburg haemorrhagic fever, initial susceptibility, lethality and pathogenesis studies were performed. Low doses of virus, between 4 and 28 TCID50 , were sufficient to cause a lethal, reproducible infection. Animals became febrile between days 5 and 6, maintaining a high fever before succumbing to disease between 8 and 11 days postchallenge. Typical signs of Marburg virus infection were observed including haemorrhaging and a transient rash. In pathogenesis studies, virus was isolated from the animals' lungs from day 3 postchallenge and from the liver, spleen and blood from day 5 postchallenge. Early signs of histopathology were apparent in the kidney and liver from day 3. The most striking features were observed in animals exhibiting severe clinical signs, which included high viral titres in all organs, with the highest levels in the blood, increased levels in liver function enzymes and blood clotting times, decreased levels in platelets, multifocal moderate-to-severe hepatitis and perivascular oedema. © 2013 Crown copyright. International Journal of Experimental Pathology © 2013 International Journal of Experimental Pathology.

Simian hemorrhagic fever virus cell entry is dependent on CD163 and uses a clathrin-mediated endocytosis-like pathway.

PubMed

Caì, Yíngyún; Postnikova, Elena N; Bernbaum, John G; Yú, Shu Qìng; Mazur, Steven; Deiuliis, Nicole M; Radoshitzky, Sheli R; Lackemeyer, Matthew G; McCluskey, Adam; Robinson, Phillip J; Haucke, Volker; Wahl-Jensen, Victoria; Bailey, Adam L; Lauck, Michael; Friedrich, Thomas C; O'Connor, David H; Goldberg, Tony L; Jahrling, Peter B; Kuhn, Jens H

2015-01-01

Simian hemorrhagic fever virus (SHFV) causes a severe and almost uniformly fatal viral hemorrhagic fever in Asian macaques but is thought to be nonpathogenic for humans. To date, the SHFV life cycle is almost completely uncharacterized on the molecular level. Here, we describe the first steps of the SHFV life cycle. Our experiments indicate that SHFV enters target cells by low-pH-dependent endocytosis. Dynamin inhibitors, chlorpromazine, methyl-β-cyclodextrin, chloroquine, and concanamycin A dramatically reduced SHFV entry efficiency, whereas the macropinocytosis inhibitors EIPA, blebbistatin, and wortmannin and the caveolin-mediated endocytosis inhibitors nystatin and filipin III had no effect. Furthermore, overexpression and knockout study and electron microscopy results indicate that SHFV entry occurs by a dynamin-dependent clathrin-mediated endocytosis-like pathway. Experiments utilizing latrunculin B, cytochalasin B, and cytochalasin D indicate that SHFV does not hijack the actin polymerization pathway. Treatment of target cells with proteases (proteinase K, papain, α-chymotrypsin, and trypsin) abrogated entry, indicating that the SHFV cell surface receptor is a protein. Phospholipases A2 and D had no effect on SHFV entry. Finally, treatment of cells with antibodies targeting CD163, a cell surface molecule identified as an entry factor for the SHFV-related porcine reproductive and respiratory syndrome virus, diminished SHFV replication, identifying CD163 as an important SHFV entry component. Simian hemorrhagic fever virus (SHFV) causes highly lethal disease in Asian macaques resembling human illness caused by Ebola or Lassa virus. However, little is known about SHFV's ecology and molecular biology and the mechanism by which it causes disease. The results of this study shed light on how SHFV enters its target cells. Using electron microscopy and inhibitors for various cellular pathways, we demonstrate that SHFV invades cells by low-pH-dependent, actin-independent endocytosis, likely with the help of a cellular surface protein. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Epidemiology and pathogenesis of Bolivian hemorrhagic fever.

PubMed

Patterson, Michael; Grant, Ashley; Paessler, Slobodan

2014-04-01

The etiologic agent of Bolivian hemorrhagic fever (BHF), Machupo virus (MACV) is reported to have a mortality rate of 25-35%. First identified in 1959, BHF was the cause of a localized outbreak in San Joaquin until rodent population controls were implemented in 1964. The rodent Calomys collosus was identified as the primary vector and reservoir for the virus. Multiple animal models were considered during the 1970s with the most human-like disease identified in Rhesus macaques but minimal characterization of the pathogenesis has been published since. A reemergence of reported BHF cases has been reported in recent years, which necessitates the further study and development of a vaccine to prevent future outbreaks. Copyright © 2014 Elsevier B.V. All rights reserved.

Controversies in dengue pathogenesis

PubMed Central

Halstead, Scott B

2012-01-01

Research into the pathogenesis of dengue fever has exploded over the last half-century, with issues that were considered simple becoming more complex as additional data are found. This has led to the development of a number of controversies that are being studied across the globe and debated in the literature. In this paper, the following six controversies are analysed and, where possible, resolved: the 1997 World Health Organization (WHO) case definition of dengue haemorrhagic fever (DHF) is not useful; DHF is not significantly associated with secondary dengue infection; DHF results from infection with a ‘virulent’ dengue virus; DHF is owing to abnormal T-cell responses; DHF results from auto-immune responses; and DHF results from direct infection of endothelial cells. PMID:22668442

Shipping lanes or offshore rigs

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

Not Available

1980-09-01

This information was from the Los Angeles Steamship Association (LASSA) luncheon meeting. The problems of limiting access and availability of the Santa Barbara/Santa Catalina channels to commercial vessel traffic and other related uses. LASSA speaks for about 85% of the maritime industry in Southern California. The Association is actively seeking a compromise with the oil companies in keeping the Vessel Traffic Separation Scheme (VTSS) in the channels; however, the Western Oil and Gas Association (WOGA) is seeking to abolish VTSS as currently established in the channels and move the sea lanes outside the Channel Islands, and open up the entiremore » Santa Barbara Channel to unlimited drilling sites. LASSA claims that moving the VTSS sea lanes outside of the Channel Islands would add 18 to 22 miles to the average trip from San Francisco to Los Angeles, with fuel cost etc. would make for a big loss to the merchant ship operators. LASSA has offered to support the concept of opening up the Buffer Zone that separates the Sea Lanes themselves to exploratory drilling. This two mile wide stretch of water is off limits to vessels and it would open new areas to the oil companies heretofore unaccessible to them. (DP)« less

The Z Proteins of Pathogenic but Not Nonpathogenic Arenaviruses Inhibit RIG-i-Like Receptor-Dependent Interferon Production

PubMed Central

Xing, Junji; Ly, Hinh

2014-01-01

ABSTRACT Arenavirus pathogens cause a wide spectrum of diseases in humans ranging from central nervous system disease to lethal hemorrhagic fevers with few treatment options. The reason why some arenaviruses can cause severe human diseases while others cannot is unknown. We find that the Z proteins of all known pathogenic arenaviruses, lymphocytic choriomeningitis virus (LCMV) and Lassa, Junin, Machupo, Sabia, Guanarito, Chapare, Dandenong, and Lujo viruses, can inhibit retinoic acid-inducible gene 1 (RIG-i) and Melanoma Differentiation-Associated protein 5 (MDA5), in sharp contrast to those of 14 other nonpathogenic arenaviruses. Inhibition of the RIG-i-like receptors (RLRs) by pathogenic Z proteins is mediated by the protein-protein interactions of Z and RLRs, which lead to the disruption of the interactions between RLRs and mitochondrial antiviral signaling (MAVS). The Z-RLR interactive interfaces are located within the N-terminal domain (NTD) of the Z protein and the N-terminal CARD domains of RLRs. Swapping of the LCMV Z NTD into the nonpathogenic Pichinde virus (PICV) genome does not affect virus growth in Vero cells but significantly inhibits the type I interferon (IFN) responses and increases viral replication in human primary macrophages. In summary, our results show for the first time an innate immune-system-suppressive mechanism shared by the diverse pathogenic arenaviruses and thus shed important light on the pathogenic mechanism of human arenavirus pathogens. IMPORTANCE We show that all known human-pathogenic arenaviruses share an innate immune suppression mechanism that is based on viral Z protein-mediated RLR inhibition. Our report offers important insights into the potential mechanism of arenavirus pathogenesis, provides a convenient way to evaluate the pathogenic potential of known and/or emerging arenaviruses, and reveals a novel target for the development of broad-spectrum therapies to treat this group of diverse pathogens. More broadly, our report provides a better understanding of the mechanisms of viral immune suppression and host-pathogen interactions. PMID:25552708

Differences in Pathogenesis for Salmonella enterica serovar Typhimurium in the Mouse Versus the Swine Model Identify Bacterial Gene Products Required for Systemic but not Gastrointestinal Disease

USDA-ARS?s Scientific Manuscript database

Over the last several decades, the mouse model of Typhoid fever has been an extremely productive model to investigate Salmonella enterica serovar Typhimurium pathogenesis. The mouse is the paradigm for investigating systemic disease due to infection by Salmonella; however, the swine model of gastro...

Animal models for some important RNA viruses of public health concern in SEARO countries: viral hemorrhagic fever.

PubMed

Badole, Sachin L; Yadav, Pragya D; Patil, Dilip R; Mourya, Devendra T

2015-03-01

Viral hemorrhagic fevers (VHFs) are major public health problems in the South-East Asia Regional (SEAR) countries. VHFs are a group of illnesses; that are caused by four families of viruses, viz. Arenaviridae, Bunyaviridae, Filoviridae and Flaviviridae. All VHFs have common features: they affect several organs and damage the blood vessels. These symptoms are often accompanied by hemorrhage. To understand pathogenesis, genetic and environmental influence that increase the risk of VHFs, efficacy and safety studies on candidate vaccines and testing of various therapeutic agents, appropriate animal models are essential tools in public and animals health. In the current review, the suitable animal models for Flavivirus [Dengue hemorhagic fever (DHF), Kyasanur forest disease (KFD)]; Bunyavirus [Crimean-Congo hemorrhagic fever (CCHF), Hantavirus fever (HF)]; and Paramyxovirus [Nipah virus fever (NiV)] have been reviewed with specific emphasis on emerging and reemerging viruses in SEAR countries.

US Federal Travel Restrictions for Persons with Higher-Risk Exposures to Communicable Diseases of Public Health Concern.

PubMed

Vonnahme, Laura A; Jungerman, M Robynne; Gulati, Reena K; Illig, Petra; Alvarado-Ramy, Francisco

2017-12-01

Published guidance recommends controlled movement for persons with higher-risk exposures (HREs) to communicable diseases of public health concern; US federal public health travel restrictions (PHTRs) might be implemented to enforce these measures. We describe persons eligible for and placed on PHTRs because of HREs during 2014-2016. There were 160 persons placed on PHTRs: 142 (89%) involved exposure to Ebola virus, 16 (10%) to Lassa fever virus, and 2 (1%) to Middle East respiratory syndrome coronavirus. Most (90%) HREs were related to an epidemic. No persons attempted to travel; all persons had PHTRs lifted after completion of a maximum disease-specific incubation period or a revised exposure risk classification. PHTR enforced controlled movement and removed risk for disease transmission among travelers who had contacts who refused to comply with public health recommendations. PHTRs are mechanisms to mitigate spread of communicable diseases and might be critical in enhancing health security during epidemics.

Dysregulation of Serum Gamma Interferon Levels in Vascular Chronic Q Fever Patients Provides Insights into Disease Pathogenesis

PubMed Central

Kremers, Marjolein N. T.; Hodemaekers, Hennie M.; Hagenaars, Julia C. J. P.; Koning, Olivier H. J.; Renders, Nicole H. M.; Hermans, Mirjam H. A.; de Klerk, Arja; Notermans, Daan W.; Wever, Peter C.; Janssen, Riny

2015-01-01

A large community outbreak of Q fever occurred in the Netherlands in the period 2007 to 2010. Some of the infected patients developed chronic Q fever, which typically includes pathogen dissemination to predisposed cardiovascular sites, with potentially fatal consequences. To identify the immune mechanisms responsible for ineffective clearance of Coxiella burnetii in patients who developed chronic Q fever, we compared serum concentrations of 47 inflammation-associated markers among patients with acute Q fever, vascular chronic Q fever, and past resolved Q fever. Serum levels of gamma interferon were strongly increased in acute but not in vascular chronic Q fever patients, compared to past resolved Q fever patients. Interleukin-18 levels showed a comparable increase in acute as well as vascular chronic Q fever patients. Additionally, vascular chronic Q fever patients had lower serum levels of gamma interferon-inducible protein 10 (IP-10) and transforming growth factor β (TGF-β) than did acute Q fever patients. Serum responses for these and other markers indicate that type I immune responses to C. burnetii are affected in chronic Q fever patients. This may be attributed to an affected immune system in cardiovascular patients, which enables local C. burnetii replication at affected cardiovascular sites. PMID:25924761

STUDIES ON THE PATHOGENESIS OF FEVER

PubMed Central

Hahn, Helmut H.; Char, David C.; Postel, Wilfred B.; Wood, W. Barry

1967-01-01

Macrophages from oil-induced peritoneal exudates in rabbits produce endogenous pyrogen when first activated by incubation in 4 hr exudate fluid and then stimulated by incubation in potassium-free isotonic sodium chloride solution. The failure of earlier investigators to obtain pyrogen from macrophages is explained, and the relevance of macrophage pyrogen to fevers of agranulocytosis and other diseases, in which mononuclear rather than granulocytic exudates predominate, is discussed. PMID:6028492

Present status of yellow fever: memorandum from a PAHO meeting.

PubMed

1986-01-01

An international seminar on the treatment and laboratory diagnosis of yellow fever, sponsored by the Pan American Health Organization (PAHO) and held in 1984, differed from previous meetings on yellow fever because of its emphasis on the care and management of patients and because the participants included specialists from several branches of medicine, such as hepatology, haematology, cardiology, infectious diseases, pathology and nephrology. The meeting reviewed the current status of yellow fever and problems associated with case-finding and notification; features of yellow fever in individual countries of Latin America; health services and facilities for medical care as they relate to diagnosis and management of cases; prevention strategies for and current status of immunization programmes; clinical and pathological aspects of yellow fever in humans; pathogenesis and pathophysiology of yellow fever in experimental animal models; clinical and specific laboratory diagnosis; treatment of the disease and of complications in the functioning of individual organ systems; prognosis and prognostic indicators; and directions for future clinical and experimental research on pathophysiology and treatment.

An unusual case of osteonecrosis of the jaw associated with dengue fever and periodontitis.

PubMed

Indurkar, M S; Sethi, R

2016-03-01

Osteonecrosis is a disorder rarely occurring in the jaw. Dengue fever is a common mosquito-borne disease prevalent in many countries including India. The following report presents an interesting case of maxillary osteonecrosis in a middle aged male with a history of dengue infection. We also diagnosed symptoms of chronic periodontitis, which may have potentiated the necrosis. This case report will describe a novel clinical presentation and management of osteonecrosis of the jaw (ONJ) of unknown origin and a possible pathogenesis explaining the association of ONJ with dengue fever and periodontitis. © 2015 Australian Dental Association.

Detection of Xenotropic Murine Leukemia Virus-Related Virus (XMRV) in Gulf War Illness: Role in Pathogenesis or Biomarker?

DTIC Science & Technology

2012-10-01

Co-­‐Infections           Epstein   Barr   virus  (EBV)   □Yes...fever, lymphadenopathy, headache, myalgia, arthralgia, depression, and memory loss; candidate etiologic agents include Epstein - Barr and other... Virus -Related Virus (XMRV) in Gulf War Illness: Role in Pathogenesis or Biomarker? PRINCIPAL INVESTIGATOR: Vincent C Lombardi

[EBOLA HEMORRHAGIC FEVER; ETIOLOGY, EPIDEMIOLOGY, PATHOGENESIS, AND CLINICAL SYMPTOMS].

PubMed

Zhdanov, K W; Zakharenko, S M; Kovalenko, A N; Semenov, A V; Fusin, A Ya

2015-01-01

The data on the prevalence of disease caused by Ebola virus, biological features of its pathogen, character of the epidemiological process, pathogenesis and clinical symptoms are presented. The disease is characterized by suppression of protective immunological mechanisms and systemic inflammatory reaction accounting for the lesions of vascular endothelium, hemostatic and immune systems. It eventually leads to polyorgan insufficiency and severe shock. Lethality amounts to 50%.

Dengue and Dengue Hemorrhagic Fever

PubMed Central

Gubler, Duane J.

1998-01-01

Dengue fever, a very old disease, has reemerged in the past 20 years with an expanded geographic distribution of both the viruses and the mosquito vectors, increased epidemic activity, the development of hyperendemicity (the cocirculation of multiple serotypes), and the emergence of dengue hemorrhagic fever in new geographic regions. In 1998 this mosquito-borne disease is the most important tropical infectious disease after malaria, with an estimated 100 million cases of dengue fever, 500,000 cases of dengue hemorrhagic fever, and 25,000 deaths annually. The reasons for this resurgence and emergence of dengue hemorrhagic fever in the waning years of the 20th century are complex and not fully understood, but demographic, societal, and public health infrastructure changes in the past 30 years have contributed greatly. This paper reviews the changing epidemiology of dengue and dengue hemorrhagic fever by geographic region, the natural history and transmission cycles, clinical diagnosis of both dengue fever and dengue hemorrhagic fever, serologic and virologic laboratory diagnoses, pathogenesis, surveillance, prevention, and control. A major challenge for public health officials in all tropical areas of the world is to devleop and implement sustainable prevention and control programs that will reverse the trend of emergent dengue hemorrhagic fever. PMID:9665979

Typhoid toxin provides a window into typhoid fever and the biology of Salmonella Typhi.

PubMed

Galán, Jorge E

2016-06-07

Salmonella Typhi is the cause of typhoid fever, a disease that has challenged humans throughout history and continues to be a major public health concern. Unlike infections with most other Salmonellae, which result in self-limiting gastroenteritis, typhoid fever is a life-threatening systemic disease. Furthermore, in contrast to most Salmonellae, which can infect a broad range of hosts, S. Typhi is a strict human pathogen. The unique features of S. Typhi pathogenesis and its stringent host specificity have been a long-standing puzzle. The discovery of typhoid toxin not only has provided major insight into these questions but also has offered unique opportunities to develop novel therapeutic and prevention strategies to combat typhoid fever.

Typhoid toxin provides a window into typhoid fever and the biology of Salmonella Typhi

PubMed Central

Galán, Jorge E.

2016-01-01

Salmonella Typhi is the cause of typhoid fever, a disease that has challenged humans throughout history and continues to be a major public health concern. Unlike infections with most other Salmonellae, which result in self-limiting gastroenteritis, typhoid fever is a life-threatening systemic disease. Furthermore, in contrast to most Salmonellae, which can infect a broad range of hosts, S. Typhi is a strict human pathogen. The unique features of S. Typhi pathogenesis and its stringent host specificity have been a long-standing puzzle. The discovery of typhoid toxin not only has provided major insight into these questions but also has offered unique opportunities to develop novel therapeutic and prevention strategies to combat typhoid fever. PMID:27222578

[Yellow fever].

PubMed

Sabbatani, Sergio; Fiorino, Sirio

2007-06-01

After the discovery of the New World, yellow fever proved to be an important risk factor of morbidity and mortality for Caribbean populations. In the following centuries epidemic risk, expanded by sea trade and travel, progressively reached the settlements in North America and Brazil as well as the Atlantic seaboard of tropical and equatorial Africa. In the eighteenth century and the first half of the nineteenth century epidemics of yellow fever were reported in some coastal towns in the Iberian peninsula, French coast, Great Britain and Italy, where, in 1804 at Leghorn, only one epidemic was documented. Prevention and control programs against yellow fever, developed at the beginning of the twentieth century in Cuba and in Panama, were a major breakthrough in understanding definitively its aetiology and pathogenesis. Subsequently, further advances in knowledge of yellow fever epidemiology were obtained when French scientists, working in West and Central Africa, showed that monkeys were major hosts of the yellow fever virus (the wild yellow fever virus), besides man. In addition, advances in research, contributing to the development of vaccines against the yellow fever virus in the first half of the nineteenth century, are reported in this paper.

Mediators of Fever and Muscle Proteolysis,

DTIC Science & Technology

1983-01-27

PGE Leukocytic Pyrogen (LP)2 2 Endogenous Pyrogen (EP) "r AMTIACT (’Cbmdw 40 .vGw 061 N neem sin idemt by block mumbe.) This is an invited editorial...tissues. Mediator activities are reflected by a variety of names (5), including LP, endogenous pyrogen (EP), leukocytic endogenous mediator (LEM...Pathogenesis of fever in man. N Engl J Med. 1978; 298:607-12. 5. Powanda MC, Beisel WR. Hypothesis: leukocyte endogenous mediator/ endogenous pyrogen

Studies on the pathogenesis of fever. XV. The production of endogenous pyrogen by peritoneal macrophages.

PubMed

Hahn, H H; Char, D C; Postel, W B; Wood, W B

1967-08-01

Macrophages from oil-induced peritoneal exudates in rabbits produce endogenous pyrogen when first activated by incubation in 4 hr exudate fluid and then stimulated by incubation in potassium-free isotonic sodium chloride solution. The failure of earlier investigators to obtain pyrogen from macrophages is explained, and the relevance of macrophage pyrogen to fevers of agranulocytosis and other diseases, in which mononuclear rather than granulocytic exudates predominate, is discussed.

Hypocalcemia in dairy cows: meta-analysis and dietary cation anion difference theory revisited.

PubMed

Lean, I J; DeGaris, P J; McNeil, D M; Block, E

2006-02-01

Data from 137 published trials involving 2,545 calvings were analyzed using random effects normal logistic regression models to identify risk factors for clinical hypocalcemia in dairy cows. The aim of the study was to examine which form, if any, of the dietary cation anion difference (DCAD) equation provided the best estimate of milk fever risk and to clarify roles of calcium, magnesium, and phosphorus concentrations of prepartum diets in the pathogenesis of milk fever. Two statistically equivalent and biologically plausible models were developed that predict incidence of milk fever. These models were validated using data from 37 trials excluded from the original data used to generate the models; missing variables were replaced with mean values from the analyzed data. The preferred models differed slightly; Model 1 included prepartum DCAD, and Model 2 included prepartum dietary concentrations of potassium and sulfur alone, but not sodium and chloride. Other factors, included in both models were prepartum dietary concentrations of calcium, magnesium, phosphorus; days exposed to the prepartum diet; and breed. Jersey cows were at 2.25 times higher risk of milk fever than Holstein cows in Model 1. The results support the DCAD theory of greater risk of milk fever with higher prepartum dietary DCAD (odds ratio = 1.015). The only DCAD equation supported in statistical analyses was (Na(+) + K(+)) - (Cl(-) + S(2-)). This finding highlights the difference between developing equations to predict DCAD and those to predict milk fever. The results support a hypothesis of a quadratic role for Ca in the pathogenesis of milk fever (model 1, odds ratio = 0.131; Model 2, odds ratio = 0.115). Milk fever risk was highest with a prepartum dietary concentration of 1.35% calcium. Increasing prepartum dietary magnesium concentrations had the largest effect on decreasing incidence of milk fever in both Model 1 (odds ratio = 0.006) and Model 2 (odds ratio = 0.001). Increasing dietary phosphorus concentrations prepartum increased the risk of milk fever (Model 1, odds ratio = 6.376; Model 2, odds ratio = 9.872). The models presented provide the basis for the formulation of diets to reduce the risk of milk fever and strongly support the need to evaluate macro mineral nutrition apart from DCAD of the diet.

Tissue and cellular tropism, pathology and pathogenesis of Ebola and Marburg viruses.

PubMed

Martines, Roosecelis Brasil; Ng, Dianna L; Greer, Patricia W; Rollin, Pierre E; Zaki, Sherif R

2015-01-01

Ebola viruses and Marburg viruses include some of the most virulent and fatal pathogens known to humans. These viruses cause severe haemorrhagic fevers, with case fatality rates in the range 25-90%. The diagnosis of filovirus using formalin-fixed tissues from fatal cases poses a significant challenge. The most characteristic histopathological findings are seen in the liver; however, the findings overlap with many other viral and non-viral haemorrhagic diseases. The need to distinguish filovirus infections from other haemorrhagic fevers, particularly in areas with multiple endemic viral haemorrhagic agents, is of paramount importance. In this review we discuss the current state of knowledge of filovirus infections and their pathogenesis, including histopathological findings, epidemiology, modes of transmission and filovirus entry and spread within host organisms. The pathogenesis of filovirus infections is complex and involves activation of the mononuclear phagocytic system, with release of pro-inflammatory cytokines, chemokines and growth factors, endothelial dysfunction, alterations of the innate and adaptive immune systems, direct organ and endothelial damage from unrestricted viral replication late in infection, and coagulopathy. Although our understanding of the pathogenesis of filovirus infections has rapidly increased in the past few years, many questions remain unanswered. Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Elevated serum levels of decoy receptor 3 are associated with disease severity in patients with hemorrhagic fever with renal syndrome.

PubMed

Dong, Yanying; Shi, Dongsha; Li, Man; Dai, Pengfei; Wang, Xiangling; Xie, Ming

2015-08-01

Hemorrhagic fever with renal syndrome (HFRS) is an acute viral infectious disease characterized by fever, hemorrhage and renal failure. HFRS has become a serious public health problem in China. Unfortunately, the pathogenesis of HFRS has not been completely clarified. The aim of this study is to investigate the changes of decoy receptor 3 (DcR3) and to further explore its potential roles in HFRS. The levels of serum DcR3 were measured by sandwich ELISA. We found serum DcR3 levels increased significantly, which reached peak value during the oliguric phase and in the critical group. Moreover, serum DcR3 levels were closely related to the levels of pro-inflammatory cytokines tumor necrosis factor-α (TNF-α) and parameters reflecting kidney injury including BUN, creatinine (Cr) and proteinuria. This study indicates that high levels of serum DcR3 have associations with the disease stages, severity and degree of kidney damage. Meanwhile, our results suggest that DcR3 may play a dual role in HFRS pathogenesis. First, DcR3 is involved in the inflammatory cascade response resulting in capillary permeability and kidney injury in the early stage. Secondly, HTNV infection induced DcR3 expression at the convalescent phase may act as a feed-back mechanism in anti-inflammatory response. Thus, a study of DcR3 is essential for a better understanding of HFRS pathogenesis.

Distribution of IgA subclass response to Coxiella burnetii in patients with acute and chronic Q fever.

PubMed

Camacho, M T; Outschoorn, I; Echevarría, C; Kovácová, E; Yebra, M; Maté, I; Auffray, P; Téllez, A

1998-07-01

The progression of Coxiella burnetii infection to acute or chronic Q fever has been attributed to biological characteristics of the bacterium and to the host immune response. We measured whether serum levels of total and specific subclasses IgA1 and IgA2 could be correlated with the course of disease in acute and chronic Q fever infections, and with the occurrence of endocarditis. In patients with chronic infection, total IgA2 levels were significantly increased. Q-fever-specific IgA1 antibodies were detectable in both acute and chronic infections, but only patients with endocarditis had IgA2 antibodies to C. burnetii phase II antigens. These findings indicate that the measurement of IgA subclasses may be a useful aid in the serological diagnosis of Q fever. Our results reinforce the idea that immunologically mediated host factors are important in the pathogenesis of Q fever and in the disease outcome of this infection. Copyright 1998 Academic Press.

Lassa-Vesicular Stomatitis Chimeric Virus Safely Destroys Brain Tumors

PubMed Central

Wollmann, Guido; Drokhlyansky, Eugene; Davis, John N.; Cepko, Connie

2015-01-01

ABSTRACT High-grade tumors in the brain are among the deadliest of cancers. Here, we took a promising oncolytic virus, vesicular stomatitis virus (VSV), and tested the hypothesis that the neurotoxicity associated with the virus could be eliminated without blocking its oncolytic potential in the brain by replacing the neurotropic VSV glycoprotein with the glycoprotein from one of five different viruses, including Ebola virus, Marburg virus, lymphocytic choriomeningitis virus (LCMV), rabies virus, and Lassa virus. Based on in vitro infections of normal and tumor cells, we selected two viruses to test in vivo. Wild-type VSV was lethal when injected directly into the brain. In contrast, a novel chimeric virus (VSV-LASV-GPC) containing genes from both the Lassa virus glycoprotein precursor (GPC) and VSV showed no adverse actions within or outside the brain and targeted and completely destroyed brain cancer, including high-grade glioblastoma and melanoma, even in metastatic cancer models. When mice had two brain tumors, intratumoral VSV-LASV-GPC injection in one tumor (glioma or melanoma) led to complete tumor destruction; importantly, the virus moved contralaterally within the brain to selectively infect the second noninjected tumor. A chimeric virus combining VSV genes with the gene coding for the Ebola virus glycoprotein was safe in the brain and also selectively targeted brain tumors but was substantially less effective in destroying brain tumors and prolonging survival of tumor-bearing mice. A tropism for multiple cancer types combined with an exquisite tumor specificity opens a new door to widespread application of VSV-LASV-GPC as a safe and efficacious oncolytic chimeric virus within the brain. IMPORTANCE Many viruses have been tested for their ability to target and kill cancer cells. Vesicular stomatitis virus (VSV) has shown substantial promise, but a key problem is that if it enters the brain, it can generate adverse neurologic consequences, including death. We tested a series of chimeric viruses containing genes coding for VSV, together with a gene coding for the glycoprotein from other viruses, including Ebola virus, Lassa virus, LCMV, rabies virus, and Marburg virus, which was substituted for the VSV glycoprotein gene. Ebola and Lassa chimeric viruses were safe in the brain and targeted brain tumors. Lassa-VSV was particularly effective, showed no adverse side effects even when injected directly into the brain, and targeted and destroyed two different types of deadly brain cancer, including glioblastoma and melanoma. PMID:25878115

Molecular Pathogenesis of Rickettsioses and Development of Novel Anti-Rickettsia Treatment by Comginatorial Peptide-Based Libraries

DTIC Science & Technology

2005-02-01

in many parts of the world and include Rocky Mountain spotted fever (the most common rickettsiosis in the US), epidemic and endemic typhus (1-4). The... Mountain spotted fever and other rickettsioses. In: Schaecter M, Engleberg NC, Eisenstein BI, MedoffG, editors. Mechanisms of microbial disease. Baltimore...Brouqui P, editors. Rickettsiae and rickettsial diseases at the turn of the millenium. Paris: Elsevier; 1999. p. 274-277. 3. Walker DH. Rocky

Hantaan Virus Nucleocapsid Protein Binds to Importin alpha Proteins and Inhibits Tumor Necrosis Factor Alpha-Induced Activation of Nuclear Factor Kappa B

DTIC Science & Technology

2008-11-19

two dis- tinct types of human disease: hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS) * Corresponding author ...School of Medicine, New York, New York 100292 Received 12 May 2008/Accepted 14 November 2008 Hantaviruses such as Hantaan virus (HTNV) and Andes virus...cause two human diseases, hemorrhagic fever with renal syndrome and hantavirus pulmonary syndrome, respectively. For both, disease pathogenesis is

Immunity and immune response, pathology and pathologic changes: progress and challenges in the immunopathology of yellow fever.

PubMed

Quaresma, Juarez A S; Pagliari, Carla; Medeiros, Daniele B A; Duarte, Maria I S; Vasconcelos, Pedro F C

2013-09-01

Yellow fever is a viral hemorrhagic fever, which affects people living in Africa and South America and is caused by the yellow fever virus, the prototype species in the Flavivirus genus (Flaviviridae family). Yellow fever virus infection can produce a wide spectrum of symptoms, ranging from asymptomatic infection or oligosymptomatic illness to severe disease with a high fatality rate. In this review, we focus in the mechanisms associated with the physiopathology of yellow fever in humans and animal models. It has been demonstrated that several factors play a role in the pathological outcome of the severe form of the disease including direct viral cytopathic effect, necrosis and apoptosis of hepatocyte cells in the midzone, and a minimal inflammatory response as well as low-flow hypoxia and cytokine overproduction. New information has filled several gaps in the understanding of yellow fever pathogenesis and helped comprehend the course of illness. Finally, we discuss prospects for an immune therapy in the light of new immunologic, viral, and pathologic tools. Copyright © 2013 John Wiley & Sons, Ltd.

Biological roles and functional mechanisms of arenavirus Z protein in viral replication.

PubMed

Wang, Jialong; Danzy, Shamika; Kumar, Naveen; Ly, Hinh; Liang, Yuying

2012-09-01

Arenaviruses can cause severe hemorrhagic fever diseases in humans, with limited prophylactic or therapeutic measures. A small RING-domain viral protein Z has been shown to mediate the formation of virus-like particles and to inhibit viral RNA synthesis, although its biological roles in an infectious viral life cycle have not been directly addressed. By taking advantage of the available reverse genetics system for a model arenavirus, Pichinde virus (PICV), we provide the direct evidence for the essential biological roles of the Z protein's conserved residues, including the G2 myristylation site, the conserved C and H residues of RING domain, and the poorly characterized C-terminal L79 and P80 residues. Dicodon substitutions within the late (L) domain (PSAPPYEP) of the PICV Z protein, although producing viable mutant viruses, have significantly reduced virus growth, a finding suggestive of an important role for the intact L domain in viral replication. Further structure-function analyses of both PICV and Lassa fever virus Z proteins suggest that arenavirus Z proteins have similar molecular mechanisms in mediating their multiple functions, with some interesting variations, such as the role of the G2 residue in blocking viral RNA synthesis. In summary, our studies have characterized the biological roles of the Z protein in an infectious arenavirus system and have shed important light on the distinct functions of its domains in virus budding and viral RNA regulation, the knowledge of which may lead to the development of novel antiviral drugs.

Shedding of Soluble Glycoprotein 1 Detected During Acute Lassa Virus Infection in Human Subjects

DTIC Science & Technology

2010-11-09

12701 - 12705. 29. Urata S, Noda T , Kawaoka Y, Yokosawa H, Yasuda J: Cellular factors required for Lassa virus budding. J Virol 2006, (8):4191 - 4195...and exposed to HyBlot CL Film (Denville Scientific, Inc). Blots used in reprobing experiments were briefly rinsed in PBS- T (1X PBS, pH 7.4, 0.1...Blots were then washed extensively in PBS- T , re-blocked, and reprobed as outlined above. Blots were reprobed a maximum of three times. - 16

A mouse model for the human pathogen Salmonella Typhi

PubMed Central

Song, Jeongmin; Willinger, Tim; Rongvaux, Anthony; Eynon, Elizabeth E.; Stevens, Sean; Manz, Markus G.; Flavell, Richard A.; Galán, Jorge E.

2010-01-01

SUMMARY Salmonella enterica serovar Typhi (S. Typhi) is the cause of typhoid fever, a life-threatening disease of humans. The lack of an animal model due to S. typhi's strict human host specificity has been a significant obstacle in the understanding of its pathogenesis and the development of a safe and effective vaccine against typhoid fever. We report here the development of a mouse model for S. Typhi infection. We showed that immunodeficient Rag2 -/- γc -/- mice engrafted with human fetal liver hematopoietic stem and progenitor cells were able to support S. Typhi replication and persistent infection. A S. Typhi strain carrying a mutation in a gene required for its virulence in humans was not able to replicate in these humanized mice. In contrast, another mutant strain unable to produce the recently identified typhoid toxin, exhibited increased replication suggesting a potential role for this toxin in the establishment of persistent infection. Furthermore, infected animals mounted a human innate and adaptive immune response to S. Typhi resulting in the production of cytokines and pathogen-specific antibodies. These results therefore indicate that this animal model can be used to study S. Typhi pathogenesis and to evaluate potential vaccine candidates against typhoid fever. PMID:20951970

Tick-borne typhus fever of northern Asia: some characteristics of the pathogenesis.

PubMed

Nelyubov, M V

2002-09-01

Morphological changes in the viscera of albino mice were studied over the course of North Asia typhus fever. In general, the microcirculatory bed in the studied organs (brain, liver, spleen, peritoneum, and testicle) corresponded to angioparalytical capillary and venular hyperemia. Macrophagic reaction (proliferation of stellate macrophages) transformed into granulomatous reaction in the course of the experiment. Macrophagic reaction of the spleen was characterized by blurred follicular pattern. In the testes a tendency to the loss of normal spermatogenesis was observed.

Molecular Insights into Crimean-Congo Hemorrhagic Fever Virus

DOE PAGES

Zivcec, Marko; Scholte, Florine; Spiropoulou, Christina; ...

2016-04-21

Crimean-Congo hemorrhagic fever virus (CCHFV) is a tick-borne pathogen that causes high morbidity and mortality. Efficacy of vaccines and antivirals to treat human CCHFV infections remains limited and controversial. Research into pathology and underlying molecular mechanisms of CCHFV and other nairoviruses is limited. Significant progress has been made in our understanding of CCHFV replication and pathogenesis in the past decade. Here we review the most recent molecular advances in CCHFV-related research, and provide perspectives on future research.

Molecular Insights into Crimean-Congo Hemorrhagic Fever Virus.

PubMed

Zivcec, Marko; Scholte, Florine E M; Spiropoulou, Christina F; Spengler, Jessica R; Bergeron, Éric

2016-04-21

Crimean-Congo hemorrhagic fever virus (CCHFV) is a tick-borne pathogen that causes high morbidity and mortality. Efficacy of vaccines and antivirals to treat human CCHFV infections remains limited and controversial. Research into pathology and underlying molecular mechanisms of CCHFV and other nairoviruses is limited. Significant progress has been made in our understanding of CCHFV replication and pathogenesis in the past decade. Here we review the most recent molecular advances in CCHFV-related research, and provide perspectives on future research.

Molecular Insights into Crimean-Congo Hemorrhagic Fever Virus

PubMed Central

Zivcec, Marko; Scholte, Florine E. M.; Spiropoulou, Christina F.; Spengler, Jessica R.; Bergeron, Éric

2016-01-01

Crimean-Congo hemorrhagic fever virus (CCHFV) is a tick-borne pathogen that causes high morbidity and mortality. Efficacy of vaccines and antivirals to treat human CCHFV infections remains limited and controversial. Research into pathology and underlying molecular mechanisms of CCHFV and other nairoviruses is limited. Significant progress has been made in our understanding of CCHFV replication and pathogenesis in the past decade. Here we review the most recent molecular advances in CCHFV-related research, and provide perspectives on future research. PMID:27110812

Molecular Insights into Crimean-Congo Hemorrhagic Fever Virus

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

Zivcec, Marko; Scholte, Florine; Spiropoulou, Christina

Crimean-Congo hemorrhagic fever virus (CCHFV) is a tick-borne pathogen that causes high morbidity and mortality. Efficacy of vaccines and antivirals to treat human CCHFV infections remains limited and controversial. Research into pathology and underlying molecular mechanisms of CCHFV and other nairoviruses is limited. Significant progress has been made in our understanding of CCHFV replication and pathogenesis in the past decade. Here we review the most recent molecular advances in CCHFV-related research, and provide perspectives on future research.

Pattern differences in experimental fevers induced by endotoxin, endogenous pyrogen, and prostaglandins.

PubMed

Morimoto, A; Nakamori, T; Watanabe, T; Ono, T; Murakami, N

1988-04-01

To distinguish pattern differences in experimentally induced fevers, we investigated febrile responses induced by intravenous (IV), intracerebroventricular (ICV), and intra-preoptic/anterior hypothalamic (POA) administration of bacterial endotoxin (lipopolysaccharide, LPS), endogenous pyrogen (EP), human recombinant interleukin-1 alpha (IL-1), and prostaglandins E2 and F2 alpha (PGE2 and PGF2 alpha). Intravenous LPS, EP, or IL-1 in high concentrations caused biphasic fever. In low concentrations, they induced only the first phase of fever. Latency to onset and time to first peak of fever induced by IV injection of LPS or EP were almost the same as those after ICV or POA injection of PGE2. Fever induced by ICV or POA administration of LPS, EP, IL-1, or PGF2 alpha had a long latency to onset and a prolonged time course. There were significant differences among the latencies to fever onset exhibited by groups that received ICV or POA injections of LPS, EP, or PGF2 alpha and by groups given IV injections of LPS or EP and ICV or POA injections of PGE2. Present observations indicate different patterns of fever produced by several kinds of pyrogens when given by various routes. These results permit us to consider the possibility that there are several mediators or multiprocesses underlying the pathogenesis of fever.

A case suspected for yellow fever vaccine-associated viscerotropic disease in the Netherlands.

PubMed

van de Pol, Eva M; Gisolf, Elizabeth H; Richter, Clemens

2014-01-01

Yellow fever (YF) 17D vaccine is one of the most successful vaccines ever developed. Since 2001, 56 cases of yellow fever vaccine-associated viscerotropic disease (YEL-AVD) have been published in the peer-reviewed literature. Here, we report a new case suspected for YEL-AVD in the Netherlands. Further research is needed to determine the true incidence of YEL-AVD and to clarify host and vaccine-associated factors in the pathogenesis of YEL-AVD. Because of the potential adverse events, healthcare providers should carefully consider vaccination only in people who are truly at risk for YF infection, especially in primary vaccine recipients. © 2014 International Society of Travel Medicine.

Disinfection of aircraft : Appropriate disinfectants and standard operating procedures for highly infectious diseases.

PubMed

Klaus, Joachim; Gnirs, Peter; Hölterhoff, Sabine; Wirtz, Angela; Jeglitza, Matthias; Gaber, Walter; Gottschalk, Rene

2016-12-01

For infectious diseases caused by highly pathogenic agents (e. g., Ebola/Lassa fever virus, SARS-/MERS-CoV, pandemic influenza virus) which have the potential to spread over several continents within only a few days, international Health Protection Authorities have taken appropriate measures to limit the consequences of a possible spread. A crucial point in this context is the disinfection of an aircraft that had a passenger on board who is suspected of being infected with one of the mentioned diseases. Although, basic advice on hygiene and sanitation on board an aircraft is given by the World Health Organization, these guidelines lack details on available and effective substances as well as standardized operating procedures (SOP). The purpose of this paper is to give guidance on the choice of substances that were tested by a laboratory of Lufthansa Technik and found compatible with aircraft components, as well as to describe procedures which ensure a safe and efficient disinfection of civil aircrafts. This guidance and the additional SOPs are made public and are available as mentioned in this paper.

Highly Pathogenic Porcine Reproductive and Respiratory Syndrome Virus Induces Prostaglandin E2 Production through Cyclooxygenase 1, Which Is Dependent on the ERK1/2-p-C/EBP-β Pathway

PubMed Central

Bi, Yanmin; Guo, Xue-kun; Zhao, Haiyan; Gao, Li; Wang, Lianghai; Tang, Jun

2014-01-01

ABSTRACT Atypical porcine reproductive and respiratory syndrome (PRRS) caused by highly pathogenic porcine reproductive and respiratory syndrome virus (HP-PRRSV) is characterized by high fever and high mortality. However, the mechanism underlying the fever induction is still unknown. Prostaglandin E2 (PGE2), synthesized by cyclooxygenase type 1/2 (COX-1/2) enzymes, is essential for inducing fever. In this study, we found that PGE2, together with COX-1, was significantly elevated by HP-PRRSV. We subsequently demonstrated that extracellular signal-regulated kinase 1/2 (ERK1/2) and phosphorylated ERK (p-ERK) were the key nodes to trigger COX-1 expression after HP-PRRSV infection. Furthermore, we proved the direct binding of p-C/EBP-β to the COX-1 promoter by luciferase reporter and chromatin immunoprecipitation assays. In addition, silencing of C/EBP-β remarkably impaired the enhancement of COX-1 production induced by HP-PRRSV infection. Taken together, our results indicate that HP-PPRSV elicits the expression of COX-1 through the ERK1/2-p-C/EBP-β signaling pathway, resulting in the increase of PGE2, which might be the cause of high fever in infected pigs. Our findings might provide new insights into the molecular mechanisms underlying the pathogenesis of HP-PRRSV infection. IMPORTANCE The atypical PRRS caused by HP-PRRSV was characterized by high fever, high morbidity, and high mortality in pigs of all ages, yet how HP-PRRSV induces high fever in pigs remains unknown. In the present study, we found out that HP-PRRSV infection could increase PGE2 production by upregulation of COX-1, and we subsequently characterized the underlying mechanisms about how HP-PRRSV enhances COX-1 production. PGE2 plays a critical role in inducing high temperature in hosts during pathogen infections. Thus, our findings here could help us have a better understanding of HP-PRRSV pathogenesis. PMID:24352469

[A Case of Clinically Mild Encephalitis/encephalopathy with a Reversible Splenial Lesion due to Dengue Fever].

PubMed

Saito, Nobuo; Kitashouji, Emi; Kojiro, Maiko; Furumoto, Akitugu; Morimoto, Konosuke; Morita, Kouichi; Ariyoshi, Koya

2015-07-01

Clinically mild encephalitis/encephalopathy with a reversible splenial lesion (MERS) has been recently proposed as a clinical-radiological syndrome. Several causes of MERS have been reported including infectious diseases. We present herein on a case of MERS induced by dengue fever in a Japanese traveler. A 48-year-old male returning from Thailand and Cambodia was admitted for an unknown fever. Following admission, the dengue virus was diagnosed with a positive RT-PCR result. On day 5 of the illness, regardless of reduced fever, weakness suddenly developed in both upper limbs. A cerebral MRI showed hyperintensities in the splenium of the corpus callosum on T2-weighted and diffusion-weighted images. The symptoms resolved completely within two days of onset. The patient was diagnosed as having MERS due to the MRI features and the mild clinical course. Although only a few cases of MERS caused by dengue fever have been reported, the condition is possibly underdiagnosed. It is hypothesized that dengue fever can induce MERS as dengue fever can cause increased endothelium permeability and hypo-sodium which have been proposed in the pathogenesis of MERS. However, there is currently limited evidence for this. Further research is recommended to demonstrate a causal association between dengue fever and MERS.

[Ebola virus disease].

PubMed

Nazimek, Katarzyna; Bociaga-Jasik, Monika; Bryniarski, Krzysztof; Gałas, Aleksander; Garlicki, Aleksander; Gawda, Anna; Gawlik, Grzegorz; Gil, Krzysztof; Kosz-Vnenchak, Magdalena; Mrozek-Budzyn, Dorota; Olszanecki, Rafał; Piatek, Anna; Zawilińska, Barbara; Marcinkiewicz, Janusz

2014-01-01

Ebola is one of the most virulent zoonotic RNA viruses causing in humans haemorrhagic fever with fatality ratio reaching 90%. During the outbreak of 2014 the number of deaths exceeded 8.000. The "imported" cases reported in Western Europe and USA highlighted the extreme risk of Ebola virus spreading outside the African countries. Thus, haemorrhagic fever outbreak is an international epidemiological problem, also due to the lack of approved prevention and therapeutic strategies. The editorial review article briefly summarizes current knowledge on Ebola virus disease epidemiology, etiology, pathogenesis, clinical presentation, diagnosis as well as possible prevention and treatment.

Rift Valley Fever: Recent Insights into Pathogenesis and Prevention▿

PubMed Central

Boshra, Hani; Lorenzo, Gema; Busquets, Núria; Brun, Alejandro

2011-01-01

Rift Valley fever virus (RVFV) is a zoonotic pathogen that primarily affects ruminants but can also be lethal in humans. A negative-stranded RNA virus of the family Bunyaviridae, this pathogen is transmitted mainly via mosquito vectors. RVFV has shown the ability to inflict significant damage to livestock and is also a threat to public health. While outbreaks have traditionally occurred in sub-Saharan Africa, recent outbreaks in the Middle East have raised awareness of the potential of this virus to spread to Europe, Asia, and the Americas. Although the virus was initially characterized almost 80 years ago, the only vaccine approved for widespread veterinary use is an attenuated strain that has been associated with significant pathogenic side effects. However, increased understanding of the molecular biology of the virus over the last few years has led to recent advances in vaccine design and has enabled the development of more-potent prophylactic measures to combat infection. In this review, we discuss several aspects of RVFV, with particular emphasis on the molecular components of the virus and their respective roles in pathogenesis and an overview of current vaccine candidates. Progress in understanding the epidemiology of Rift Valley fever has also enabled prediction of potential outbreaks well in advance, thus providing another tool to combat the physical and economic impact of this disease. PMID:21450816

Inactivation of Lassa, Marburg, and Ebola viruses by gamma irradiation

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

Elliott, L.H.; McCormick, J.B.; Johnson, K.M.

1982-10-01

Because of the cumbersome conditions experienced in a maximum containment laboratory, methods for inactivating highly pathogenic viruses were investigated. The infectivity of Lassa, Marburg, and Ebola viruses was inactivated without altering the immunological activity after radiation with /sup 60/Co gamma rays. At 4 degrees C, Lassa virus was the most difficult to inactivate with a rate of 5.3 X 10(-6) log 50% tissue culture infective dose per rad of /sup 60/Co radiation, as compared with 6.8 X 10(-6) log 50% tissue culture infective dose per rad for Ebola virus and 8.4 X 10(-6) log 50% tissue culture infective dose permore » rad for Marburg virus. Experimental inactivation curves, as well as curves giving the total radiation needed to inactivate a given concentration of any of the three viruses, are presented. We found this method of inactivation to be superior to UV light or beta-propiolactone inactivation and now routinely use it for preparation of material for protein-chemistry studies or for preparation of immunological reagents.« less

Inactivation of Lassa, Marburg, and Ebola viruses by gamma irradiation

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

Elliott, L.H.; McCormick, J.B.; Johnson, K.M.

1982-10-01

Because of the cumbersome conditions experienced in a maximum containment laboratory, methods for inactivating highly pathogenic viruses were investigated. The infectivity of Lassa, Marburg, and Ebola viruses was inactivated without altering the immunological activity after radiation with /sup 60/CO gamma rays. At 4 degrees C, Lassa virus was the most difficult to inactivate with a rate of 5.3 X 10(-6) log 50% tissue culture infective dose per rad of /sup 60/CO radiation, as compared with 6.8 X 10(-6) log 50% tissue culture infective dose per rad for Ebola virus and 8.4 X 10(-6) log 50% tissue culture infective dose permore » rad for Marburg virus. Experimental inactivation curves, as well as curves giving the total radiation needed to inactivate a given concentration of any of the three viruses, are presented. The authors found this method of inactivation to be superior to UV light or beta-propiolactone inactivation and now routinely use it for preparation of material for protein-chemistry studies or for preparation of immunological reagents.« less

Comparative Structural and Functional Analysis of Bunyavirus and Arenavirus Cap-Snatching Endonucleases

PubMed Central

Reguera, Juan; Gerlach, Piotr; Rosenthal, Maria; Gaudon, Stephanie; Coscia, Francesca; Günther, Stephan; Cusack, Stephen

2016-01-01

Segmented negative strand RNA viruses of the arena-, bunya- and orthomyxovirus families uniquely carry out viral mRNA transcription by the cap-snatching mechanism. This involves cleavage of host mRNAs close to their capped 5′ end by an endonuclease (EN) domain located in the N-terminal region of the viral polymerase. We present the structure of the cap-snatching EN of Hantaan virus, a bunyavirus belonging to hantavirus genus. Hantaan EN has an active site configuration, including a metal co-ordinating histidine, and nuclease activity similar to the previously reported La Crosse virus and Influenza virus ENs (orthobunyavirus and orthomyxovirus respectively), but is more active in cleaving a double stranded RNA substrate. In contrast, Lassa arenavirus EN has only acidic metal co-ordinating residues. We present three high resolution structures of Lassa virus EN with different bound ion configurations and show in comparative biophysical and biochemical experiments with Hantaan, La Crosse and influenza ENs that the isolated Lassa EN is essentially inactive. The results are discussed in the light of EN activation mechanisms revealed by recent structures of full-length influenza virus polymerase. PMID:27304209

Fever of Unknown Origin in a Patient with Confirmed West Nile Virus Meningoencephalitis

PubMed Central

Sabre, Alexander; Farricielli, Laurie

2014-01-01

West Nile Virus (WNV), an RNA arbovirus and member of the Japanese encephalitis virus antigenic complex, causes a wide range of clinical symptoms, from asymptomatic to encephalitis and meningitis. Nearly all human infections of WNV are due to mosquito bites with birds being the primary amplifying hosts. Advanced age is the most important risk factor for neurological disease leading most often to poor prognosis in those afflicted. We report a case of WNV meningoencephalitis in a 93-year-old Caucasian male who presented with fever of unknown origin (FUO) and nuchal rigidity that rapidly decompensated within 24 h to a persistent altered mental state during inpatient stay. The patient's ELISA antibody titers confirmed pathogenesis of disease by WNV; he given supportive measures and advanced to an excellent recovery. In regard to the approach of FUO, it is important to remain impartial yet insightful to all elements when determining pathogenesis in atypical presentation. PMID:25580318

[Multicentric inflammatory pseudotumor with asynchronic presentation in meninges, liver, spleen and lymph nodes in a patient with seronegative spondiloarthropathy. Case report and review of the literature].

PubMed

Vicuña-González, R M; Rivera-Salgado, M I; García-Velarde, P M Pasquel; de León-Bojorge, B; Ortiz-Hidalgo, C

Inflammatory pseudotumor is a reactive process in which the etiology and pathogenesis are not well defined, that can be found in any location. The cases with central nervous system affection have been described in meninges, brain, choroid plexus and cranial and spinal nerves. Multicentric cases, synchronous and asynchronous have been described. A 45 years-old woman with a rheumatologic disease (a seronegative spondiloarthropathy) who developed an inflammatory pseudotumor in spleen, liver and abdominal lymph nodes in 1995, associated to fever of unknown origin, six years later she presented with an inflammatory pseudotumor of the meninges in the convexity of the right frontoparietal region, with fever, malaise, and increase of globular sedimentation rate, microcytic hypochromic anemia and thrombocytosis. The clinicopathologic features of this lesion are revised, including the different theories in regard to the etiology and pathogenesis, and the role of cytokines produced by inflammatory cells in the tumor.

Advances in Rift Valley Fever Research: Insights for Disease Prevention

PubMed Central

LaBeaud, A. Desiree; Kazura, James W.; King, Charles H.

2011-01-01

Purpose of review The purpose of the study was to review recent research on Rift Valley fever virus (RVFV) infection, encompassing four main areas: epidemiology and outbreak prediction, viral pathogenesis, human diagnostics and therapeutics, and vaccine and therapeutic candidates. Recent findings RVFV continues to extend its range in Africa and the Middle East. Better definition of RVFV-related clinical syndromes and human risk factors for severe disease, combined with early-warning systems based on remote-sensing, simplified rapid diagnostics, and tele-epidemiology, hold promise for earlier deployment of effective outbreak control measures. Advances in understanding of viral replication pathways and host cell-related pathogenesis suggest means for antiviral therapeutics and for more effective vaccination strategies based on genetically engineered virus strains or subunit vaccines. Summary RVFV is a significant health and economic burden in many areas of Africa, and remains a serious threat to other parts of the world. Development of more effective methods for RVFV outbreak prevention and control remains a global health priority. PMID:20613512

STUDIES ON THE PATHOGENESIS OF FEVER

PubMed Central

Petersdorf, Robert G.; Bennett, Ivan L.

1957-01-01

Intravenous administration of bacterial endotoxins in dogs is followed within 2 hours by the appearance of a fever-producing substance in the blood. This endogenous pyrogen differs from the endotoxins originally administered by its ability to produce fever in tolerant recipients and failure to promote tolerance after repeated daily injections. Endogenous serum pyrogen is destroyed by heating at 90°C. for 30 minutes, and is also inactivated to some degree by incubation at 37°C. for 24 hours. Suppression of fever by aminopyrine does not affect appearance of the endogenous factor. Animals made febrile with dinitrophenol, kaolin, or lysergic acid do not elaborate a fever-promoting substance in the blood. Sterile abscesses, accompanied by elevations in body temperature of the host, are unassociated with detectable amounts of secondary pyrogen in the serum. The absence of endogenous pyrogen in the blood of febrile dogs made leukopenic with nitrogen mustard favors the idea that polymorphonuclear leukocytes injured by endotoxins release the endogenous factor. On the other hand, the finding that the granulocytopenic animals are febrile when no circulating endogenous pyrogen is present, casts doubt upon the essential role of this substance in endotoxin fever. PMID:13449238

Pathogenesis of African swine fever in domestic pigs and European wild boar.

PubMed

Blome, Sandra; Gabriel, Claudia; Beer, Martin

2013-04-01

African swine fever (ASF) is among the most important viral diseases that can affect domestic and feral pigs. Both clinical signs and pathomorphological changes vary considerably depending on strain virulence and host factors. Acute infections with highly virulent virus strains lead to a clinical course that resembles a viral haemorrhagic fever that is characterized by pronounced depletion of lymphoid tissues, apoptosis of lymphocyte subsets, and impairment of haemostasis and immune functions. It is generally accepted that most lesions can be attributed to cytokine-mediated interactions triggered by infected and activated monocytes and macrophages, rather than by virus-induced direct cell damage. Nevertheless, most pathogenetic mechanisms are far from being understood. This review summarizes the current knowledge and discusses implications and research gaps. Copyright © 2012 Elsevier B.V. All rights reserved.

Influenza A virus pathogenesis and vaccination in swine

USDA-ARS?s Scientific Manuscript database

Swine influenza is an acute respiratory disease of pigs that is characterized by fever followed by lethargy, anorexia, and serous nasal discharge. The disease progresses rapidly and may be complicated when associated with other respiratory pathogens. Influenza A virus (IAV) is one of the most preval...

A Three-way Comparative Genomic Analysis of Mannheimia haemolytica Isolates

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

Lawrence, Paulraj; Kittichotirat, Weerayuth; McDermott, Jason E.

2010-10-04

Mannhemia haemolytica is a Gram- negative bacterium and the principal etiological agent associated with bovine respiratory disease complex. They transform from a benign commensal to a deadly pathogen during stress such as viral infection and transportation to feedlots, and cause acute pleuropneumonia commonly known as shipping fever. The U.S beef industry alone loses more than one billion dollars annually to shipping fever and despite its enormous economic importance there are no specific and accurate genetic markers, which would aid in understanding M. haemolytica pathogenesis and epidemiology at molecular level and assist in devising an effective control strategy.

What's new in Rocky Mountain spotted fever?

PubMed

Chen, Luke F; Sexton, Daniel J

2008-09-01

Rocky Mountain spotted fever (RMSF) remains an important illness despite an effective therapy because it is difficult to diagnose and is capable of producing a fatal outcome. The pathogenesis of RMSF remains, in large part, an enigma. However, recent research has helped shed light on this mystery. Importantly, the diagnosis of RMSF must be considered in all febrile patients who have known or possible exposure to ticks, especially if they live in or have traveled to endemic regions during warmer months. Decisions about giving empiric therapy to such patients are difficult and require skill and careful judgement.

Role of cognitive parameters in dengue hemorrhagic fever and dengue shock syndrome

PubMed Central

2013-01-01

Dengue is becoming recognized as one of the most important vector-borne human diseases. It is predominant in tropical and subtropical zones but its geographical distribution is progressively expanding, making it an escalating global health problem of today. Dengue presents with spectrum of clinical manifestations, ranging from asymptomatic, undifferentiated mild fever, dengue fever (DF), to dengue hemorrhagic fever (DHF) with or without shock (DSS), a life-threatening illness characterized by plasma leakage due to increased vascular permeability. Currently, there are no antiviral modalities or vaccines available to treat and prevent dengue. Supportive care with close monitoring is the standard clinical practice. The mechanisms leading to DHF/DSS remains poorly understood. Multiple factors have been attributed to the pathological mechanism, but only a couple of these hypotheses are popular in scientific circles. The current discussion focuses on underappreciated factors, temperature, natural IgM, and endotoxin, which may be critical components playing roles in dengue pathogenesis. PMID:24305068

Rheumatic fever in New Zealand: what are the teeth trying to tell us?

PubMed

Thornley, S; Sundborn, G; Schmidt-Uili, S M

2014-03-01

Rheumatic fever remains an important disease of childhood in New Zealand, despite increasing access and awareness of the need for preventive antibiotic treatment. Mãori and Pacific children have an incidence rate about 30 times and 70 times higher than European children, from annual notification data (77.7 per 100,000 for Pacific, 30.4 per 100,000 for Mãori, and 1 per 100,000 for European). In the early 20th century, a Canadian dentist, Weston A. Price, noted that 95% of children who presented with acute rheumatic fever also had advanced dental caries. Oral health surveys show that Mãori and Pacific children are disproportionately affected by dental caries compared to European. Excess dietary sugar intake is widely recognised to cause dental decay and also provides energy to some species of bacteria implicated in the pathogenesis of dental decay and rheumatic fever. We suggest that a case-control study be conducted to evaluate the evidence for an association between sugar intake, dental decay and incidence of disease.

Molecular Factors and Biological Pathways Associated with Malaria Fever and the Pathogenesis of Cerebral Malaria

DTIC Science & Technology

2007-04-09

Novakovic , P. Gerold, R. T. Schwarz, M. J. McConville, and S. D. Tachado. 1996. Glycosylphosphatidylinositol toxin of Plasmodium up-regulates...Schofield, L., S. Novakovic , P. Gerold, R. T. Schwarz, M. J. McConville, and S. D. Tachado. 1996. Glycosylphosphatidylinositol toxin of Plasmodium up

Crimean-Congo haemorrhagic fever.

PubMed

Peyrefitte, C; Marianneau, P; Tordo, N; Bouloy, M

2015-08-01

Crimean-Congo haemorrhagic fever (CCHF) is one of the most widespread arboviroses in the world. It is present in Africa, south-east Europe, the Middle East and Asia. It is caused by a nairovirus (Bunyaviridae family) transmitted by several species of ticks. The geographical distribution of the disease coincides with the distribution of Hyalomma ticks. While infected livestock do not show signs of illness, humans are severely affected, with a high mortality rate. The most common symptoms are high fever, dizziness, headache, vomiting and haemorrhages. Pathogenesis studies in interferon-receptor-deficient mice indicated that the interferon response is crucial in controlling virus propagation and in protecting against the disease. Detection of the virus in biological material is currently performed by reverse-transcription polymerase chain reaction. Enzyme-linked immunosorbent assay and indirect immunofluorescence are used to detect the presence of CCHF virus-specific antibodies. In the 1970s, a formalin-inactivated vaccine prepared from suckling mouse brain was used in Eastern Europe and the former Soviet Union, but its efficacy remains to be proven. Treatment of patients with ribavirin is recommended by the World Health Organization, but it should be administered as early as possible. Although important progress has been made over the last few decades, many questions about the pathogenesis and epidemiology of the disease are still to be addressed and there is a need to develop efficient vaccines and antivirals.

Arenavirus Glycan Shield Promotes Neutralizing Antibody Evasion and Protracted Infection

PubMed Central

Malinge, Pauline; Magistrelli, Giovanni; Fischer, Nicolas; Sahin, Mehmet; Bergthaler, Andreas; Igonet, Sebastien; ter Meulen, Jan; Rigo, Dorothée; Meda, Paolo; Rabah, Nadia; Coutard, Bruno; Bowden, Thomas A.; Lambert, Paul-Henri; Siegrist, Claire-Anne; Pinschewer, Daniel D.

2015-01-01

Arenaviruses such as Lassa virus (LASV) can cause severe hemorrhagic fever in humans. As a major impediment to vaccine development, delayed and weak neutralizing antibody (nAb) responses represent a unifying characteristic of both natural infection and all vaccine candidates tested to date. To investigate the mechanisms underlying arenavirus nAb evasion we engineered several arenavirus envelope-chimeric viruses and glycan-deficient variants thereof. We performed neutralization tests with sera from experimentally infected mice and from LASV-convalescent human patients. NAb response kinetics in mice correlated inversely with the N-linked glycan density in the arenavirus envelope protein’s globular head. Additionally and most intriguingly, infection with fully glycosylated viruses elicited antibodies, which neutralized predominantly their glycan-deficient variants, both in mice and humans. Binding studies with monoclonal antibodies indicated that envelope glycans reduced nAb on-rate, occupancy and thereby counteracted virus neutralization. In infected mice, the envelope glycan shield promoted protracted viral infection by preventing its timely elimination by the ensuing antibody response. Thus, arenavirus envelope glycosylation impairs the protective efficacy rather than the induction of nAbs, and thereby prevents efficient antibody-mediated virus control. This immune evasion mechanism imposes limitations on antibody-based vaccination and convalescent serum therapy. PMID:26587982

Q Fever in Pregnant Goats: Pathogenesis and Excretion of Coxiella burnetii

PubMed Central

Roest, Hendrik-Jan; van Gelderen, Betty; Dinkla, Annemieke; Frangoulidis, Dimitrios; van Zijderveld, Fred; Rebel, Johanna; van Keulen, Lucien

2012-01-01

Coxiella burnetii is an intracellular bacterial pathogen that causes Q fever. Infected pregnant goats are a major source of human infection. However, the tissue dissemination and excretion pathway of the pathogen in goats are still poorly understood. To better understand Q fever pathogenesis, we inoculated groups of pregnant goats via the intranasal route with a recent Dutch outbreak C. burnetii isolate. Tissue dissemination and excretion of the pathogen were followed for up to 95 days after parturition. Goats were successfully infected via the intranasal route. PCR and immunohistochemistry showed strong tropism of C. burnetii towards the placenta at two to four weeks after inoculation. Bacterial replication seemed to occur predominantly in the trophoblasts of the placenta and not in other organs of goats and kids. The amount of C. burnetii DNA in the organs of goats and kids increased towards parturition. After parturition it decreased to undetectable levels: after 81 days post-parturition in goats and after 28 days post-parturition in kids. Infected goats gave birth to live or dead kids. High numbers of C. burnetii were excreted during abortion, but also during parturition of liveborn kids. C. burnetii was not detected in faeces or vaginal mucus before parturition. Our results are the first to demonstrate that pregnant goats can be infected via the intranasal route. C. burnetii has a strong tropism for the trophoblasts of the placenta and is not excreted before parturition; pathogen excretion occurs during birth of dead as well as healthy animals. Besides abortions, normal deliveries in C. burnetii-infected goats should be considered as a major zoonotic risk for Q fever in humans. PMID:23152826

Rapidly Escalating Hepcidin and Associated Serum Iron Starvation Are Features of the Acute Response to Typhoid Infection in Humans

PubMed Central

Darton, Thomas C.; Blohmke, Christoph J.; Giannoulatou, Eleni; Waddington, Claire S.; Jones, Claire; Sturges, Pamela; Webster, Craig; Drakesmith, Hal; Pollard, Andrew J.; Armitage, Andrew E.

2015-01-01

Background Iron is a key pathogenic determinant of many infectious diseases. Hepcidin, the hormone responsible for governing systemic iron homeostasis, is widely hypothesized to represent a key component of nutritional immunity through regulating the accessibility of iron to invading microorganisms during infection. However, the deployment of hepcidin in human bacterial infections remains poorly characterized. Typhoid fever is a globally significant, human-restricted bacterial infection, but understanding of its pathogenesis, especially during the critical early phases, likewise is poorly understood. Here, we investigate alterations in hepcidin and iron/inflammatory indices following experimental human typhoid challenge. Methodology/Principal Findings Fifty study participants were challenged with Salmonella enterica serovar Typhi and monitored for evidence of typhoid fever. Serum hepcidin, ferritin, serum iron parameters, C-reactive protein (CRP), and plasma IL-6 and TNF-alpha concentrations were measured during the 14 days following challenge. We found that hepcidin concentrations were markedly higher during acute typhoid infection than at baseline. Hepcidin elevations mirrored the kinetics of fever, and were accompanied by profound hypoferremia, increased CRP and ferritin, despite only modest elevations in IL-6 and TNF-alpha in some individuals. During inflammation, the extent of hepcidin upregulation associated with the degree of hypoferremia. Conclusions/Significance We demonstrate that strong hepcidin upregulation and hypoferremia, coincident with fever and systemic inflammation, are hallmarks of the early innate response to acute typhoid infection. We hypothesize that hepcidin-mediated iron redistribution into macrophages may contribute to S. Typhi pathogenesis by increasing iron availability for macrophage-tropic bacteria, and that targeting macrophage iron retention may represent a strategy for limiting infections with macrophage-tropic pathogens such as S. Typhi. PMID:26394303

The pathogenesis of severe fever with thrombocytopenia syndrome virus infection in alpha/beta interferon knockout mice: insights into the pathologic mechanisms of a new viral hemorrhagic fever.

PubMed

Liu, Yan; Wu, Bin; Paessler, Slobodan; Walker, David H; Tesh, Robert B; Yu, Xue-jie

2014-02-01

Severe fever with thrombocytopenia syndrome virus (SFTSV) is a newly discovered Phlebovirus causing an emerging hemorrhagic fever in East Asia, with reported case fatality rates up to 30%. Despite the high case fatality rate and large number of persons at risk of infection, the pathobiology of the disease is unknown, and no effective animal model has been available for investigating its pathogenesis. We have studied mice and hamsters as potential small-animal models of SFTSV infection following subcutaneous, intraperitoneal, or intracerebral inoculation. Animal tissues were processed for viral load determination, histopathology, immunohistochemistry, and confocal microscopic studies. We found that immunocompetent adult mice and hamsters did not become ill after SFTSV infection. However, alpha/beta interferon receptor knockout (IFNAR(-/-)) mice were highly susceptible to SFTSV infection, and all mice died within 3 to 4 days after subcutaneous inoculation of 10(6) focus-forming units of SFTSV. Histologic examination of tissues of IFNAR(-/-) mice infected with SFTSV showed no detectable lesions. In contrast, by immunohistochemistry virus antigen was found in liver, intestine, kidney, spleen, lymphoid tissue, and brain, but not in the lungs. Mesenteric lymph nodes and spleen were the most heavily infected tissues. Quantitative reverse transcription-PCR (RT-PCR) confirmed the presence of virus in these tissues. Confocal microscopy showed that SFTSV colocalized with reticular cells but did not colocalize with dendritic cells, monocytes/macrophages, neutrophils, or endothelium. Our results indicate that SFTSV multiplied in all organs except for lungs and that mesenteric lymph nodes and spleen were the most heavily infected tissues. The major target cells of SFTSV appear to be reticular cells in lymphoid tissues of intestine and spleen.

Q fever in pregnant goats: pathogenesis and excretion of Coxiella burnetii.

PubMed

Roest, Hendrik-Jan; van Gelderen, Betty; Dinkla, Annemieke; Frangoulidis, Dimitrios; van Zijderveld, Fred; Rebel, Johanna; van Keulen, Lucien

2012-01-01

Coxiella burnetii is an intracellular bacterial pathogen that causes Q fever. Infected pregnant goats are a major source of human infection. However, the tissue dissemination and excretion pathway of the pathogen in goats are still poorly understood. To better understand Q fever pathogenesis, we inoculated groups of pregnant goats via the intranasal route with a recent Dutch outbreak C. burnetii isolate. Tissue dissemination and excretion of the pathogen were followed for up to 95 days after parturition. Goats were successfully infected via the intranasal route. PCR and immunohistochemistry showed strong tropism of C. burnetii towards the placenta at two to four weeks after inoculation. Bacterial replication seemed to occur predominantly in the trophoblasts of the placenta and not in other organs of goats and kids. The amount of C. burnetii DNA in the organs of goats and kids increased towards parturition. After parturition it decreased to undetectable levels: after 81 days post-parturition in goats and after 28 days post-parturition in kids. Infected goats gave birth to live or dead kids. High numbers of C. burnetii were excreted during abortion, but also during parturition of liveborn kids. C. burnetii was not detected in faeces or vaginal mucus before parturition. Our results are the first to demonstrate that pregnant goats can be infected via the intranasal route. C. burnetii has a strong tropism for the trophoblasts of the placenta and is not excreted before parturition; pathogen excretion occurs during birth of dead as well as healthy animals. Besides abortions, normal deliveries in C. burnetii-infected goats should be considered as a major zoonotic risk for Q fever in humans.

STUDIES ON THE PATHOGENESIS OF FEVER. 13. THE EFFECT OF PHAGOCYTOSIS ON THE RELEASE OF ENDOGENOUS PYROGEN BY POLYMORPHONUCLEAR LEUKOCYTES.

PubMed

BERLIN, R D; WOOD, W B

1964-05-01

1. Phagocytosis promotes the release of endogenous pyrogen from polymorphonuclear leucocytes. 2. The release of pyrogen, though initiated by the phagocytic event, is not synchronous with it. 3. The postphagocytic release mechanism is not inhibited by sodium fluoride and, therefore, appears not to require continued production of energy by the cell. 4. The release process, on the other hand, is inhibited by arsenite, suggesting the participation of one or more sulfhydryl-dependent enzymes in the over-all reaction. 5. Particle for particle, the ingestion of heat-killed rough pneumococci causes the release of approximately 100 times as much pyrogen as the ingestion of polystyrene beads of the same size. 6. The pyrogen release mechanism of polymorphonuclear leucocytes separated directly from blood, unlike that of granulocytes in acute inflammatory exudates, is not readily activated by incubation of the cells in K-free saline. Despite this difference, both blood and exudate leucocytes following phagocytosis release large amounts of pyrogen, even in the presence of K(+). The fact that the postphagocytic reaction is uninhibited by the concentrations of K(+) which are present in plasma and extracellular fluids, suggests that this mechanism of pyrogen release may well operate in vivo. 7. As might be expected from the foregoing observations, the intravenous injection of a sufficiently large number of heat-killed pneumococci causes fever in the intact host. Intravenously injected polystyrene beads, on the other hand, are significantly less pyrogenic. Evidence is presented to support the conclusion that the fever in both instances is caused by pyrogen released from the circulating leucocytes which have phagocyted the injected particles. 8. The possible relationships of these findings to the pathogenesis of fevers caused by acute bacterial infections are discussed.

Yellow fever: an update.

PubMed

Monath, T P

2001-08-01

Yellow fever, the original viral haemorrhagic fever, was one of the most feared lethal diseases before the development of an effective vaccine. Today the disease still affects as many as 200,000 persons annually in tropical regions of Africa and South America, and poses a significant hazard to unvaccinated travellers to these areas. Yellow fever is transmitted in a cycle involving monkeys and mosquitoes, but human beings can also serve as the viraemic host for mosquito infection. Recent increases in the density and distribution of the urban mosquito vector, Aedes aegypti, as well as the rise in air travel increase the risk of introduction and spread of yellow fever to North and Central America, the Caribbean and Asia. Here I review the clinical features of the disease, its pathogenesis and pathophysiology. The disease mechanisms are poorly understood and have not been the subject of modern clinical research. Since there is no specific treatment, and management of patients with the disease is extremely problematic, the emphasis is on preventative vaccination. As a zoonosis, yellow fever cannot be eradicated, but reduction of the human disease burden is achievable through routine childhood vaccination in endemic countries, with a low cost for the benefits obtained. The biological characteristics, safety, and efficacy of live attenuated, yellow fever 17D vaccine are reviewed. New applications of yellow fever 17D virus as a vector for foreign genes hold considerable promise as a means of developing new vaccines against other viruses, and possibly against cancers.

Production of endogenous pyrogen.

PubMed

Dinarello, C A

1979-01-01

The production and release of endogenous pyrogen by the host is the first step in the pathogenesis of fever. Endogenous pyrogen is a low-molecular-weight protein released from phagocytic leukocytes in response to several substances of diverse nature. Some of these agents stimulate production of endogenous pyrogen because they are toxic; others act as antigens and interact with either antibody or sensitized lymphocytes in order to induce its production. Some tumors of macrophage origin produce the molecule spontaneously. Whatever the mechanism involved, endogenous pyrogen is synthesized following transcription of new DNA and translation of mRNA into new protein. Once synthesis is completed, the molecule is released without significant intracellular storage. Recent evidence suggests that following release, molecular aggregates form which are biologically active. In its monomer form, endogenous pyrogen is a potent fever-producing substance and mediates fever by its action on the thermoregulatory center.

Midzonal lesions in yellow fever: a specific pattern of liver injury caused by direct virus action and in situ inflammatory response.

PubMed

Quaresma, Juarez A S; Duarte, Maria I S; Vasconcelos, Pedro F C

2006-01-01

Yellow fever is an acute infectious, non-contagious disease characterized by intense vasculopathy and lesions in different organs. In the liver, one of the main targets of the virus, the infection induces a characteristic midzonal injury characterized by hepatocyte necrosis, apoptosis and steatosis. This characteristics pattern of liver injury in yellow fever is also observed in conditions of low-flow hypoxia and other infections such as dengue and Rift Valley fever. There are no reports in the literature explaining the genesis of this peculiar histopathological pattern in yellow fever. Some hypotheses have been proposed to explain the mechanism of this midzonal distribution pattern observed in the liver such as low-flow hypoxia and tropism of the virus toward hepatocytes in this area. These hypotheses are discussed in view of more recent findings regarding the pathogenesis of yellow fever and regarding hepatic physiopathology, and a new hypothesis is proposed: the midzonal necrosis is consequence of action of combined factors mainly the direct cytopathic effect of YFV associated with a potent immune response in which CD4+ and CD8+ lymphocytes and the cytokines, especially TGF-beta, but also TNF-alpha and IFN-gamma play an important role.

Favipiravir Pharmacokinetics in Nonhuman Primates and Insights for Future Efficacy Studies of Hemorrhagic Fever Viruses.

PubMed

Madelain, Vincent; Guedj, Jérémie; Mentré, France; Nguyen, Thi Huyen Tram; Jacquot, Frédéric; Oestereich, Lisa; Kadota, Takumi; Yamada, Koichi; Taburet, Anne-Marie; de Lamballerie, Xavier; Raoul, Hervé

2017-01-01

Favipiravir is an RNA polymerase inhibitor that showed strong antiviral efficacy in vitro and in small-animal models of several viruses responsible for hemorrhagic fever (HF), including Ebola virus. The aim of this work was to characterize the complex pharmacokinetics of favipiravir in nonhuman primates (NHPs) in order to guide future efficacy studies of favipiravir in large-animal models. Four different studies were conducted in 30 uninfected cynomolgus macaques of Chinese (n = 17) or Mauritian (n = 13) origin treated with intravenous favipiravir for 7 to 14 days with maintenance doses of 60 to 180 mg/kg of body weight twice a day (BID). A pharmacokinetic model was developed to predict the plasma concentrations obtained with different dosing regimens, and the model predictions were compared to the 50% effective concentration (EC 50 ) of favipiravir against several viruses. Favipiravir pharmacokinetics were described by a model accounting for concentration-dependent aldehyde oxidase inhibition. The enzyme-dependent elimination rate increased over time and was higher in NHPs of Mauritian origin than in those of Chinese origin. Maintenance doses of 100 and 120 mg/kg BID in Chinese and Mauritian NHPs, respectively, are predicted to achieve median trough plasma free concentrations above the EC 50 for Lassa and Marburg viruses until day 7. For Ebola virus, higher doses are required. After day 7, a 20% dose increase is needed to compensate for the increase in drug clearance over time. These results will help rationalize the choice of dosing regimens in future studies evaluating the antiviral effect of favipiravir in NHPs and support its development against a variety of HF viruses. Copyright © 2016 American Society for Microbiology.

Rapid detection of all known ebolavirus species by reverse transcription-loop-mediated isothermal amplification (RT-LAMP).

PubMed

Oloniniyi, Olamide K; Kurosaki, Yohei; Miyamoto, Hiroko; Takada, Ayato; Yasuda, Jiro

2017-08-01

Ebola virus disease (EVD), a highly virulent infectious disease caused by ebolaviruses, has a fatality rate of 25-90%. Without a licensed chemotherapeutic agent or vaccine for the treatment and prevention of EVD, control of outbreaks requires accurate and rapid diagnosis of cases. In this study, five sets of six oligonucleotide primers targeting the nucleoprotein gene were designed for specific identification of each of the five ebolavirus species using reverse transcription-loop mediated isothermal amplification (RT-LAMP) assay. The detection limits of the ebolavirus species-specific primer sets were evaluated using in vitro transcribed RNAs. The detection limit of species-specific RT-LAMP assays for Zaire ebolavirus, Sudan ebolavirus, Taï Forest ebolavirus, and Bundibugyo ebolavirus was 256 copies/reaction, while the detection limit for Reston ebolavirus was 64 copies/reaction, and the detection time for each of the RT-LAMP assays was 13.3±3.0, 19.8±4.6, 14.3±0.6, 16.1±4.7, and 19.8±2.4min (mean±SD), respectively. The sensitivity of the species-specific RT-LAMP assays were similar to that of the established RT-PCR and quantitative RT-PCR assays for diagnosis of EVD and are suitable for field or point-of-care diagnosis. The RT-LAMP assays were specific for the detection of the respective species of ebolavirus with no cross reaction with other species of ebolavirus and other viral hemorrhagic fever viruses such as Marburg virus, Lassa fever virus, and Dengue virus. The species-specific RT-LAMP assays developed in this study are rapid, sensitive, and specific and could be useful in case of an EVD outbreak. Copyright © 2017 Elsevier B.V. All rights reserved.

East Coast Fever Caused by Theileria parva Is Characterized by Macrophage Activation Associated with Vasculitis and Respiratory Failure

PubMed Central

Schneider, David A.; Frevert, Charles W.; Nelson, Danielle D.; Morrison, W. Ivan; Knowles, Donald P.

2016-01-01

Respiratory failure and death in East Coast Fever (ECF), a clinical syndrome of African cattle caused by the apicomplexan parasite Theileria parva, has historically been attributed to pulmonary infiltration by infected lymphocytes. However, immunohistochemical staining of tissue from T. parva infected cattle revealed large numbers of CD3- and CD20-negative intralesional mononuclear cells. Due to this finding, we hypothesized that macrophages play an important role in Theileria parva disease pathogenesis. Data presented here demonstrates that terminal ECF in both Holstein and Boran cattle is largely due to multisystemic histiocytic responses and resultant tissue damage. Furthermore, the combination of these histologic changes with the clinical findings, including lymphadenopathy, prolonged pyrexia, multi-lineage leukopenia, and thrombocytopenia is consistent with macrophage activation syndrome. All animals that succumbed to infection exhibited lymphohistiocytic vasculitis of small to medium caliber blood and lymphatic vessels. In pulmonary, lymphoid, splenic and hepatic tissues from Holstein cattle, the majority of intralesional macrophages were positive for CD163, and often expressed large amounts of IL-17. These data define a terminal ECF pathogenesis in which parasite-driven lymphoproliferation leads to secondary systemic macrophage activation syndrome, mononuclear vasculitis, pulmonary edema, respiratory failure and death. The accompanying macrophage phenotype defined by CD163 and IL-17 is presented in the context of this pathogenesis. PMID:27195791

East Coast Fever Caused by Theileria parva Is Characterized by Macrophage Activation Associated with Vasculitis and Respiratory Failure.

PubMed

Fry, Lindsay M; Schneider, David A; Frevert, Charles W; Nelson, Danielle D; Morrison, W Ivan; Knowles, Donald P

2016-01-01

Respiratory failure and death in East Coast Fever (ECF), a clinical syndrome of African cattle caused by the apicomplexan parasite Theileria parva, has historically been attributed to pulmonary infiltration by infected lymphocytes. However, immunohistochemical staining of tissue from T. parva infected cattle revealed large numbers of CD3- and CD20-negative intralesional mononuclear cells. Due to this finding, we hypothesized that macrophages play an important role in Theileria parva disease pathogenesis. Data presented here demonstrates that terminal ECF in both Holstein and Boran cattle is largely due to multisystemic histiocytic responses and resultant tissue damage. Furthermore, the combination of these histologic changes with the clinical findings, including lymphadenopathy, prolonged pyrexia, multi-lineage leukopenia, and thrombocytopenia is consistent with macrophage activation syndrome. All animals that succumbed to infection exhibited lymphohistiocytic vasculitis of small to medium caliber blood and lymphatic vessels. In pulmonary, lymphoid, splenic and hepatic tissues from Holstein cattle, the majority of intralesional macrophages were positive for CD163, and often expressed large amounts of IL-17. These data define a terminal ECF pathogenesis in which parasite-driven lymphoproliferation leads to secondary systemic macrophage activation syndrome, mononuclear vasculitis, pulmonary edema, respiratory failure and death. The accompanying macrophage phenotype defined by CD163 and IL-17 is presented in the context of this pathogenesis.

Plasma oxidative stress and total thiol levels in Crimean-Congo hemorrhagic fever.

PubMed

Karadag-Oncel, Eda; Erel, Ozcan; Ozsurekci, Yasemin; Caglayik, Dilek Yagci; Kaya, Ali; Gozel, Mustafa Gokhan; Icagasioglu, Fusun Dilara; Engin, Aynur; Korukluoglu, Gulay; Uyar, Yavuz; Elaldi, Nazif; Ceyhan, Mehmet

2014-01-01

In this study, we investigated the pro- and antioxidant status of patients with a pathogenesis of Crimean-Congo hemorrhagic fever (CCHF) in terms of their role in its pathogenesis. During the study period, 34 children and 41 adults were diagnosed with CCHF. The control group consisted of healthy age- and gender-matched children and adults. Serum levels of the total antioxidant capacity (TAC), total oxidant status (TOS), oxidative stress index (OSI), and plasma total thiol (TTL) were evaluated and compared between groups. The difference in mean TAC values between CCHF patients and healthy controls was not statistically significant (P > 0.05). Mean TOS, OSI, and TTL values were significantly lower in CCHF patients than in healthy controls (P < 0.001). Comparisons between the 2 groups revealed that mean TOS and OSI values were significantly lower in adults with CCHF than in their healthy counterparts (P < 0.001). Similarly, mean TTL levels were lower in both children and adults with CCHF when compared separately with healthy controls (P < 0.05). There was no significant difference in the mean serum TTL levels between children and adults with CCHF (P > 0.05). Our results suggest that TTL may play a more important role in CCHF pathogenesis than the other parameters investigated. The mean TOS and OSI values were higher in the control group than in CCHF patients.

Interferon Antagonism as a Common Virulence Factor of Hemorrhagic Fever Viruses

DTIC Science & Technology

2009-02-01

pathogenesis. Proc Soc Exp Biol Med 223:241-57. 11. Kohler, M., S. Ansieau, S. Prehn , A. Leutz, H. Haller, and E. Hartmann. 1997. Cloning of two novel human...Christiansen, F. R. Bischoff, S. Prehn , H. Haller, D. Gorlich, and E. Hartmann. 1999. Evidence for distinct substrate specificities of importin

Invasive Non-typhoidal Salmonella Disease – epidemiology, pathogenesis and diagnosis

PubMed Central

Gordon, Melita A

2012-01-01

Purpose of review To highlight and discuss important publications over the past 12 months providing new insights on invasive non-typhoidal Salmonella disease (iNTS). Recent findings There have been informative new estimates of the burden of iNTS in Asia and in high-resource low-incidence settings. Important information has emerged in the last year about the relationships between HIV, malaria, iNTS and typhoid fever in adults and children in Africa. HIV causes susceptibility to iNTS disease, but has been shown to be protective against typhoid fever. Clinical guidelines for presumptive diagnosis frequently fail to identify iNTS disease in Africa, and there remains a need for improved diagnostic tools. Experimental studies in humans have helped us to understand the intracellular pathogenesis of iNTS and to direct the search for appropriate protein vaccine targets. Summary The most important remaining gap in our knowledge is probably an understanding of how NTS are transmitted, and the nature of the relationship between diarrhoeal disease, carriage and invasive disease in Africa, so that diagnostic and prevention tools can be appropriately directed. PMID:21844803

Pathogenesis of emerging severe fever with thrombocytopenia syndrome virus in C57/BL6 mouse model

PubMed Central

Jin, Cong; Liang, Mifang; Ning, Junyu; Gu, Wen; Jiang, Hong; Wu, Wei; Zhang, Fushun; Zhang, Quanfu; Zhu, Hua; Chen, Ting; Han, Ying; Zhang, Weilun; Zhang, Shuo; Wang, Qin; Sun, Lina; Liu, Qinzhi; Wang, Tao; Wei, Qiang; Wang, Shiwen; Deng, Ying; Qin, Chuan; Li, Dexin

2012-01-01

The discovery of an emerging viral disease, severe fever with thrombocytopenia syndrome (SFTS), caused by SFTS virus (SFTSV), has prompted the need to understand pathogenesis of SFTSV. We are unique in establishing an infectious model of SFTS in C57/BL6 mice, resulting in hallmark symptoms of thrombocytopenia and leukocytopenia. Viral RNA and histopathological changes were identified in the spleen, liver, and kidney. However, viral replication was only found in the spleen, which suggested the spleen to be the principle target organ of SFTSV. Moreover, the number of macrophages and platelets were largely increased in the spleen, and SFTSV colocalized with platelets in cytoplasm of macrophages in the red pulp of the spleen. In vitro cellular assays further revealed that SFTSV adhered to mouse platelets and facilitated the phagocytosis of platelets by mouse primary macrophages, which in combination with in vivo findings, suggests that SFTSV-induced thrombocytopenia is caused by clearance of circulating virus-bound platelets by splenic macrophages. Thus, this study has elucidated the pathogenic mechanisms of thrombocytopenia in a mouse model resembling human SFTS disease. PMID:22665769

Crimean-Congo hemorrhagic fever: CXCL10 correlates with the viral load.

PubMed

Papa, Anna; Yagci Caglayık, Dilek; Christova, Iva; Tsergouli, Katerina; Korukluoglu, Gulay; Uyar, Yavuz

2015-06-01

Crimean-Congo hemorrhagic fever (CCHF) is a human disease with high fatality rate. Although its pathogenesis is not elucidated yet, it is considered that cytokines play a significant role in the progression and outcome of the disease. Serum CXCL10 levels were estimated in 35 patients with acute CCHF and were correlated with the viral load, and various demographic and clinical parameters. The mean CXCL10 concentration in the patients' group was higher compared to the respective value in the control group (4421.74 pg/ml vs. 28.47 pg/ml, P < 0.05). A strong positive correlation between CXCL10 and viral load was seen (rs = 0.57, P < 0.001), while the outcome of the disease was related with the viral load (rs = 0.47, P = 0.004) and the presence of hemorrhagic manifestations (P < 0.001). The study provides an insight into the strong correlation between CXCL10 and viral load in acute CCHF cases suggesting that it plays an important role in CCHF pathogenesis. © 2015 Wiley Periodicals, Inc.

Understanding the Dengue Viruses and Progress towards Their Control

PubMed Central

Gould, Ernest A.

2013-01-01

Traditionally, the four dengue virus serotypes have been associated with fever, rash, and the more severe forms, haemorrhagic fever and shock syndrome. As our knowledge as well as understanding of these viruses increases, we now recognise not only that they are causing increasing numbers of human infections but also that they may cause neurological and other clinical complications, with sequelae or fatal consequences. In this review we attempt to highlight some of these features in the context of dengue virus pathogenesis. We also examine some of the efforts currently underway to control this “scourge” of the tropical and subtropical world. PMID:23936833

Filgrastim as a Rescue Therapy for Persistent Neutropenia in a Case of Dengue Hemorrhagic Fever with Acute Respiratory Distress Syndrome and Myocarditis

PubMed Central

Deepak, Desh; Garg, Rakesh; Pawar, Mridula; Banerjee, Neerja; Solanki, Rakesh; Maurya, Indubala

2011-01-01

Pathogenesis of dengue involves suppression of immune system leading to development of characteristic presentation of haematological picture of thrombocytopenia and leucopenia. Sometimes, this suppression in immune response is responsible for deterioration in clinical status of the patient in spite of all specific and supportive therapy. Certain drugs like steroids are used for rescue therapy in conditions like sepsis. We present a novel use of filgrastim as a rescue therapy in a patient with dengue hemorrhagic fever (DHF) with acute respiratory distress syndrome (ARDS), myocarditis, and febrile neutropenia and not responding to standard management. PMID:22606398

Involvement of matrix metalloproteinases in chronic Q fever.

PubMed

Jansen, A F M; Schoffelen, T; Textoris, J; Mege, J L; Bleeker-Rovers, C P; Roest, H I J; Wever, P C; Joosten, L A B; Netea, M G; van de Vosse, E; van Deuren, M

2017-07-01

Chronic Q fever is a persistent infection with the intracellular Gram-negative bacterium Coxiella burnetii, which can lead to complications of infected aneurysms. Matrix metalloproteinases (MMPs) cleave extracellular matrix and are involved in infections as well as aneurysms. We aimed to study the role of MMPs in the pathogenesis of chronic Q fever. We investigated gene expression of MMPs through microarray analysis and MMP production with ELISA in C. burnetii-stimulated peripheral blood mononuclear cells (PBMCs) of patients with chronic Q fever and healthy controls. Twenty single nucleotide polymorphisms (SNPs) of MMP and tissue inhibitor of MMP genes were genotyped in 139 patients with chronic Q fever and 220 controls with similar cardiovascular co-morbidity. Additionally, circulating MMPs levels in patients with chronic Q fever were compared with those in cardiovascular controls with and without a history of past Q fever. In healthy controls, the MMP pathway involving four genes (MMP1, MMP7, MMP10, MMP19) was significantly up-regulated in C. burnetii-stimulated but not in Escherichia coli lipopolysaccharide -stimulated PBMCs. Coxiella burnetii induced MMP-1 and MMP-9 production in PBMCs of healthy individuals (both p<0.001), individuals with past Q fever (p<0.05, p<0.01, respectively) and of patients with chronic Q fever (both p<0.001). SNPs in MMP7 (rs11568810) (p<0.05) and MMP9 (rs17576) (p<0.05) were more common in patients with chronic Q fever. Circulating MMP-7 serum levels were higher in patients with chronic Q fever (median 33.5 ng/mL, interquartile range 22.3-45.7 ng/mL) than controls (20.6 ng/mL, 15.9-33.8 ng/mL). Coxiella burnetii-induced MMP production may contribute to the development of chronic Q fever. Copyright © 2017 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Polymorphism of DC-SIGN (CD209) promoter in association with clinical symptoms of dengue fever.

PubMed

Oliveira, Layanna Freitas de; Lima, Clayton Pereira Silva de; Azevedo, Raimunda do Socorro Silva; Mendonça, Dafne Silva Furtado de; Rodrigues, Sueli Guerreiro; Carvalho, Valéria Lima; Pinto, Eliana Vieira; Maia, Andreza Lopes; Maia, Maria Helena Thomaz; Vasconcelos, Janaina Mota; Silva, Andrea Luciana Soares da; Nunes, Márcio Roberto Teixeira; Sena, Leonardo; Vasconcelos, Pedro Fernando; Santos, Eduardo José Melo dos

2014-06-01

C-type lectin DC-SIGN receptor, encoded by CD209, plays a key role in the infection of dendritic cells by dengue virus (DENV). Because the -336A/G SNP (rs4804803) polymorphism in the promoter of CD209 modulates DC-SIGN expression, we investigated the putative association of this polymorphism with DENV infection and its pathogenesis. A control sample of 72 individuals, rigorously selected through a clinical investigation for absence of past dengue fever (DF) was compared to a sample of 168 patients (156 classical DF; 12 dengue hemorrhagic fever), all residents from Pará, Brazil. However, the prevalence of symptoms showed a trend higher in the AA genotype (Wilcoxon test; Z=2.02; p=0.04). Hence, our findings indicate that the G allele downregulates the spectrum of symptoms during the early acute phase of DENV infection, putatively decreasing the viremia, as suggested in the literature.

Exploring the Immunopathogenesis of Viral Hemorrhagic Fever in Mice with a Humanized Immune System.

PubMed

Schönrich, Günther; Raftery, Martin J

2017-01-01

Viral hemorrhagic fever (VHF) as a disease entity was first codified in the 1930s by soviet scientists investigating patients suffering from hantavirus infection. The group of hemorrhagic fever viruses (HFVs) has since expanded to include members from at least four different virus families: Arenaviridae, Bunyaviridae, Filoviridae , and Flaviviridae , all enveloped single-stranded RNA viruses. After infection, the natural hosts of HFVs do not develop symptoms, whereas humans can be severely affected. This observation and other evidence from experimental data suggest that the human immune system plays a crucial role in VHF pathogenesis. For this reason mice with a human immune system, referred to here as humanized mice (humice), are valuable tools that provide insight into disease mechanisms and allow for preclinical testing of novel vaccinations approaches as well as antiviral agents. In this article, we review the impact of humice in VHF research.

Crimean-Congo Hemorrhagic Fever.

PubMed

Shayan, Sara; Bokaean, Mohammad; Shahrivar, Mona Ranjvar; Chinikar, Sadegh

2015-01-01

Crimean-Congo hemorrhagic fever virus (CCHFV) is a member of the Bunyaviridae family and Nairovirus genus. The viral genome consists of 3 RNA segments of 12 kb (L), 6.8 kb (M), and 3 kb (S). Crimean-Congo hemorrhagic fever (CCHF) is the most widespread tickborne viral infection worldwide: it has been reported in many regions of Africa, the Middle East, and Asia. The geographical distribution of CCHFV corresponds most closely with the distribution of members of the tick genera, and Hyalomma ticks are the principal source of human infection. In contrast to human infection, CCHFV infection is asymptomatic in all species. Treatment options for CCHF are limited; immunotherapy and ribavirin are effective in the treatment of CCHF; the efficacy of ribavirin in the treatment of CCHF has not yet been proven. This article reviews the history, epidemiology, clinical symptoms, pathogenesis, diagnosis, and treatment of CCHFV, as well as the development of a vaccine against it.

Autoinflammatory Diseases with Periodic Fevers.

PubMed

Sag, Erdal; Bilginer, Yelda; Ozen, Seza

2017-07-01

One purpose of this review was to raise awareness for the new autoinflammatory syndromes. These diseases are increasingly recognized and are in the differential diagnosis of many disease states. We also aimed to review the latest recommendations for the diagnosis, management, and treatment of these patients. Familial Mediterranean fever (FMF), cryopyrin-associated periodic syndrome (CAPS), tumor necrosis factor receptor-associated periodic fever syndrome (TRAPS), and hyperimmunoglobulinemia D and periodic fever syndrome/mevalonate kinase deficiency (HIDS/MVKD) are the more common autoinflammatory diseases that are characterized by periodic fevers and attacks of inflammation. Recently much collaborative work has been done to understand the characteristics of these patients and to develop recommendations to guide the physicians in the care of these patients. These recent recommendations will be summarized for all four diseases. FMF is the most common periodic fever disease. We need to further understand the pathogenesis and the role of single mutations in the disease. Recently, the management and treatment of the disease have been nicely reviewed. CAPS is another interesting disease associated with severe complications. Anti-interleukin-1 (anti-IL-1) treatment provides cure for these patients. TRAPS is characterized by the longest delay in diagnosis; thus, both pediatricians and internists should be aware of the characteristic features and the follow-up of these patients. HIDS/MVKD is another autoinflammatory diseases characterized with fever attacks. The spectrum of disease manifestation is rather large in this disease, and we need further research on biomarkers for the optimal management of these patients.

First Calderón Prize

NASA Astrophysics Data System (ADS)

Rundell, William; Somersalo, Erkki

2008-07-01

The Inverse Problems International Association (IPIA) awarded the first Calderón Prize to Matti Lassas for his outstanding contributions to the field of inverse problems, especially in geometric inverse problems. The Calderón Prize is given to a researcher under the age of 40 who has made distinguished contributions to the field of inverse problems broadly defined. The first Calderón Prize Committee consisted of Professors Adrian Nachman, Lassi Päivärinta, William Rundell (chair), and Michael Vogelius. William Rundell For the Calderón Prize Committee Prize ceremony The ceremony awarding the Calderón Prize. Matti Lassas is on the left. He and William Rundell are on the right. Photos by P Stefanov. Brief Biography of Matti Lassas Matti Lassas was born in 1969 in Helsinki, Finland, and studied at the University of Helsinki. He finished his Master's studies in 1992 in three years and earned his PhD in 1996. His PhD thesis, written under the supervision of Professor Erkki Somersalo was entitled `Non-selfadjoint inverse spectral problems and their applications to random bodies'. Already in his thesis, Matti demonstrated a remarkable command of different fields of mathematics, bringing together the spectral theory of operators, geometry of Riemannian surfaces, Maxwell's equations and stochastic analysis. He has continued to develop all of these branches in the framework of inverse problems, the most remarkable results perhaps being in the field of differential geometry and inverse problems. Matti has always been a very generous researcher, sharing his ideas with his numerous collaborators. He has authored over sixty scientific articles, among which a monograph on inverse boundary spectral problems with Alexander Kachalov and Yaroslav Kurylev and over forty articles in peer reviewed journals of the highest standards. To get an idea of the wide range of Matti's interests, it is enough to say that he also has three US patents on medical imaging applications. Matti is currently professor of mathematics at Helsinki University of Technology, where he has created his own line of research with young talented researchers around him. He is a central person in the Centre of Excellence in Inverse Problems Research of the Academy of Finland. Previously, Matti Lassas has won several awards in his home country, including the prestigious Vaisala price of the Finnish Academy of Science and Letters in 2004. He is a highly esteemed colleague, teacher and friend, and the Great Diving Beetle of the Finnish Inverse Problems Society (http://venda.uku.fi/research/FIPS/), an honorary title for a person who has no fear of the deep. Erkki Somersalo

Forty-Five Years of Marburg Virus Research

PubMed Central

Brauburger, Kristina; Hume, Adam J.; Mühlberger, Elke; Olejnik, Judith

2012-01-01

In 1967, the first reported filovirus hemorrhagic fever outbreak took place in Germany and the former Yugoslavia. The causative agent that was identified during this outbreak, Marburg virus, is one of the most deadly human pathogens. This article provides a comprehensive overview of our current knowledge about Marburg virus disease ranging from ecology to pathogenesis and molecular biology. PMID:23202446

Forty-five years of Marburg virus research.

PubMed

Brauburger, Kristina; Hume, Adam J; Mühlberger, Elke; Olejnik, Judith

2012-10-01

In 1967, the first reported filovirus hemorrhagic fever outbreak took place in Germany and the former Yugoslavia. The causative agent that was identified during this outbreak, Marburg virus, is one of the most deadly human pathogens. This article provides a comprehensive overview of our current knowledge about Marburg virus disease ranging from ecology to pathogenesis and molecular biology.

The roles of ebolavirus glycoproteins in viral pathogenesis.

PubMed

Ning, Yun-Jia; Deng, Fei; Hu, Zhihong; Wang, Hualin

2017-02-01

Ebolaviruses are highly dangerous pathogens exhibiting extreme virulence in humans and nonhuman primates. The majority of ebolavirus species, most notably Zaire ebolavirus, can cause Ebola virus disease (EVD), formerly known as Ebola hemorrhagic fever, in humans. EVD is associated with case-fatality rates as high as 90%, and there is currently no specific treatment or licensed vaccine available against EVD. Understanding the molecular biology and pathogenesis of ebolaviruses is important for the development of antiviral therapeutics. Ebolavirus encodes several forms of glycoproteins (GPs), which have some interesting characteristics, including the transcriptional editing coding strategy and extensive O-glycosylation modification, clustered in the mucin-like domain of GP1, full-length GP (GP 1,2 ), and shed GP. In addition to the canonical role of the spike protein, GP 1,2 , in viral entry, ebolavirus GPs appear to have multiple additional functions, likely contributing to the complex pathogenesis of the virus. Here, we review the roles of ebolavirus GPs in viral pathogenesis.

The pathogenesis of Ebola hemorrhagic fever.

PubMed

Takada, A; Kawaoka, Y

2001-10-01

Ebola virus causes lethal hemorrhagic disease in humans, yet there are still no satisfactory biological explanations to account for its extreme virulence. This review focuses on recent findings relevant to understanding the pathogenesis of Ebola virus infection and developing vaccines and effective therapy. The available data suggest that the envelope glycoprotein and the interaction of some viral proteins with the immune system are likely to play important roles in the extraordinary pathogenicity of this virus. There are also indications that genetically engineered vaccines, including plasmid DNA and viral vectors expressing Ebola virus proteins, and passive transfer of neutralizing antibodies could be feasible options for the control of Ebola virus-associated disease.

Recent advances in research on Crimean-Congo hemorrhagic fever

PubMed Central

Papa, Anna; Mirazimi, Ali; Köksal, Iftihar; Estrada-Pena, Augustin; Feldmann, Heinz

2014-01-01

Crimean-Congo hemorrhagic fever (CCHF) is an expanding tick-borne hemorrhagic disease with increasing human and animal health impact. Immense knowledge was gained over the past 10 years mainly due to advances in molecular biology, but also driven by an increased global interest in CCHFV as an emerging/re-emerging zoonotic pathogen. In the present article we discuss the advances in research with focus on CCHF ecology, epidemiology, pathogenesis, diagnostics, prophylaxis and treatment. Despite tremendous achievements, future activities have to concentrate on the development of vaccines and antivirals/therapeutics to combat CCHF. Vector studies need to continue for better public and animal health preparedness and response. We conclude with a roadmap for future research priorities. PMID:25453328

Quantifying known and emerging uterine pathogens, and evaluating their association with metritis and fever in dairy cows.

PubMed

Cunha, Federico; Jeon, Soo Jin; Daetz, Rodolfo; Vieira-Neto, Achilles; Laporta, Jimena; Jeong, K Casey; Barbet, Anthony F; Risco, Carlos A; Galvão, Klibs N

2018-07-01

Metritis is caused by polymicrobial infection; however, recent metagenomic work challenges the importance of known pathogens such as Escherichia coli and Trueperella pyogenes while identifying potential new pathogens such as Bacteroides pyogenes, Porphyromonas levii and Helcococcus ovis. This study aims to quantify known and emerging uterine pathogens, and to evaluate their association with metritis and fever in dairy cows. Metritis was diagnosed at 6 ± 2 days postpartum, a uterine swab was collected and rectal temperature was measured. 39 cows were classified into three groups: Healthy (n = 14), Metritis without fever (MNoFever; n = 12), and Metritis with fever (MFever; n = 13). Absolute copy number was determined for total bacteria and for 8 potentially pathogenic bacteria using droplet digital PCR. Both MNoFever and MFever cows had higher copy number of total bacteria, Fusobacterium necrophorum, Prevotella melaninogenica, Bacteroides pyogenes, Porphyromonas levii, and Helcococcus ovis than Healthy cows. MNoFever and MFever groups were similar. There was no difference among groups in copy number of Escherichia coli, Trueperella pyogenes, and Bacteroides heparinolyticus, and they all had low copy numbers. Our work confirms the importance of some bacteria identified by culture-based studies in the pathogenesis of metritis such as Fusobacterium necrophorum and Prevotella melaninogenica; however, it challenges the importance of others such as Escherichia coli and Trueperella pyogenes at the time of metritis diagnosis. Additionally, Bacteroides pyogenes, Porphyromonas levii, and Helcococcus ovis were recognized as emerging pathogens involved in the etiology of metritis. Furthermore, fever was not associated with the total bacterial load or specific bacteria. Copyright © 2018 Elsevier Inc. All rights reserved.

Animal Models for the Study of Rodent-Borne Hemorrhagic Fever Viruses: Arenaviruses and Hantaviruses

PubMed Central

Golden, Joseph W.; Hammerbeck, Christopher D.; Mucker, Eric M.; Brocato, Rebecca L.

2015-01-01

Human pathogenic hantaviruses and arenaviruses are maintained in nature by persistent infection of rodent carrier populations. Several members of these virus groups can cause significant disease in humans that is generically termed viral hemorrhagic fever (HF) and is characterized as a febrile illness with an increased propensity to cause acute inflammation. Human interaction with rodent carrier populations leads to infection. Arenaviruses are also viewed as potential biological weapons threat agents. There is an increased interest in studying these viruses in animal models to gain a deeper understating not only of viral pathogenesis, but also for the evaluation of medical countermeasures (MCM) to mitigate disease threats. In this review, we examine current knowledge regarding animal models employed in the study of these viruses. We include analysis of infection models in natural reservoirs and also discuss the impact of strain heterogeneity on the susceptibility of animals to infection. This information should provide a comprehensive reference for those interested in the study of arenaviruses and hantaviruses not only for MCM development but also in the study of viral pathogenesis and the biology of these viruses in their natural reservoirs. PMID:26266264

Kidney lesions in Rocky Mountain spotted fever: a light-, immunofluorescence-, and electron-microscopic study.

PubMed Central

Bradford, W. D.; Croker, B. P.; Tisher, C. C.

1979-01-01

The essential pathologic lesion in Rocky Mountain spotted fever (RMSF) is a vasculitis that may involve the kidneys as well as the heart, brain, skin, and subcutaneous tissues. Histopathologic information concerning the response of the kidneys in RMSF is rather limited, however. In this study renal tissue from 17 children who died of RMSF was examined by light, electron, and immunofluorescence microscopy. A lymphocytic or mixed inflammation, or both, involving vessels and interstitium of the kidney was found in all patients. In addition, 10 patients had histologic evidence of acute tubular necrosis, and another 3 had glomerular lesions consisting of focal segmental tuft necrosis or increased cellularity secondary to neutophilic infiltration, or both. Immunofluorescence- and electron-microscopic studies failed to demonstrate immune-complex deposition within glomeruli, a finding that suggests that immunoglobulin and classic immune complexes were not involved in the pathogenesis of the renal lesions at the time of death. These findings suggest the possibility that the pathogenesis of the renal lesion in RMSF may be due to a direct action of the organism (Rickettsia rickettsii) on the vessel wall. Images Figure 2 Figure 1 PMID:525676

Experimental Respiratory Infection of Marmosets (Callithrix jacchus) With Ebola Virus Kikwit.

PubMed

Smither, Sophie J; Nelson, Michelle; Eastaugh, Lin; Nunez, Alejandro; Salguero, Francisco J; Lever, Mark S

2015-10-01

Ebola virus (EBOV) causes a highly infectious and lethal hemorrhagic fever in primates with high fatality rates during outbreaks and EBOV may be exploited as a potential biothreat pathogen. There is therefore a need to develop and license appropriate medical countermeasures against this virus. To determine whether the common marmoset (Callithrix jacchus) would be an appropriate model to assess vaccines or therapies against EBOV disease (EVD), initial susceptibility, lethality and pathogenesis studies were performed. Low doses of EBOV-Kikwit, between 4 and 27 times the 50% tissue culture infectious dose, were sufficient to cause a lethal, reproducible infection. Animals became febrile between days 5 and 6, maintaining a high fever before succumbing to EVD between 6 and 8 days after challenge. Typical signs of EVD were observed. Pathogenesis studies revealed that virus was isolated from the lungs of animals beginning on day 3 after challenge and from the liver, spleen and blood beginning on day 5. The most striking features were observed in animals that succumbed to infection, including high viral titers in all organs, increased levels of liver function enzymes and blood clotting times, decreased levels of platelets, multifocal moderate to severe hepatitis, and perivascular edema. © Crown copyright 2015.

Differences in Intracellular Fate of Two Spotted Fever Group Rickettsia in Macrophage-Like Cells.

PubMed

Curto, Pedro; Simões, Isaura; Riley, Sean P; Martinez, Juan J

2016-01-01

Spotted fever group (SFG) rickettsiae are recognized as important agents of human tick-borne diseases worldwide, such as Mediterranean spotted fever (Rickettsia conorii) and Rocky Mountain spotted fever (Rickettsia rickettsii). Recent studies in several animal models have provided evidence of non-endothelial parasitism by pathogenic SFG Rickettsia species, suggesting that the interaction of rickettsiae with cells other than the endothelium may play an important role in pathogenesis of rickettsial diseases. These studies raise the hypothesis that the role of macrophages in rickettsial pathogenesis may have been underappreciated. Herein, we evaluated the ability of two SFG rickettsial species, R. conorii (a recognized human pathogen) and Rickettsia montanensis (a non-virulent member of SFG) to proliferate in THP-1 macrophage-like cells, or within non-phagocytic cell lines. Our results demonstrate that R. conorii was able to survive and proliferate in both phagocytic and epithelial cells in vitro. In contrast, R. montanensis was able to grow in non-phagocytic cells, but was drastically compromised in the ability to proliferate within both undifferentiated and PMA-differentiated THP-1 cells. Interestingly, association assays revealed that R. montanensis was defective in binding to THP-1-derived macrophages; however, the invasion of the bacteria that are able to adhere did not appear to be affected. We have also demonstrated that R. montanensis which entered into THP-1-derived macrophages were rapidly destroyed and partially co-localized with LAMP-2 and cathepsin D, two markers of lysosomal compartments. In contrast, R. conorii was present as intact bacteria and free in the cytoplasm in both cell types. These findings suggest that a phenotypic difference between a non-pathogenic and a pathogenic SFG member lies in their respective ability to proliferate in macrophage-like cells, and may provide an explanation as to why certain SFG rickettsial species are not associated with disease in mammals.

Differences in Intracellular Fate of Two Spotted Fever Group Rickettsia in Macrophage-Like Cells

PubMed Central

Curto, Pedro; Simões, Isaura; Riley, Sean P.; Martinez, Juan J.

2016-01-01

Spotted fever group (SFG) rickettsiae are recognized as important agents of human tick-borne diseases worldwide, such as Mediterranean spotted fever (Rickettsia conorii) and Rocky Mountain spotted fever (Rickettsia rickettsii). Recent studies in several animal models have provided evidence of non-endothelial parasitism by pathogenic SFG Rickettsia species, suggesting that the interaction of rickettsiae with cells other than the endothelium may play an important role in pathogenesis of rickettsial diseases. These studies raise the hypothesis that the role of macrophages in rickettsial pathogenesis may have been underappreciated. Herein, we evaluated the ability of two SFG rickettsial species, R. conorii (a recognized human pathogen) and Rickettsia montanensis (a non-virulent member of SFG) to proliferate in THP-1 macrophage-like cells, or within non-phagocytic cell lines. Our results demonstrate that R. conorii was able to survive and proliferate in both phagocytic and epithelial cells in vitro. In contrast, R. montanensis was able to grow in non-phagocytic cells, but was drastically compromised in the ability to proliferate within both undifferentiated and PMA-differentiated THP-1 cells. Interestingly, association assays revealed that R. montanensis was defective in binding to THP-1-derived macrophages; however, the invasion of the bacteria that are able to adhere did not appear to be affected. We have also demonstrated that R. montanensis which entered into THP-1-derived macrophages were rapidly destroyed and partially co-localized with LAMP-2 and cathepsin D, two markers of lysosomal compartments. In contrast, R. conorii was present as intact bacteria and free in the cytoplasm in both cell types. These findings suggest that a phenotypic difference between a non-pathogenic and a pathogenic SFG member lies in their respective ability to proliferate in macrophage-like cells, and may provide an explanation as to why certain SFG rickettsial species are not associated with disease in mammals. PMID:27525249

Retinoids, race and the pathogenesis of dengue hemorrhagic fever.

PubMed

Mawson, Anthony R

2013-12-01

Dengue hemorrhagic fever (DHF) is the most significant mosquito-borne viral disease worldwide in terms of illness, mortality and economic cost, but the pathogenesis of DHF is not well understood and there is no specific treatment or vaccine. Based on evidence of liver involvement, it is proposed that dengue virus and retinoids interact to cause cholestatic liver damage, resulting in the spillage of stored retinoids into the circulation and in an endogenous form of hypervitaminosisis A manifested by the signs and symptoms of the disease, including: fever, severe joint and bone pain, capillary leakage, thrombocytopenia, headache, and gastrointestinal symptoms. While retinoids in low concentration are essential for numerous biological functions, they are prooxidant, cytotoxic, mutagenic and teratogenic in higher concentration, especially when unbound to protein, and an endogenous form of vitamin A intoxication is recognized in cholestasis. The model tentatively explains the observations that 1) repeat infections are more severe than initial dengue virus infections; 2) the incidence of denue has increased dramatically worldwide in recent decades; 3) DHF is less prevalent in people of African ancestry than those of other racial backgrounds; and 4) infants are protected from dengue. The retinoid toxicity hypothesis of DHF predicts the co-existence of low serum concentrations of retinol coupled with high concentrations of retinoic acid and an increased percentage of retinyl esters to total vitamin A. Subject to such tests, it may be possible to treat DHF effectively using drugs that target the metabolism and expression of retinoids. Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.

STUDIES ON THE PATHOGENESIS OF FEVER WITH INFLUENZAL VIRUSES

PubMed Central

Atkins, Elisha; Huang, Wei Cheng

1958-01-01

Observations have been made on the fever-inducing properties of an endogenous pyrogen found in the circulation of rabbits after the intravenous inoculation of Newcastle disease virus (NDV). When endogenous pyrogen was given to a normal recipient, a biphasic fever was produced which simulated that seen with bacterial endotoxins. With the use of a technique of serial passive transfer, it has been shown that the "double-humped" response results from two separate actions of the injected pyrogen. The first of these appears to be a direct stimulation of the thermoregulatory centers. The second involves the release of further endogenous pyrogen in the normal recipient to cause, in turn, the second fever peak. Since the injection of endogenous pyrogen did not produce a significant change in the number of circulating leukocytes, it is inferred that this substance is different from either bacterial or tissue polysaccharides. In rabbits rendered tolerant by a previous injection of virus the second fever peak failed to appear and the response to endogenous pyrogen was monophasic. Evidence indicates that the absence of a second fever peak in the tolerant recipient was not due to rise in temperature on the preceding day of virus injection or to the development of either serum inhibitors or tolerance to virus itself. It is postulated that prior mobilization of endogenous pyrogen by virus may have modified the ability of the tolerant recipient to liberate further amounts of this substance in response to an injection of endogenous pyrogen. PMID:13513909

Geographical distribution and surveillance of Crimean-Congo hemorrhagic fever in Iran.

PubMed

Chinikar, Sadegh; Ghiasi, Seyed Mojtaba; Moradi, Maryam; Goya, Mohammd M; Shirzadi, Mohammd R; Zeinali, Mohammd; Meshkat, Mohsen; Bouloy, Michele

2010-10-01

Crimean-Congo hemorrhagic fever (CCHF) is viral hemorrhagic fever caused by CCHF virus, which belongs to the family Bunyaviridae and the genus Nairovirus. The virus is transmitted to humans via contact with blood and tissue from infected livestock, a tick bite, or contact with an infected person. Since 2000, we have shown the disease to be prevalent in 23 out of 30 provinces of Iran. Among those, Sistan-va-Baluchistan, Isfahan, Fars, Tehran, Khorasan, and Khuzestan demonstrated the highest infection, respectively. Notably, Sistan-va-Baluchistan province, southeast of Iran, has the highest prevalence of CCHF, and has shown to be present since at least 2000. Phylogenetic study of the CCHF virus genome isolated from Iranian patients showed a close relationship with the CCHF Matin strain (Pakistan). Our epidemiological data in the last decade have implied that the severity and fatality rate of the disease has ranged variably in different provinces of Iran. More pathogenesis and phylogenetic studies should therefore be investigated to clarify these differences.

Ebola virus: the role of macrophages and dendritic cells in the pathogenesis of Ebola hemorrhagic fever.

PubMed

Bray, Mike; Geisbert, Thomas W

2005-08-01

Ebola hemorrhagic fever is a severe viral infection characterized by fever, shock and coagulation defects. Recent studies in macaques show that major features of illness are caused by effects of viral replication on macrophages and dendritic cells. Infected macrophages produce proinflammatory cytokines, chemokines and tissue factor, attracting additional target cells and inducing vasodilatation, increased vascular permeability and disseminated intravascular coagulation. However, they cannot restrict viral replication, possibly because of suppression of interferon responses. Infected dendritic cells also secrete proinflammatory mediators, but cannot initiate antigen-specific responses. In consequence, virus disseminates to these and other cell types throughout the body, causing multifocal necrosis and a syndrome resembling septic shock. Massive "bystander" apoptosis of natural killer and T cells further impairs immunity. These findings suggest that modifying host responses would be an effective therapeutic strategy, and treatment of infected macaques with a tissue-factor inhibitor reduced both inflammation and viral replication and improved survival.

Second International Conference on Crimean-Congo Hemorrhagic Fever.

PubMed

Spengler, Jessica R; Bente, Dennis A; Bray, Mike; Burt, Felicity; Hewson, Roger; Korukluoglu, Gülay; Mirazimi, Ali; Weber, Friedemann; Papa, Anna

2018-02-01

The Second International Conference on Crimean-Congo Hemorrhagic Fever (CCHF) was held in Thessaloniki, Greece, from September 10-13, 2017, and brought together international public health professionals, clinicians, ecologists, and basic laboratory researchers. Nearly 100 participants, representing 24 countries and the World Health Organization (WHO), were in attendance. Meeting sessions covered the epidemiology of CCHF in humans; ticks and virus-tick interactions; wild and domestic animal hosts; molecular virology; taxonomic classification; pathogenesis and animal models; clinical aspects and diagnosis; clinical management and clinical trials; and disease prevention in humans. The concluding session focused on recent WHO recommendations for public health measures and future research. This report summarizes lectures by the invited speakers and highlights advances in the field. Copyright © 2017. Published by Elsevier B.V.

Delayed Disease Progression in Cynomolgus Macaques Infected with Ebola Virus Makona Strain.

PubMed

Marzi, Andrea; Feldmann, Friederike; Hanley, Patrick W; Scott, Dana P; Günther, Stephan; Feldmann, Heinz

2015-10-01

In late 2013, the largest documented outbreak of Ebola hemorrhagic fever started in Guinea and has since spread to neighboring countries, resulting in almost 27,000 cases and >11,000 deaths in humans. In March 2014, Ebola virus (EBOV) was identified as the causative agent. This study compares the pathogenesis of a new EBOV strain, Makona, which was isolated in Guinea in 2014 with the prototype strain from the 1976 EBOV outbreak in the former Zaire. Both strains cause lethal disease in cynomolgus macaques with similar pathologic changes and hallmark features of Ebola hemorrhagic fever. However, disease progression was delayed in EBOV-Makona-infected animals, suggesting decreased rather than increased virulence of this most recent EBOV strain.

Recent progress in West Nile virus diagnosis and vaccination

PubMed Central

2012-01-01

West Nile virus (WNV) is a positive-stranded RNA virus belonging to the Flaviviridae family, a large family with 3 main genera (flavivirus, hepacivirus and pestivirus). Among these viruses, there are several globally relevant human pathogens including the mosquito-borne dengue virus (DENV), yellow fever virus (YFV), Japanese encephalitis virus (JEV) and West Nile virus (WNV), as well as tick-borne viruses such as tick-borne encephalitis virus (TBEV). Since the mid-1990s, outbreaks of WN fever and encephalitis have occurred throughout the world and WNV is now endemic in Africa, Asia, Australia, the Middle East, Europe and the Unites States. This review describes the molecular virology, epidemiology, pathogenesis, and highlights recent progress regarding diagnosis and vaccination against WNV infections. PMID:22380523

Recent advances in research on Crimean-Congo hemorrhagic fever.

PubMed

Papa, Anna; Mirazimi, Ali; Köksal, Iftihar; Estrada-Pena, Augustin; Feldmann, Heinz

2015-03-01

Crimean-Congo hemorrhagic fever (CCHF) is an expanding tick-borne hemorrhagic disease with increasing human and animal health impact. Immense knowledge was gained over the past 10 years mainly due to advances in molecular biology, but also driven by an increased global interest in CCHFV as an emerging/re-emerging zoonotic pathogen. In the present article, we discuss the advances in research with focus on CCHF ecology, epidemiology, pathogenesis, diagnostics, prophylaxis and treatment. Despite tremendous achievements, future activities have to concentrate on the development of vaccines and antivirals/therapeutics to combat CCHF. Vector studies need to continue for better public and animal health preparedness and response. We conclude with a roadmap for future research priorities. Copyright © 2014 Elsevier B.V. All rights reserved.

African swine fever: A re-emerging viral disease threatening the global pig industry.

PubMed

Sánchez-Cordón, P J; Montoya, M; Reis, A L; Dixon, L K

2018-03-01

African swine fever (ASF) recently has spread beyond sub-Saharan Africa to the Trans-Caucasus region, parts of the Russian Federation and Eastern Europe. In this new epidemiological scenario, the disease has similarities, but also important differences, compared to the situation in Africa, including the substantial involvement of wild boar. A better understanding of this new situation will enable better control and prevent further spread of disease. In this article, these different scenarios are compared, and recent information on the pathogenesis of ASF virus strains, the immune response to infection and prospects for developing vaccines is presented. Knowledge gaps and the prospects for future control are discussed. Copyright © 2018 The Pirbright Institute. Published by Elsevier Ltd.. All rights reserved.

The possible role of CCR5Δ32 mutation in Crimean-Congo hemorrhagic fever infection.

PubMed

Rustemoglu, Aydin; Ekinci, Duygu; Nursal, Ayşe F; Barut, Sener; Duygu, Fazilet; Günal, Özgür

2017-10-01

Crimean-Congo hemorrhagic fever infection (CCHF) is a viral zoonosis. The pathogenesis of this disease has not been established so far, however, cytokines account for its progression and outcome. The aim of the present study is to investigate the association between chemokine receptor 5 (CCR5) gene Δ32 mutation and pathogenity, severity, and mortality of CCHF. This case-control study included 133 CCHF patients diagnosed by detection of CCHV RNA positivity and 97 healthy control subjects. CCR5 gene Δ32 mutation analyzed by polymerase chain reaction (PCR) method. The results were compared by using SPSS 16.0 and WINPEPI software's. The genotype distribution and allele frequency of the CCR5Δ32 were statistically different between the patients and the control group (P = 0.017; OR: 4.98 95% CI = 1.65-14.99 and P = 0.019; OR:4.76 95%CI = 1.30-17.50, respectively). CCR5/CCR5 (W/W) genotype and W allele of CCR5 gene were more common in patient group than in controls. There was no significant difference in severe and mild cases with regard to genotype distribution and allele distribution of CCR5Δ32 mutation (P >0.05). These results suggest that the CCR5 gene and its product might play a role in the pathogenesis of CCHF disease. Future studies will help us to uncover the exact role of CCR5 in the pathogenesis and prognosis of CCHF and to treat the disease. © 2017 Wiley Periodicals, Inc.

Pathogenesis of highly virulent African swine fever virus in domestic pigs exposed via intraoropharyngeal, intranasopharyngeal, and intramuscular inoculation, and by direct contact with infected pigs.

PubMed

Howey, Erin B; O'Donnell, Vivian; de Carvalho Ferreira, Helena C; Borca, Manuel V; Arzt, Jonathan

2013-12-26

To investigate the pathogenesis of African swine fever virus (ASFV), domestic pigs (n=18) were challenged with a range (10(2)-10(6) 50% hemadsorbing doses (HAD50)) of the highly virulent ASFV-Malawi strain by inoculation via the intraoropharyngeal (IOP), intranasopharyngeal (INP), or intramuscular (IM) routes. A subsequent contact challenge experiment was performed in which six IOP-inoculated donor pigs were allowed to have direct contact (DC) with six naïve pigs for exposure times that varied from 24 to 72 h. All challenge routes resulted in clinical progression and postmortem lesions similar to those previously described in experimental and natural infection. The onset of clinical signs occurred between 1 and 7 days post inoculation (dpi) and included pyrexia with variable progression to obtundation, hematochezia, melena, moribundity and death with a duration of 4-11 days. Viremia was first detected between 4 and 5 dpi in all inoculation groups whereas ASFV shedding from the nasal cavity and tonsil was first detected at 3-9 dpi. IM and DC were the most consistent modes of infection, with 12/12 (100%) of pigs challenged by these routes becoming infected. Several clinical and virological parameters were significantly different between IM and DC groups indicating dissimilarity between these modes of infection. Amongst the simulated natural routes, INP inoculation resulted in the most consistent progression of disease across the widest range of doses whilst preserving simulation of natural exposure and therefore may provide a superior system for pathogenesis and vaccine efficacy investigation. Published by Elsevier B.V.

Dejection and/or prevention of human diseases through remote sensing

NASA Technical Reports Server (NTRS)

Edmisten, J. A.

1976-01-01

The use of remote sensors for the detection of probable areas of disease infestation, and possibly as a tool in the control of these diseases, is discussed. Particular attention is given to malaria, encephalitis, and Rocky Mountain Spotted Fever. The vector ecology, epidemiology, and pathogenesis of these diseases are examined. The use of remote sensors to detect the presence of Red Tide is also discussed.

Microvascular Physiologic and Anatomic Responses of the Guinea Pig to Experimental Arenavirus Infection

DTIC Science & Technology

1989-03-25

tumor necrosis factor results in dextran leaks and blot heorrhages. This may be important in the splanchnic pathogenesis of hemorrhagic fever. 20...Characterization of GP13 mesenteric microcirculatory module with measurement of microvascular blood flow, granulocyte adherence, and mesenteric local ...are measurable, and 4) topical tumor necrosis factor results in dextran leaks and blot hemorrhages. This may be important in the splanchnic

Recent advances in rheumatic fever control and future prospects: a WHO Memorandum*

PubMed Central

1978-01-01

The public health importance of rheumatic fever is not directly related to its prevalence but is a complex function of many factors, such as incidence, prevalence, mortality, disability, and cost to the community, all relative to the importance of other diseases. Although the prevalence is low and still decreasing in developed countries, rheumatic fever is the commonest form of heart disease in many developing countries. Advances in the bacterial and serological characterization of group A streptococci are reviewed in this Memorandum, with emphasis on the nature of the structural elements of the cell wall. Microbiological methods play an important role in the diagnosis and control of rheumatic fever and up-to-date information is given concerning methods of isolation and grouping and of typing. Methods of assessing streptococcal activity in the host, in particular the different antibody responses found in relation to different pathological conditions, are discussed, as are the improvements required in laboratory services to enable them to carry out these duties adequately. Current concepts concerning the pathogenesis of rheumatic fever are reviewed together with differences in the epidemiology related to the different sites of infection and the problems of carriership. The Memorandum is also concerned with the methods of prevention and treatment, including prevention of recurrences, control of the disease in communities, and strategies for nationwide control. PMID:310731

Studies on the pathogenesis of fever with influenzal viruses. II. The effects of endogenous pyrogen in normal and virus-tolerant recipients.

PubMed

ATKINS, E; HUANG, W C

1958-03-01

Observations have been made on the fever-inducing properties of an endogenous pyrogen found in the circulation of rabbits after the intravenous inoculation of Newcastle disease virus (NDV). When endogenous pyrogen was given to a normal recipient, a biphasic fever was produced which simulated that seen with bacterial endotoxins. With the use of a technique of serial passive transfer, it has been shown that the "double-humped" response results from two separate actions of the injected pyrogen. The first of these appears to be a direct stimulation of the thermoregulatory centers. The second involves the release of further endogenous pyrogen in the normal recipient to cause, in turn, the second fever peak. Since the injection of endogenous pyrogen did not produce a significant change in the number of circulating leukocytes, it is inferred that this substance is different from either bacterial or tissue polysaccharides. In rabbits rendered tolerant by a previous injection of virus the second fever peak failed to appear and the response to endogenous pyrogen was monophasic. Evidence indicates that the absence of a second fever peak in the tolerant recipient was not due to rise in temperature on the preceding day of virus injection or to the development of either serum inhibitors or tolerance to virus itself. It is postulated that prior mobilization of endogenous pyrogen by virus may have modified the ability of the tolerant recipient to liberate further amounts of this substance in response to an injection of endogenous pyrogen.

Genome sequence and comparative microarray analysis of serotype M18 group A Streptococcus strains associated with acute rheumatic fever outbreaks.

PubMed

Smoot, James C; Barbian, Kent D; Van Gompel, Jamie J; Smoot, Laura M; Chaussee, Michael S; Sylva, Gail L; Sturdevant, Daniel E; Ricklefs, Stacy M; Porcella, Stephen F; Parkins, Larye D; Beres, Stephen B; Campbell, David S; Smith, Todd M; Zhang, Qing; Kapur, Vivek; Daly, Judy A; Veasy, L George; Musser, James M

2002-04-02

Acute rheumatic fever (ARF), a sequelae of group A Streptococcus (GAS) infection, is the most common cause of preventable childhood heart disease worldwide. The molecular basis of ARF and the subsequent rheumatic heart disease are poorly understood. Serotype M18 GAS strains have been associated for decades with ARF outbreaks in the U.S. As a first step toward gaining new insight into ARF pathogenesis, we sequenced the genome of strain MGAS8232, a serotype M18 organism isolated from a patient with ARF. The genome is a circular chromosome of 1,895,017 bp, and it shares 1.7 Mb of closely related genetic material with strain SF370 (a sequenced serotype M1 strain). Strain MGAS8232 has 178 ORFs absent in SF370. Phages, phage-like elements, and insertion sequences are the major sources of variation between the genomes. The genomes of strain MGAS8232 and SF370 encode many of the same proven or putative virulence factors. Importantly, strain MGAS8232 has genes encoding many additional secreted proteins involved in human-GAS interactions, including streptococcal pyrogenic exotoxin A (scarlet fever toxin) and two uncharacterized pyrogenic exotoxin homologues, all phage-associated. DNA microarray analysis of 36 serotype M18 strains from diverse localities showed that most regions of variation were phages or phage-like elements. Two epidemics of ARF occurring 12 years apart in Salt Lake City, UT, were caused by serotype M18 strains that were genetically identical, or nearly so. Our analysis provides a critical foundation for accelerated research into ARF pathogenesis and a molecular framework to study the plasticity of GAS genomes.

Dynamic Modularity of Host Protein Interaction Networks in Salmonella Typhi Infection

PubMed Central

Dhal, Paltu Kumar; Barman, Ranjan Kumar; Saha, Sudipto; Das, Santasabuj

2014-01-01

Background Salmonella Typhi is a human-restricted pathogen, which causes typhoid fever and remains a global health problem in the developing countries. Although previously reported host expression datasets had identified putative biomarkers and therapeutic targets of typhoid fever, the underlying molecular mechanism of pathogenesis remains incompletely understood. Methods We used five gene expression datasets of human peripheral blood from patients suffering from S. Typhi or other bacteremic infections or non-infectious disease like leukemia. The expression datasets were merged into human protein interaction network (PIN) and the expression correlation between the hubs and their interacting proteins was measured by calculating Pearson Correlation Coefficient (PCC) values. The differences in the average PCC for each hub between the disease states and their respective controls were calculated for studied datasets. The individual hubs and their interactors with expression, PCC and average PCC values were treated as dynamic subnetworks. The hubs that showed unique trends of alterations specific to S. Typhi infection were identified. Results We identified S. Typhi infection-specific dynamic subnetworks of the host, which involve 81 hubs and 1343 interactions. The major enriched GO biological process terms in the identified subnetworks were regulation of apoptosis and biological adhesions, while the enriched pathways include cytokine signalling in the immune system and downstream TCR signalling. The dynamic nature of the hubs CCR1, IRS2 and PRKCA with their interactors was studied in detail. The difference in the dynamics of the subnetworks specific to S. Typhi infection suggests a potential molecular model of typhoid fever. Conclusions Hubs and their interactors of the S. Typhi infection-specific dynamic subnetworks carrying distinct PCC values compared with the non-typhoid and other disease conditions reveal new insight into the pathogenesis of S. Typhi. PMID:25144185

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

Antibiotic-Enhanced Phagocytosis of ’Borrelia recurrentis’ by Blood Polymorphonuclear Leukocytes.

DTIC Science & Technology

1979-11-30

hours after Butler 7 institution of antibiotic treatment. Polymorphonuclear leukocytes are known to release endogenous pyrogen after phagocytosis of...other bacteria (6), and endogenous pyrogen may be one of the mediators of the rigor and temperature rise in the Jarisch-Herxheimer reaction (2). Release...the pathogenesis of fever. XII. The effect of phagocytosis on the release of endogenous pyrogen by polymorphonuclear leukocytes. J. Exp. Med. 119:715

Ebola haemorrhagic fever virus: pathogenesis, immune responses, potential prevention.

PubMed

Marcinkiewicz, Janusz; Bryniarski, Krzysztof; Nazimek, Katarzyna

2014-01-01

Ebola zoonotic RNA filovirus represents human most virulent and lethal pathogens, which induces acute hemorrhagic fever and death within few days in a range of 60-90% of symptomatic individuals. Last outbreak in 2014 in West Africa caused panic that Ebola epidemic can be spread to other continents. Number of deaths in late December reached almost 8,000 individuals out of more than 20,000 symptomatic patients. It seems that only a coordinated international response could counteract the further spread of Ebola. Major innate immunity mechanisms against Ebola are associated with the production of interferons, that are inhibited by viral proteins. Activation of host NK cells was recognized as a leading immune function responsible for recovery of infected people. Uncontrolled cell infection by Ebola leads to an impairment of immunity with cytokine storm, coagulopathy, systemic bleeding, multi-organ failure and death. Tested prevention strategies to induce antiviral immunity include: i. recombinant virus formulations (vaccines); ii. cocktail of monoclonal antibodies (serotherapy); iii. alternative RNA-interference-based antiviral methods. Maintaining the highest standards of aseptic and antiseptic precautions is equally important. Present brief review summarizes a current knowledge concerning pathogenesis of Ebola hemorrhagic disease and the virus interaction with the immune system and discusses recent advances in prevention of Ebola infection by vaccination and serotherapy.

Viral hemorrhagic fever in the tropics: Report from the task force on tropical diseases by the World Federation of Societies of Intensive and Critical Care Medicine.

PubMed

Hidalgo, Jorge; Richards, Guy A; Jiménez, Juan Ignacio Silesky; Baker, Tim; Amin, Pravin

2017-12-01

Viral hemorrhagic fevers (VHFs) are a group of illnesses caused by four families of viruses namely Arenaviruses, Filoviruses, Bunyaviruses, and Flaviviruses. Humans are not the natural reservoir for any of these organisms and acquire the disease through vectors from animal reservoirs. In some conditions human to human transmission is possible increasing the risk to healthy individuals in the vicinity, more so to Health Care Workers (HCW). The pathogenesis of VHF, though poorly understood, varies according to the viruses involved. The resultant microvascular damage leads to increased vascular permeability, organ dysfunction and even death. The management is generally supportive but antiviral agents are of benefit in certain circumstances. Copyright © 2017 Elsevier Inc. All rights reserved.

Viral haemorrhagic fever and vascular alterations.

PubMed

Aleksandrowicz, P; Wolf, K; Falzarano, D; Feldmann, H; Seebach, J; Schnittler, H

2008-02-01

Pathogenesis of viral haemorrhagic fever (VHF) is closely associated with alterations of the vascular system. Among the virus families causing VHF, filoviruses (Marburg and Ebola) are the most fatal, and will be focused on here. After entering the body, Ebola primarily targets monocytes/macrophages and dendritic cells. Infected dendritic cells are largely impaired in their activation potency, likely contributing to the immune suppression that occurs during filovirus infection. Monocytes/macrophages, however, immediately activate after viral contact and release reasonable amounts of cytokines that target the vascular system, particularly the endothelial cells. Some underlying molecular mechanisms such as alteration of the vascular endothelial cadherin/catenin complex, tyrosine phosphorylation, expression of cell adhesion molecules, tissue factor and the effect of soluble viral proteins released from infected cells to the blood stream will be discussed.

Progress towards the treatment of Ebola haemorrhagic fever.

PubMed

Ströher, Ute; Feldmann, Heinz

2006-12-01

Being highly pathogenic for human and nonhuman primates and the subject of former weapon programmes makes Ebola virus one of the most feared pathogens worldwide today. Due to a lack of licensed pre- and postexposure intervention, the current response depends on rapid diagnostics, proper isolation procedures and supportive care of case patients. Consequently, the development of more specific countermeasures is of high priority for the preparedness of many nations. Over the past years, enhanced research efforts directed to better understand virus replication and pathogenesis have identified potential new targets for intervention strategies. The authors discuss the most promising therapeutic approaches for Ebola haemorrhagic fever as judged by their efficacy in animal models. The current development in this field encourages discussions on how to move some of the experimental approaches towards clinical application.

STUDIES ON THE PATHOGENESIS OF FEVER

PubMed Central

Petersdorf, Robert G.; Keene, Willis R.; Bennett, Ivan L.

1957-01-01

The "endogenous serum pyrogen" that appears in the circulating blood after a single intravenous injection of endotoxin does not produce leukopenia in normal animals, fails to provoke the local Shwartzman reaction, and elicits no "tolerance" when injected daily. Suppression of the febrile response to endotoxin by prednisone does not prevent the appearance of pyrogen in the blood. Animals given large amounts of endotoxin daily continue to respond with high fevers despite failure of endogenous serum pyrogen to appear in detectable amounts after the first two or three injections. Analysis of the response to daily injections shows clearly that the fever during the first 2 hours after administration of endotoxin is unrelated to levels of endogenous serum pyrogen; in contrast, the magnitude of the fever after the 2nd hour correlates well with endogenous pyrogen in some instances. The leukopenic response to endotoxin could not be correlated with the appearance of endogenous serum pyrogen. The differences between endotoxin and endogenous pyrogen and the similarities between leukocyte extracts (sterile exudates) and endogenous pyrogen are summarized and discussed. Dissociation of the febrile response to bacterial endotoxin and levels of endogenous serum pyrogen are discussed and it is concluded that a mechanism involving both direct and indirect action of endotoxins offers the best explanation for the pyrogenic action of these bacterial products. PMID:13481245

Hemophagocytic lymphohistiocytosis in acute African swine fever clinic.

PubMed

Karalyan, Z R; Ter-Pogossyan, Z R; Karalyan, N Yu; Semerjyan, Z B; Tatoyan, M R; Karapetyan, S A; Karalova, E M

2017-05-01

Hemophagocytic lymphohistiocytosis (HLH) usually has been defined as the combination of a proliferation of cytologically benign, actively phagocytic macrophages in bone marrow, spleen, lymph nodes, etc. in association with fever, cytopenia, splenomegaly, and hypertriglyceridemia. HLH is often triggered by viral infection. The aim of this study was to ascertain the features of HLH involvement in African swine fever virus (ASFV) (genotype II) pathogenesis. The serum levels of macrophage colony-stimulating factor (MCSF) and granulocyte-macrophage colony-stimulating factor (GMCSF), as well as the histological constitution (for hemophagocytic macrophages detection) of various organs of pigs infected with ASFV genotype II were investigated. The diagnosis of HLH was made according to universally accepted human criteria. The association of fever, cytopenias, splenomegaly, and hemophagocytosis was present in 87.5% of the infected pigs (absence of hyperthermia in one of eight pigs). Marked hypertriglyceridemia was observed at 3-4days post infection. Previously it was shown that ASFV induced a significant decrease in the level of fibrinogen from day 5 till the end of experiment. Progression of the HLH coincided with a temporary increase in the serum levels of MCSF levels (early stage of disease) and GMCSF levels (2-3 pays post infection). Hemophagocytic syndrome should be suspected in ASFV (genotypeII) infected pigs. Copyright © 2017 Elsevier B.V. All rights reserved.

Physicochemical inactivation of Lassa, Ebola, and Marburg viruses and effect on clinical laboratory analyses

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

Mitchell, S.W.; McCormick, J.B.

1984-09-01

Clinical specimens from patients infected with Lassa, Ebola, or Marburg virus may present a serious biohazard to laboratory workers. The authors have examined the effects of heat, alteration of pH, and gamma radiation on these viruses in human blood and on the electrolytes, enzymes, and coagulation factors measured in laboratory tests that are important in the care of an infected patient. Heating serum at 60 degrees C for 1 h reduced high titers of these viruses to noninfectious levels without altering the serum levels of glucose, blood urea nitrogen, and electrolytes. Dilution of blood in 3% acetic acid, diluent formore » a leukocyte count, inactivated all of these viruses. All of the methods tested for viral inactivation markedly altered certain serum proteins, making these methods unsuitable for samples that are to be tested for certain enzyme levels and coagulation factors.« less

Typhoid fever as cellular microbiological model.

PubMed

de Andrade, Dahir Ramos; de Andrade Júnior, Dahir Ramos

2003-01-01

The knowledge about typhoid fever pathogenesis is growing in the last years, mainly about the cellular and molecular phenomena that are responsible by clinical manifestations of this disease. In this article are discussed several recent discoveries, as follows: a) Bacterial type III protein secretion system; b) The five virulence genes of Salmonella spp. that encoding Sips (Salmonella invasion protein) A, B, C, D and E, which are capable of induce apoptosis in macrophages; c) The function of Toll R2 and Toll R4 receptors present in the macrophage surface (discovered in the Drosophila). The Toll family receptors are critical in the signalizing mediated by LPS in macrophages in association with LBP and CD14; d) The lines of immune defense between intestinal lumen and internal organs; e) The fundamental role of the endothelial cells in the inflammatory deviation from bloodstream into infected tissues by bacteria. In addition to above subjects, the authors comment the correlation between the clinical features of typhoid fever and the cellular and molecular phenomena of this disease, as well as the therapeutic consequences of this knowledge.

Rapamycin modulation of p70 S6 kinase signaling inhibits Rift Valley fever virus pathogenesis.

PubMed

Bell, Todd M; Espina, Virginia; Senina, Svetlana; Woodson, Caitlin; Brahms, Ashwini; Carey, Brian; Lin, Shih-Chao; Lundberg, Lindsay; Pinkham, Chelsea; Baer, Alan; Mueller, Claudius; Chlipala, Elizabeth A; Sharman, Faye; de la Fuente, Cynthia; Liotta, Lance; Kehn-Hall, Kylene

2017-07-01

Despite over 60 years of research on antiviral drugs, very few are FDA approved to treat acute viral infections. Rift Valley fever virus (RVFV), an arthropod borne virus that causes hemorrhagic fever in severe cases, currently lacks effective treatments. Existing as obligate intracellular parasites, viruses have evolved to manipulate host cell signaling pathways to meet their replication needs. Specifically, translation modulation is often necessary for viruses to establish infection in their host. Here we demonstrated phosphorylation of p70 S6 kinase, S6 ribosomal protein, and eIF4G following RVFV infection in vitro through western blot analysis and in a mouse model of infection through reverse phase protein microarrays (RPPA). Inhibition of p70 S6 kinase through rapamycin treatment reduced viral titers in vitro and increased survival and mitigated clinical disease in RVFV challenged mice. Additionally, the phosphorylation of p70 S6 kinase was decreased following rapamycin treatment in vivo. Collectively these data demonstrate modulating p70 S6 kinase can be an effective antiviral strategy. Copyright © 2017 Elsevier B.V. All rights reserved.

Mobile phone-based interactive voice response as a tool for improving access to healthcare in remote areas in Ghana - an evaluation of user experiences.

PubMed

Brinkel, J; May, J; Krumkamp, R; Lamshöft, M; Kreuels, B; Owusu-Dabo, E; Mohammed, A; Bonacic Marinovic, A; Dako-Gyeke, P; Krämer, A; Fobil, J N

2017-05-01

To investigate and determine the factors that enhanced or constituted barriers to the acceptance of an mHealth system which was piloted in Asante-Akim North District of Ghana to support healthcare of children. Four semi-structured focus group discussions were conducted with a total of 37 mothers. Participants were selected from a study population of mothers who subscribed to a pilot mHealth system which used an interactive voice response (IVR) for its operations. Data were evaluated using qualitative content analysis methods. In addition, a short quantitative questionnaire assessed system's usability (SUS). Results revealed 10 categories of factors that facilitated user acceptance of the IVR system including quality-of-care experience, health education and empowerment of women. The eight categories of factors identified as barriers to user acceptance included the lack of human interaction, lack of update and training on the electronic advices provided and lack of social integration of the system into the community. The usability (SUS median: 79.3; range: 65-97.5) of the system was rated acceptable. The principles of the tested mHealth system could be of interest during infectious disease outbreaks, such as Ebola or Lassa fever, when there might be a special need for disease-specific health information within populations. © 2017 John Wiley & Sons Ltd.

Self-Association of Lymphocytic Choriomeningitis Virus Nucleoprotein Is Mediated by Its N-Terminal Region and Is Not Required for Its Anti-Interferon Function

PubMed Central

Ortiz-Riaño, Emilio; Cheng, Benson Yee Hin

2012-01-01

Arenaviruses have a bisegmented, negative-strand RNA genome. Both the large (L) and small (S) genome segments use an ambisense coding strategy to direct the synthesis of two viral proteins. The L segment encodes the virus polymerase (L protein) and the matrix Z protein, whereas the S segment encodes the nucleoprotein (NP) and the glycoprotein precursor (GPC). NPs are the most abundant viral protein in infected cells and virions and encapsidate genomic RNA species to form an NP-RNA complex that, together with the virus L polymerase, forms the virus ribonucleoprotein (RNP) core capable of directing both replication and transcription of the viral genome. RNP formation predicts a self-association property of NPs. Here we document self-association (homotypic interaction) of the NP of the prototypic arenavirus lymphocytic choriomeningitis virus (LCMV), as well as those of the hemorrhagic fever (HF) arenaviruses Lassa virus (LASV) and Machupo virus (MACV). We also show heterotypic interaction between NPs from both closely (LCMV and LASV) and distantly (LCMV and MACV) genetically related arenaviruses. LCMV NP self-association was dependent on the presence of single-stranded RNA and mediated by an N-terminal region of the NP that did not overlap with the previously described C-terminal NP domain involved in either counteracting the host type I interferon response or interacting with LCMV Z. PMID:22258244

Isozyme and allozyme markers distinguishing two morphologically similar, medically important Mastomys species (Rodentia: Muridae)

PubMed Central

Smit, Andre A; Van der Bank, Herman FH

2001-01-01

Background Two common southern African mice species, Mastomys coucha and M. natalensis, are widely distributed throughout the subregion and overlap in many areas. They also share a high degree of morphological similarity, making them impossible to distinguish in the field at present. These multimammate mice are documented carriers of serious disease vectors causing Lassa fever, plague and encephalomyocarditis, which coupled to their cohabitation with humans in many areas, could pose a significant health risk. A preliminary study reported the presence of isozyme markers at three loci (GPI-2, PT-2, -3) in one population each of M. coucha and M. natalensis. Two additional populations (from the Vaal Dam and Richards Bay) were sampled to determine the reliability of these markers, and to seek additional genetic markers. Results Fifteen proteins or enzymes provided interpretable results at a total of 39 loci. Additional fixed allele differences between the species were detected at AAT-1, ADH, EST-1, PGD-1, Hb-1 and -2. Average heterozygosities for M. coucha and M. natalensis were calculated as 0.018 and 0.032 respectively, with a mean genetic distance between the species of 0.26. Conclusions The confirmation of the isozyme and the detection of the additional allozyme markers are important contributions to the identification of these two medical and agricultural pest species. PMID:11696236

Lack of Evidence of Enterotoxin Involvement in Pathogenesis of Campylobacter Diarrhea

DTIC Science & Technology

1992-01-01

co/i or 1: cholerae genes encod- diarrheal disease (7, 8). but specific virulence ing enterotoxin production (29); (ii) several mechanisms are not...or watery trast to the secretory diarrhea caused by enter- stools and the absence of fever, consistent with otoxigenic E. co/i or V cholerae (21...potential of enteric host response to the toxin. Ifpresent. these find- pathogens, for many organisms, including Vibrio ings would indicate that toxinogenesis

Non-Structural Proteins of Arthropod-Borne Bunyaviruses: Roles and Functions

PubMed Central

Eifan, Saleh; Schnettler, Esther; Dietrich, Isabelle; Kohl, Alain; Blomström, Anne-Lie

2013-01-01

Viruses within the Bunyaviridae family are tri-segmented, negative-stranded RNA viruses. The family includes several emerging and re-emerging viruses of humans, animals and plants, such as Rift Valley fever virus, Crimean-Congo hemorrhagic fever virus, La Crosse virus, Schmallenberg virus and tomato spotted wilt virus. Many bunyaviruses are arthropod-borne, so-called arboviruses. Depending on the genus, bunyaviruses encode, in addition to the RNA-dependent RNA polymerase and the different structural proteins, one or several non-structural proteins. These non-structural proteins are not always essential for virus growth and replication but can play an important role in viral pathogenesis through their interaction with the host innate immune system. In this review, we will summarize current knowledge and understanding of insect-borne bunyavirus non-structural protein function(s) in vertebrate, plant and arthropod. PMID:24100888

Differential proteomic analysis of virus-enriched fractions obtained from plasma pools of patients with dengue fever or severe dengue.

PubMed

Fragnoud, Romain; Flamand, Marie; Reynier, Frederic; Buchy, Philippe; Duong, Vasna; Pachot, Alexandre; Paranhos-Baccala, Glaucia; Bedin, Frederic

2015-11-14

Dengue is the most widespread mosquito-borne viral disease of public health concern. In some patients, endothelial cell and platelet dysfunction lead to life-threatening hemorrhagic dengue fever or dengue shock syndrome. Prognostication of disease severity is urgently required to improve patient management. The pathogenesis of severe dengue has not been fully elucidated, and the role of host proteins associated with viral particles has received little exploration. The proteomes of virion-enriched fractions purified from plasma pools of patients with dengue fever or severe dengue were compared. Virions were purified by ultracentrifugation combined with a water-insoluble polyelectrolyte-based technique. Following in-gel hydrolysis, peptides were analyzed by nano-liquid chromatography coupled to ion trap mass spectrometry and identified using data libraries. Both dengue fever and severe dengue viral-enriched fractions contained identifiable viral envelope proteins and host cellular proteins. Canonical pathway analysis revealed the identified host proteins are mainly involved in the coagulation cascade, complement pathway or acute phase response signaling pathway. Some host proteins were over- or under-represented in plasma from patients with severe dengue compared to patients with dengue fever. ELISAs were used to validate differential expression of a selection of identified host proteins in individual plasma samples of patients with dengue fever compared to patients with severe dengue. Among 22 host proteins tested, two could differentiate between dengue fever and severe dengue in two independent cohorts (olfactomedin-4: area under the curve (AUC), 0.958; and platelet factor-4: AUC, 0.836). A novel technique of virion-enrichment from plasma has allowed to identify two host proteins that have prognostic value for classifying patients with acute dengue who are more likely to develop a severe dengue. The impact of these host proteins on pathogenicity and disease outcome are discussed.

Febrile urticaria in a family: uncommon manifestation of a common disease.

PubMed

Sharma, Vishal; Singhal, Mayank; Sharma, Alka; Kumar, Vivek

2012-12-15

Cutaneous manifestations are uncommon with malaria. These include urticaria, purpura fulminans, and petechial rash. We report on a series of three patients from a single family who had an urticarial rash with fever that was subsequently diagnosed to be caused by malaria. Urticarial rash has been previously reported with both falciparum and vivax malaria infections. Although the exact pathogenesis is not clear urticarial rash might be related with IgE mediated mast cell degranulation.

Immune Protection of Nonhuman Primates Against Ebola Virus with Single Low-Dose Adenovirus Vectors Encoding Modified GPs

DTIC Science & Technology

2006-06-01

21. Geisbert TW, Hensley LE , Larsen T, Young HA, Reed DS, et al. (2003) Pathogenesis of Ebola hemorrhagic fever in cynomolgus macaques: Evidence that...Shedlock DJ, Xu L, et al. (2006) Immune protection of nonhuman primates against Ebola virus with single low-dose adenovirus vectors encoding modified...CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT SAR 18. NUMBER OF PAGES 9 19a. NAME OF RESPONSIBLE PERSON a. REPORT unclassified b. ABSTRACT

Analysis of complete genome sequence of Neorickettsia risticii: causative agent of Potomac horse fever

PubMed Central

Lin, Mingqun; Zhang, Chunbin; Gibson, Kathryn; Rikihisa, Yasuko

2009-01-01

Neorickettsia risticii is an obligate intracellular bacterium of the trematodes and mammals. Horses develop Potomac horse fever (PHF) when they ingest aquatic insects containing encysted N. risticii-infected trematodes. The complete genome sequence of N. risticii Illinois consists of a single circular chromosome of 879 977 bp and encodes 38 RNA species and 898 proteins. Although N. risticii has limited ability to synthesize amino acids and lacks many metabolic pathways, it is capable of making major vitamins, cofactors and nucleotides. Comparison with its closely related human pathogen N. sennetsu showed that 758 (88.2%) of protein-coding genes are conserved between N. risticii and N. sennetsu. Four-way comparison of genes among N. risticii and other Anaplasmataceae showed that most genes are either shared among Anaplasmataceae (525 orthologs that generally associated with housekeeping functions), or specific to each genome (>200 genes that are mostly hypothetical proteins). Genes potentially involved in the pathogenesis of N. risticii were identified, including those encoding putative outer membrane proteins, two-component systems and a type IV secretion system (T4SS). The bipolar localization of T4SS pilus protein VirB2 on the bacterial surface was demonstrated for the first time in obligate intracellular bacteria. These data provide insights toward genomic potential of N. risticii and intracellular parasitism, and facilitate our understanding of PHF pathogenesis. PMID:19661282

Analysis of complete genome sequence of Neorickettsia risticii: causative agent of Potomac horse fever.

PubMed

Lin, Mingqun; Zhang, Chunbin; Gibson, Kathryn; Rikihisa, Yasuko

2009-10-01

Neorickettsia risticii is an obligate intracellular bacterium of the trematodes and mammals. Horses develop Potomac horse fever (PHF) when they ingest aquatic insects containing encysted N. risticii-infected trematodes. The complete genome sequence of N. risticii Illinois consists of a single circular chromosome of 879 977 bp and encodes 38 RNA species and 898 proteins. Although N. risticii has limited ability to synthesize amino acids and lacks many metabolic pathways, it is capable of making major vitamins, cofactors and nucleotides. Comparison with its closely related human pathogen N. sennetsu showed that 758 (88.2%) of protein-coding genes are conserved between N. risticii and N. sennetsu. Four-way comparison of genes among N. risticii and other Anaplasmataceae showed that most genes are either shared among Anaplasmataceae (525 orthologs that generally associated with housekeeping functions), or specific to each genome (>200 genes that are mostly hypothetical proteins). Genes potentially involved in the pathogenesis of N. risticii were identified, including those encoding putative outer membrane proteins, two-component systems and a type IV secretion system (T4SS). The bipolar localization of T4SS pilus protein VirB2 on the bacterial surface was demonstrated for the first time in obligate intracellular bacteria. These data provide insights toward genomic potential of N. risticii and intracellular parasitism, and facilitate our understanding of PHF pathogenesis.

Evaluation of Prognostic Values of Tissue Plasminogen Activator and Plasminogen Activator Inhibitor-1 in Crimean-Congo Hemorrhagic Fever Patients

PubMed Central

Gurbuz, Yunus; Ozturk, Baris; Tutuncu, Emin Ediz; Sencan, Irfan; Cicek Senturk, Gonul; Altay, Fatma Aybala

2015-01-01

Background: Crimean-Congo hemorrhagic fever (CCHF) is a widespread disease in Turkey, and was responsible for many deaths in endemic regions during the last decade. The pathogenesis of the disease is not fully understood yet. Objectives: In this study we aimed to determine the levels of tissue plasminogen activator (tPA) and Plasminogen activator inhibitor-1 (PAI-1) as predictors of prognosis in CCHF. Patients and Methods: Patients who were diagnosed by the polymerase chain reaction (PCR) and IgM positivity in the reference laboratory were included in this study. Tissue Plasminogen activator and PAI-1 levels were measured by the enzyme linked immunosorbent assay (ELISA) using a commercial kit (human t-PA ELISA and human PAL-1 ELISA; BioVendor research and diagnostic products, BioVendor-Laboratorni medicina a.s., Brno, Czech Republic). Results: A total of 46 patients participated in this study. The significant differences between recovering patients and the patients who died, regarding Aspartate aminotransferase (AST), Creatine Phosphokinase (CPK), Lactate Dehydrogenase (LDH), Prothrombin Time (PT), activated Partial Thromboplastin time (aPTT), and thrombocyte and fibrinogen levels, were consistent with many clinical studies in the literature. The fatal cases were found to have higher tPA and PAI-1 levels in contrast to the patients who completely recovered. Conclusions: We think that these findings may help the progress of understanding of CCHF pathogenesis. PMID:26587219

Studies on the pathogenesis of fever. IX. Characteristics of endogenous serum pyrogen and mechanisms governing its release.

PubMed

PETERSDORF, R G; KEENE, W R; BENNETT, I L

1957-12-01

The "endogenous serum pyrogen" that appears in the circulating blood after a single intravenous injection of endotoxin does not produce leukopenia in normal animals, fails to provoke the local Shwartzman reaction, and elicits no "tolerance" when injected daily. Suppression of the febrile response to endotoxin by prednisone does not prevent the appearance of pyrogen in the blood. Animals given large amounts of endotoxin daily continue to respond with high fevers despite failure of endogenous serum pyrogen to appear in detectable amounts after the first two or three injections. Analysis of the response to daily injections shows clearly that the fever during the first 2 hours after administration of endotoxin is unrelated to levels of endogenous serum pyrogen; in contrast, the magnitude of the fever after the 2nd hour correlates well with endogenous pyrogen in some instances. The leukopenic response to endotoxin could not be correlated with the appearance of endogenous serum pyrogen. The differences between endotoxin and endogenous pyrogen and the similarities between leukocyte extracts (sterile exudates) and endogenous pyrogen are summarized and discussed. Dissociation of the febrile response to bacterial endotoxin and levels of endogenous serum pyrogen are discussed and it is concluded that a mechanism involving both direct and indirect action of endotoxins offers the best explanation for the pyrogenic action of these bacterial products.

An immunological perspective on rheumatic heart disease pathogenesis: more questions than answers.

PubMed

Bright, Philip David; Mayosi, Bongani M; Martin, William John

2016-10-01

Acute rheumatic fever (ARF) and the related rheumatic heart disease (RHD) are autoimmune diseases thought to be triggered by group A streptococcal (GAS) pharyngitis. RHD is a leading cause of mortality in the developing world. The strong epidemiological association between GAS throat infection and ARF is highly suggestive of causation, but does not exclude other infections as contributory. There is good evidence of both humoral and cellular autoreactivity and GAS/self cross-reactivity in established RHD. RHD pathogenesis could feasibly be triggered and driven by humoral and/or cellular molecular cross-reactivity between GAS and host cardiac tissues (molecular mimicry). However, good evidence of humoral pathogenicity is lacking and the specific triggering event for RHD remains unknown. It is likely that the critical immunological events leading to ARF/RHD occur at the point of contact between GAS and the immune system in the throat, strongly implicating the mucosal immune system in RHD pathogenesis. Additionally, there is circumstantial evidence that continued live GAS may play a role in ARF/RHD pathogenesis. We suggest that future avenues for study should include the exclusion of GAS components directly contributing to RHD pathogenesis; large genome-wide association studies of patients with RHD looking for candidate genes involved in RHD pathogenesis; genome-wide association studies of GAS from patients with ARF taken at diagnosis to look for characteristics of rheumatogenic strains; and performing case/control studies of GAS pharyngitis/ARF/patients with RHD, and controls to identify microbiological, immunological and environmental differences to elucidate RHD pathogenesis. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

A hamster model for Marburg virus infection accurately recapitulates Marburg hemorrhagic fever

PubMed Central

Marzi, Andrea; Banadyga, Logan; Haddock, Elaine; Thomas, Tina; Shen, Kui; Horne, Eva J.; Scott, Dana P.; Feldmann, Heinz; Ebihara, Hideki

2016-01-01

Marburg virus (MARV), a close relative of Ebola virus, is the causative agent of a severe human disease known as Marburg hemorrhagic fever (MHF). No licensed vaccine or therapeutic exists to treat MHF, and MARV is therefore classified as a Tier 1 select agent and a category A bioterrorism agent. In order to develop countermeasures against this severe disease, animal models that accurately recapitulate human disease are required. Here we describe the development of a novel, uniformly lethal Syrian golden hamster model of MHF using a hamster-adapted MARV variant Angola. Remarkably, this model displayed almost all of the clinical features of MHF seen in humans and non-human primates, including coagulation abnormalities, hemorrhagic manifestations, petechial rash, and a severely dysregulated immune response. This MHF hamster model represents a powerful tool for further dissecting MARV pathogenesis and accelerating the development of effective medical countermeasures against human MHF. PMID:27976688

A hamster model for Marburg virus infection accurately recapitulates Marburg hemorrhagic fever.

PubMed

Marzi, Andrea; Banadyga, Logan; Haddock, Elaine; Thomas, Tina; Shen, Kui; Horne, Eva J; Scott, Dana P; Feldmann, Heinz; Ebihara, Hideki

2016-12-15

Marburg virus (MARV), a close relative of Ebola virus, is the causative agent of a severe human disease known as Marburg hemorrhagic fever (MHF). No licensed vaccine or therapeutic exists to treat MHF, and MARV is therefore classified as a Tier 1 select agent and a category A bioterrorism agent. In order to develop countermeasures against this severe disease, animal models that accurately recapitulate human disease are required. Here we describe the development of a novel, uniformly lethal Syrian golden hamster model of MHF using a hamster-adapted MARV variant Angola. Remarkably, this model displayed almost all of the clinical features of MHF seen in humans and non-human primates, including coagulation abnormalities, hemorrhagic manifestations, petechial rash, and a severely dysregulated immune response. This MHF hamster model represents a powerful tool for further dissecting MARV pathogenesis and accelerating the development of effective medical countermeasures against human MHF.

A hantavirus causing hemorrhagic fever with renal syndrome requires gC1qR/p32 for efficient cell binding and infection

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

Choi, Yun; Kwon, Young-Chan; Kim, Soo-In

Hantaan virus (HTNV) is a pathogenic hantavirus that causes hemorrhagic fever with renal syndrome (HFRS). HTNV infection is mediated by {alpha}v{beta}3 integrin. We used protein blots of Vero E6 cell homogenates to demonstrate that radiolabeled HTNV virions bind to gC1qR/p32, the acidic 32-kDa protein known as the receptor for the globular head domain of complement C1q. RNAi-mediated suppression of gC1qR/p32 markedly reduced HTNV binding and infection in human lung epithelial A549 cells. Conversely, transient expression of either simian or human gC1qR/p32 rendered non-permissive CHO cells susceptible to HTNV infection. These results suggest an important role for gC1qR/p32 in HTNV infectionmore » and pathogenesis.« less

Exploratory Study on Pathogenesis of Far-Eastern Spotted Fever

PubMed Central

Duan, Changsong; Meng, Yanfen; Wang, Xile; Xiong, Xiaolu; Wen, Bohai

2011-01-01

Far-eastern spotted fever is an emerging disease caused by Rickettsia heilongjiangensis, a tick-borne obligate intracellular bacterium. In this study, R. heilongjiangensis was used to infect BALB/c mice by inoculation of retro-orbital venous plexus to imitate a blood infection caused by tick biting. We found that R. heilongjiangensis rapidly entered the circulation for systemic dissemination and the pathogen existed in liver, spleen, lungs, and brain of the mice at least 9 days post-infection (p.i.). Severe pathological lesions were observed in liver, lungs, and brain at Day 6 p.i. In addition, the elevated levels of inflammatory cytokines, including interferon-γ, tumor necrosis factor, and CC chemokine, were detected in the infected organs at Day 3 p.i. Our results reveal that R. heilongjiangensis may cause an infection in BALB/c mice and the pathological lesions in the infected mice are associated with host inflammatory response induced by R. heilongjiangensis. PMID:21896812

A Syrian golden hamster model recapitulating ebola hemorrhagic fever.

PubMed

Ebihara, Hideki; Zivcec, Marko; Gardner, Donald; Falzarano, Darryl; LaCasse, Rachel; Rosenke, Rebecca; Long, Dan; Haddock, Elaine; Fischer, Elizabeth; Kawaoka, Yoshihiro; Feldmann, Heinz

2013-01-15

Ebola hemorrhagic fever (EHF) is a severe viral infection for which no effective treatment or vaccine is currently available. While the nonhuman primate (NHP) model is used for final evaluation of experimental vaccines and therapeutic efficacy, rodent models have been widely used in ebolavirus research because of their convenience. However, the validity of rodent models has been questioned given their low predictive value for efficacy testing of vaccines and therapeutics, a result of the inconsistent manifestation of coagulopathy seen in EHF. Here, we describe a lethal Syrian hamster model of EHF using mouse-adapted Ebola virus. Infected hamsters displayed most clinical hallmarks of EHF, including severe coagulopathy and uncontrolled host immune responses. Thus, the hamster seems to be superior to the existing rodent models, offering a better tool for understanding the critical processes in pathogenesis and providing a new model for evaluating prophylactic and postexposure interventions prior to testing in NHPs.

A Syrian Golden Hamster Model Recapitulating Ebola Hemorrhagic Fever

PubMed Central

Ebihara, Hideki; Zivcec, Marko; Gardner, Donald; Falzarano, Darryl; LaCasse, Rachel; Rosenke, Rebecca; Long, Dan; Haddock, Elaine; Fischer, Elizabeth; Kawaoka, Yoshihiro; Feldmann, Heinz

2013-01-01

Ebola hemorrhagic fever (EHF) is a severe viral infection for which no effective treatment or vaccine is currently available. While the nonhuman primate (NHP) model is used for final evaluation of experimental vaccines and therapeutic efficacy, rodent models have been widely used in ebolavirus research because of their convenience. However, the validity of rodent models has been questioned given their low predictive value for efficacy testing of vaccines and therapeutics, a result of the inconsistent manifestation of coagulopathy seen in EHF. Here, we describe a lethal Syrian hamster model of EHF using mouse-adapted Ebola virus. Infected hamsters displayed most clinical hallmarks of EHF, including severe coagulopathy and uncontrolled host immune responses. Thus, the hamster seems to be superior to the existing rodent models, offering a better tool for understanding the critical processes in pathogenesis and providing a new model for evaluating prophylactic and postexposure interventions prior to testing in NHPs. PMID:23045629

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.

Crimean-Congo hemorrhagic fever virus infection is lethal for adult type I interferon receptor-knockout mice.

PubMed

Bereczky, Sándor; Lindegren, Gunnel; Karlberg, Helen; Akerström, Sara; Klingström, Jonas; Mirazimi, Ali

2010-06-01

Crimean-Congo hemorrhagic fever virus (CCHFV) poses a great threat to public health due to its high mortality, transmission and geographical distribution. To date, there is no vaccine or specific treatment available and the knowledge regarding its pathogenesis is highly limited. Using a small-animal model system, this study showed that adult mice missing the type I interferon (IFN) receptor (IFNAR(-/-)) were susceptible to CCHFV and developed an acute disease with fatal outcome. In contrast, infection of wild-type mice (129 Sv/Ew) was asymptomatic. Viral RNA was found in all analysed organs of the infected mice, but the amount of CCHFV RNA was significantly higher in the IFNAR(-/-) mice than in the wild-type mice. Furthermore, the liver of IFNAR(-/-) mice was enlarged significantly, showing that IFN is important for limiting virus spread and protecting against liver damage in mice.

Diversity, Replication, Pathogenicity and Cell Biology of Crimean Congo Hemorrhagic Fever Virus

DTIC Science & Technology

2010-10-01

in CCHFV pathogenesis or whether it is even O glycosylated. A third unusual feature is * Corresponding author. Mailing address: Department of Microbi ...CA), followed by Western blot analysis with mouse anti-V5 (Invitrogen) as the primary antibody and sheep anti-mouse horseradish peroxidase conjugate as...250) or with mouse anti-V5 MAb (diluted 1:500) (Invitrogen) in PBS containing 0.5 mM MgCl2 and 4% fetal bovine serum. In addition, TGN46, a sheep

Arrhythmias in the History: Lovesickness.

PubMed

Lippi, Donatella

2017-09-01

Lovesickness has been termed a real disorder, with a specific cause, pathogenesis, and cure: it has been attested to in the medical literature since classical times and may still have a place in current medicine in the frame of psychiatry and humoral disorders. Although in different cultures there is a general agreement on the symptoms, including fever, agitation, loss of appetite, headache, rapid breathing, and palpitations, the treatments vary greatly in the various cultural contexts. Copyright © 2017 Elsevier Inc. All rights reserved.

Characterization and Pathogenesis of Aerosolized Eastern Equine Encephalitis in the Common Marmoset (Callithrix jacchus)

DTIC Science & Technology

2016-08-10

9 Affiliations: 10 1United States Army Medical Research Institute of Infectious Diseases (USAMRIID), Virology 11 Division; 2Pathology Division...balance. Fever was evident as 27 early as day 2-3 post exposure in the highest dose groups and hypothermia was observed in 28 several cases as animals...considered to consist of four genetic lineages 55 (Arrigo, 2010). Lineage I was considered to be the North American (NA) variant of EEEV, 56 while lineages

Severe fever with thrombocytopenia syndrome, an emerging tick-borne zoonosis.

PubMed

Liu, Quan; He, Biao; Huang, Si-Yang; Wei, Feng; Zhu, Xing-Quan

2014-08-01

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging haemorrhagic fever that was first described in rural areas of China. The causative agent, SFTS virus (SFTSV), is a novel phlebovirus in the Bunyaviridae family. Since the first report in 2010, SFTS has been found in 11 provinces of China, with about 2500 reported cases, and an average case-fatality rate of 7·3%. The disease was also reported in Japan and Korea in 2012; Heartland virus, another phlebovirus genetically closely related to SFTSV, was isolated from two patients in the USA. The disease has become a substantial risk to public health, not only in China, but also in other parts of the world. The virus could undergo rapid evolution by gene mutation, reassortment, and homologous recombination in tick vectors and vertebrate reservoir hosts. No specific treatment of SFTS is available, and avoiding tick bites is an important measure to prevent the infection and transmission of SFTSV. This Review provides information on the molecular characteristics and ecology of this emerging tick-borne virus and describes the epidemiology, clinical signs, pathogenesis, diagnosis, treatment, and prevention of human infection with SFTSV. Copyright © 2014 Elsevier Ltd. All rights reserved.

[Crimean-Congo hemorrhagic fever: basics for general practitioners].

PubMed

Flusin, O; Iseni, F; Rodrigues, R; Paranhos-Baccalà, G; Crance, J M; Marianneau, P; Bouloy, M; Peyrefitte, C N

2010-12-01

Crimean-Congo hemorrhagic fever (CCHF) is a tick-borne disease described in more than 30 countries in Europe, Asia and Africa. The causative agent is the Crimean-Congo hemorrhagic fever virus (CCHFV) that is a member of the genus Nairovirus of the family Bunyaviridae. CCHFV that is characterized by a high genetic variability is transmitted to humans by tick bites or contact with fluids from an infected individual or animal. The initial symptoms of CCHF are nonspecific and gradually progress to a hemorrhagic phase that can be lethal (case-fatality rate: 10 to 50%). Characteristic laboratory findings of CCHF are thrombocytopenia, elevated liver and muscle enzymes, and coagulation defects. The pathogenesis of CCHF remains unclear but might involve excessive pro-inflammatory cytokine production and dysfunction of the innate immune response. Diagnosis of CCHF is based mainly on isolation of the virus, identification of the viral genome by molecular techniques (RT-PCR), and serological detection of anti-CCHFV antibodies. There is currently no specific treatment for CCHFV infection and the efficacy of ribavirin is controversial. In absence of an effective vaccine, prevention is based mainly on vector control, protection measures, and information to increase the awareness of the population and of healthcare workers.

High content image-based screening of a protease inhibitor library reveals compounds broadly active against Rift Valley fever virus and other highly pathogenic RNA viruses.

PubMed

Mudhasani, Rajini; Kota, Krishna P; Retterer, Cary; Tran, Julie P; Whitehouse, Chris A; Bavari, Sina

2014-08-01

High content image-based screening was developed as an approach to test a protease inhibitor small molecule library for antiviral activity against Rift Valley fever virus (RVFV) and to determine their mechanism of action. RVFV is the causative agent of severe disease of humans and animals throughout Africa and the Arabian Peninsula. Of the 849 compounds screened, 34 compounds exhibited ≥ 50% inhibition against RVFV. All of the hit compounds could be classified into 4 distinct groups based on their unique chemical backbone. Some of the compounds also showed broad antiviral activity against several highly pathogenic RNA viruses including Ebola, Marburg, Venezuela equine encephalitis, and Lassa viruses. Four hit compounds (C795-0925, D011-2120, F694-1532 and G202-0362), which were most active against RVFV and showed broad-spectrum antiviral activity, were selected for further evaluation for their cytotoxicity, dose response profile, and mode of action using classical virological methods and high-content imaging analysis. Time-of-addition assays in RVFV infections suggested that D011-2120 and G202-0362 targeted virus egress, while C795-0925 and F694-1532 inhibited virus replication. We showed that D011-2120 exhibited its antiviral effects by blocking microtubule polymerization, thereby disrupting the Golgi complex and inhibiting viral trafficking to the plasma membrane during virus egress. While G202-0362 also affected virus egress, it appears to do so by a different mechanism, namely by blocking virus budding from the trans Golgi. F694-1532 inhibited viral replication, but also appeared to inhibit overall cellular gene expression. However, G202-0362 and C795-0925 did not alter any of the morphological features that we examined and thus may prove to be good candidates for antiviral drug development. Overall this work demonstrates that high-content image analysis can be used to screen chemical libraries for new antivirals and to determine their mechanism of action and any possible deleterious effects on host cellular biology.

High Content Image-Based Screening of a Protease Inhibitor Library Reveals Compounds Broadly Active against Rift Valley Fever Virus and Other Highly Pathogenic RNA Viruses

PubMed Central

Mudhasani, Rajini; Kota, Krishna P.; Retterer, Cary; Tran, Julie P.; Whitehouse, Chris A.; Bavari, Sina

2014-01-01

High content image-based screening was developed as an approach to test a protease inhibitor small molecule library for antiviral activity against Rift Valley fever virus (RVFV) and to determine their mechanism of action. RVFV is the causative agent of severe disease of humans and animals throughout Africa and the Arabian Peninsula. Of the 849 compounds screened, 34 compounds exhibited ≥50% inhibition against RVFV. All of the hit compounds could be classified into 4 distinct groups based on their unique chemical backbone. Some of the compounds also showed broad antiviral activity against several highly pathogenic RNA viruses including Ebola, Marburg, Venezuela equine encephalitis, and Lassa viruses. Four hit compounds (C795-0925, D011-2120, F694-1532 and G202-0362), which were most active against RVFV and showed broad-spectrum antiviral activity, were selected for further evaluation for their cytotoxicity, dose response profile, and mode of action using classical virological methods and high-content imaging analysis. Time-of-addition assays in RVFV infections suggested that D011-2120 and G202-0362 targeted virus egress, while C795-0925 and F694-1532 inhibited virus replication. We showed that D011-2120 exhibited its antiviral effects by blocking microtubule polymerization, thereby disrupting the Golgi complex and inhibiting viral trafficking to the plasma membrane during virus egress. While G202-0362 also affected virus egress, it appears to do so by a different mechanism, namely by blocking virus budding from the trans Golgi. F694-1532 inhibited viral replication, but also appeared to inhibit overall cellular gene expression. However, G202-0362 and C795-0925 did not alter any of the morphological features that we examined and thus may prove to be good candidates for antiviral drug development. Overall this work demonstrates that high-content image analysis can be used to screen chemical libraries for new antivirals and to determine their mechanism of action and any possible deleterious effects on host cellular biology. PMID:25144302

A case of Crimean-Congo hemorrhagic fever complicated with acute pancreatitis.

PubMed

Bastug, Aliye; Kayaaslan, Bircan; But, Ayse; Aslaner, Halide; Sertcelik, Ahmet; Akinci, Esragul; Onguru, Pinar; Yetkin, Meltem Arzu; Bodur, Hurrem

2014-11-01

Crimean-Congo hemorrhagic fever (CCHF) is a tick-borne disease characterized by nonspecific symptoms like fever, myalgia, severe headache, nausea, vomiting, diarrhea, and abdominal pain. It can result in various complications during the course of the disease due to the diffuse endothelial injury involved in the pathogenesis of CCHF. Here we present a patient with CCHF complicated by acute pancreatitis, including pleural and intra-abdominal effusions. A 70-year-old patient was referred to our hospital from an endemic area with the suspicion of CCHF. The physical examination of the patient revealed high fever (38°C), somnolence, and petechial eruption. The diagnosis of case was confirmed with positive reverse transcriptase polymerase chain reaction (RT-PCR). The viral load of the patient was 4×10(9) copies/mL. On the fifth day of admission, upper abdominal pain, scleral ichter, and abdominal distention developed. The patient had abdominal tenderness with guarding. The laboratory tests revealed an amylase level of 1740 U/L (28-100), lipase level of 583 U/L (13-60), and total bilirubin level of 3.75 mg/dL (<0.3). The diagnosis of acute pancreatitis was confirmed with radiological findings. Until now, atypical presentations of CCHF have been reported in some case reports, but not acute pancreatitis. To the best of our knowledge, this is the first case of acute pancreatitis in the literature seen in the course of CCHF.

Clinical and hematologic variables in ponies with experimentally induced equine ehrlichial colitis (Potomac horse fever).

PubMed

Ziemer, E L; Whitlock, R H; Palmer, J E; Spencer, P A

1987-01-01

The clinical and hematologic variables of 10 ponies with experimentally induced equine ehrlichial colitis (EEC; syn: Potomac horse fever) were studied for a 30-day period (6 ponies) or until death (4 ponies). The earliest clinical sign indicative of EEC was fever (rectal temperature exceeding 39 C). All ponies became depressed (CNS) at various times during the disease, and 90% of the ponies developed diarrhea between 9 and 15 days after infection was induced. The most significant hematologic change was an increase in plasma protein concentration after the onset of fever (P less than 0.05). The PCV in all ponies became increased above base line during the diarrheic phase of EEC. Forty percent of the ponies developed anemia (PCV less than or equal to 23%) during the study. White blood cell counts were highly variable, with 80% of the ponies developing leukopenia (WBC less than 5,000/microliters) during the illness and 60% of the ponies developing leukocytosis (WBC greater than 14,000/microliters) after leukopenia was observed. Differential WBC changes varied widely and included neutropenia with a left shift, lymphopenia, and eosinopenia. Serial thrombocyte counts, which were done for only 1 pony, identified the development of marked thrombocytopenia. Some hematologic changes in ponies with EEC were similar to those reported in canine monocytic and equine granulocytic ehrlichioses. These data are discussed in the context of the pathogenesis and differential diagnosis of EEC.

Molecular determinants of Ebola virus virulence in mice.

PubMed

Ebihara, Hideki; Takada, Ayato; Kobasa, Darwyn; Jones, Steven; Neumann, Gabriele; Theriault, Steven; Bray, Mike; Feldmann, Heinz; Kawaoka, Yoshihiro

2006-07-01

Zaire ebolavirus (ZEBOV) causes severe hemorrhagic fever in humans and nonhuman primates, with fatality rates in humans of up to 90%. The molecular basis for the extreme virulence of ZEBOV remains elusive. While adult mice resist ZEBOV infection, the Mayinga strain of the virus has been adapted to cause lethal infection in these animals. To understand the pathogenesis underlying the extreme virulence of Ebola virus (EBOV), here we identified the mutations responsible for the acquisition of the high virulence of the adapted Mayinga strain in mice, by using reverse genetics. We found that mutations in viral protein 24 and in the nucleoprotein were primarily responsible for the acquisition of high virulence. Moreover, the role of these proteins in virulence correlated with their ability to evade type I interferon-stimulated antiviral responses. These findings suggest a critical role for overcoming the interferon-induced antiviral state in the pathogenicity of EBOV and offer new insights into the pathogenesis of EBOV infection.

Yellow fever: the recurring plague.

PubMed

Tomori, Oyewale

2004-01-01

Despite the availability of a safe and efficacious vaccine, yellow fever (YF) remains a disease of significant public health importance, with an estimated 200,000 cases and 30,000 deaths annually. The disease is endemic in tropical regions of Africa and South America; nearly 90% of YF cases and deaths occur in Africa. It is a significant hazard to unvaccinated travelers to these endemic areas. Virus transmission occurs between humans, mosquitoes, and monkeys. The mosquito, the true reservoir of YF, is infected throughout its life, and can transmit the virus transovarially through infected eggs. Man and monkeys, on the other hand, play the role of temporary amplifiers of the virus available for mosquito infection. Recent increases in the density and distribution of the urban mosquito vector, Aedes aegypti, as well as the rise in air travel increase the risk of introduction and spread of yellow fever to North and Central America, the Caribbean, the Middle East, Asia, Australia, and Oceania. It is an acute infectious disease characterized by sudden onset with a two-phase development, separated by a short period of remission. The clinical spectrum of yellow fever varies from very mild, nonspecific, febrile illness to a fulminating, sometimes fatal disease with pathognomic features. In severe cases, jaundice, bleeding diathesis, with hepatorenal involvement are common. The case fatality rate of severe yellow fever is 50% or higher. The pathogenesis and pathophysiology of the disease are poorly understood and have not been the subject of modern clinical research. There is no specific treatment for YF, making the management of YF patients extremely problematic. YF is a zoonotic disease that cannot be eradicated, therefore instituting preventive vaccination through routine childhood vaccination in endemic countries, can significantly reduce the burden of the disease. The distinctive properties of lifelong immunity after a single dose of yellow fever vaccination are the basis of the new applications of yellow fever 17D virus as a vector for foreign genes, "the chimeric vaccine,' and the promise of developing new vaccines against other viruses, and possibly against cancers.

The multiple roles of sGP in Ebola pathogenesis.

PubMed

de La Vega, Marc-Antoine; Wong, Gary; Kobinger, Gary P; Qiu, Xiangguo

2015-02-01

Ebola causes severe hemorrhagic fever in humans and nonhuman primates, and there are currently no approved therapeutic countermeasures. The virulence of Ebola virus (EBOV) may be partially attributed to the secreted glycoprotein (sGP), which is the main product transcribed from its GP gene. sGP is secreted from infected cells and can be readily detected in the serum of EBOV-infected hosts. This review summarizes the multiple roles that sGP may play during infection and highlights the implications for the future design of vaccines and treatments.

The Multiple Roles of sGP in Ebola Pathogenesis

PubMed Central

de La Vega, Marc-Antoine; Wong, Gary; Kobinger, Gary P.

2015-01-01

Abstract Ebola causes severe hemorrhagic fever in humans and nonhuman primates, and there are currently no approved therapeutic countermeasures. The virulence of Ebola virus (EBOV) may be partially attributed to the secreted glycoprotein (sGP), which is the main product transcribed from its GP gene. sGP is secreted from infected cells and can be readily detected in the serum of EBOV-infected hosts. This review summarizes the multiple roles that sGP may play during infection and highlights the implications for the future design of vaccines and treatments. PMID:25354393

Human Leukocyte Antigen-DQ8 Transgenic Mice: A Model to Examine the Toxicity of Aerosolized Staphylococcal Enterotoxin B

DTIC Science & Technology

2004-11-30

Que, and A. S. Bayer. 2002. Pathogenesis of streptococcal and staphylococcal endocarditis . Infect . Dis. Clin. N. Am. 16:297–318. 26. Nabozny, G. H., J... INFECTION AND IMMUNITY, Apr. 2005, p. 2452–2460 Vol. 73, No. 4 0019-9567/05/$08.000 doi:10.1128/IAI.73.4.2452–2460.2005 Copyright © 2005, American... infections , including scarlet fever, pharyngitis, dermatitis, infectious ar- thritis, and toxic shock syndrome (2, 13, 18, 25, 31). These pathogenic bacteria

Rickettsia australis and Queensland Tick Typhus: A Rickettsial Spotted Fever Group Infection in Australia.

PubMed

Stewart, Adam; Armstrong, Mark; Graves, Stephen; Hajkowicz, Krispin

2017-07-01

Rickettsia australis , the etiologic agent of Queensland tick typhus (QTT), is increasingly being recognized as a cause of community-acquired acute febrile illness in eastern Australia. Changing human population demographics, climate change, and increased understanding of expanding vector distribution indicate QTT is an emerging public health threat. This review summarizes the epidemiology, pathogenesis, clinical features, treatment principles, and future directions of this disease. Increased recognition of QTT will enable consideration of and prompt treatment of R. australis infection by clinicians in Australia.

Animal models for filovirus infections.

PubMed

Siragam, Vinayakumar; Wong, Gary; Qiu, Xiang-Guo

2018-01-18

The family Filoviridae , which includes the genera Marburgvirus and Ebolavirus , contains some of the most pathogenic viruses in humans and non-human primates (NHPs), causing severe hemorrhagic fevers with high fatality rates. Small animal models against filoviruses using mice, guinea pigs, hamsters, and ferrets have been developed with the goal of screening candidate vaccines and antivirals, before testing in the gold standard NHP models. In this review, we summarize the different animal models used to understand filovirus pathogenesis, and discuss the advantages and disadvantages of each model with respect to filovirus disease research.

Animal models for filovirus infections

PubMed Central

Siragam, Vinayakumar; Wong, Gary; Qiu, Xiang-Guo

2018-01-01

The family Filoviridae, which includes the genera Marburgvirus and Ebolavirus, contains some of the most pathogenic viruses in humans and non-human primates (NHPs), causing severe hemorrhagic fevers with high fatality rates. Small animal models against filoviruses using mice, guinea pigs, hamsters, and ferrets have been developed with the goal of screening candidate vaccines and antivirals, before testing in the gold standard NHP models. In this review, we summarize the different animal models used to understand filovirus pathogenesis, and discuss the advantages and disadvantages of each model with respect to filovirus disease research. PMID:29511141

Measles Virus Host Invasion and Pathogenesis.

PubMed

Laksono, Brigitta M; de Vries, Rory D; McQuaid, Stephen; Duprex, W Paul; de Swart, Rik L

2016-07-28

Measles virus is a highly contagious negative strand RNA virus that is transmitted via the respiratory route and causes systemic disease in previously unexposed humans and non-human primates. Measles is characterised by fever and skin rash and usually associated with cough, coryza and conjunctivitis. A hallmark of measles is the transient immune suppression, leading to increased susceptibility to opportunistic infections. At the same time, the disease is paradoxically associated with induction of a robust virus-specific immune response, resulting in lifelong immunity to measles. Identification of CD150 and nectin-4 as cellular receptors for measles virus has led to new perspectives on tropism and pathogenesis. In vivo studies in non-human primates have shown that the virus initially infects CD150⁺ lymphocytes and dendritic cells, both in circulation and in lymphoid tissues, followed by virus transmission to nectin-4 expressing epithelial cells. The abilities of the virus to cause systemic infection, to transmit to numerous new hosts via droplets or aerosols and to suppress the host immune response for several months or even years after infection make measles a remarkable disease. This review briefly highlights current topics in studies of measles virus host invasion and pathogenesis.

Inflammatory Biomarkers Associated with Lethal Rift Valley Fever Encephalitis in the Lewis Rat Model

PubMed Central

Caroline, Amy L.; Kujawa, Michael R.; Oury, Tim D.; Reed, Douglas S.; Hartman, Amy L.

2016-01-01

Rift Valley fever (RVF) is an emerging viral disease that causes significant human and veterinary illness in Africa and the Arabian Peninsula. Encephalitis is one of the severe complications arising from RVF virus (RVFV) infection of people, and the pathogenesis of this form of RVF is completely unknown. We use a novel reproducible encephalitic disease model in rats to identify biomarkers of lethal infection. Lewis rats were infected with RVFV strain ZH501 by aerosol exposure, then sacrificed daily to determine the course of infection and evaluation of clinical, virological, and immunological parameters. Weight loss, fever, and clinical signs occurred during the last 1–2 days prior to death. Prior to onset of clinical indications of disease, rats displayed marked granulocytosis and thrombocytopenia. In addition, high levels of inflammatory chemokines (MCP-1, MCS-F, Gro/KC, RANTES, and IL-1β) were detected first in serum (3–5 dpi) followed by brain (5–7 dpi). The results of this study are consistent with clinical data from human RVF patients and validate Lewis rats as an appropriate small animal model for RVF encephalitis. The biomarkers we identified here will be useful in future studies evaluating the efficacy of novel vaccines and therapeutics. PMID:26779164

Apoptosis-Related Gene Expression in an Adult Cohort with Crimean-Congo Hemorrhagic Fever.

PubMed

Guler, Nil; Eroglu, Cafer; Yilmaz, Hava; Karadag, Adil; Alacam, Hasan; Sunbul, Mustafa; Fletcher, Tom E; Leblebicioglu, Hakan

2016-01-01

Crimean-Congo Hemorrhagic Fever (CCHF) is a life threatening acute viral infection characterized by fever, bleeding, leukopenia and thrombocytopenia. It is a major emerging infectious diseases threat, but its pathogenesis remains poorly understood and few data exist for the role of apoptosis in acute infection. We aimed to assess apoptotic gene expression in leukocytes in a cross-sectional cohort study of adults with CCHF. Twenty participants with CCHF and 10 healthy controls were recruited at a tertiary CCHF unit in Turkey; at admission baseline blood tests were collected and total RNA was isolated. The RealTime ready Human Apoptosis Panel was used for real-time PCR, detecting differences in gene expression. Participants had CCHF severity grading scores (SGS) with low risk score (10 out of 20) and intermediate or high risk scores (10 out of 20) for mortality. Five of 20 participants had a fatal outcome. Gene expression analysis showed modulation of pro-apoptotic and anti-apoptotic genes that facilitate apoptosis in the CCHF patient group. Dominant extrinsic pathway activation, mostly related with TNF family members was observed. Severe and fatal cases suggest additional intrinsic pathway activation. The clinical significance of relative gene expression is not clear, and larger longitudinal studies with simultaneous measurement of host and viral factors are recommended.

Pathogenesis of Group A Streptococcal Infections

PubMed Central

Cunningham, Madeleine W.

2000-01-01

Group A streptococci are model extracellular gram-positive pathogens responsible for pharyngitis, impetigo, rheumatic fever, and acute glomerulonephritis. A resurgence of invasive streptococcal diseases and rheumatic fever has appeared in outbreaks over the past 10 years, with a predominant M1 serotype as well as others identified with the outbreaks. emm (M protein) gene sequencing has changed serotyping, and new virulence genes and new virulence regulatory networks have been defined. The emm gene superfamily has expanded to include antiphagocytic molecules and immunoglobulin-binding proteins with common structural features. At least nine superantigens have been characterized, all of which may contribute to toxic streptococcal syndrome. An emerging theme is the dichotomy between skin and throat strains in their epidemiology and genetic makeup. Eleven adhesins have been reported, and surface plasmin-binding proteins have been defined. The strong resistance of the group A streptococcus to phagocytosis is related to factor H and fibrinogen binding by M protein and to disarming complement component C5a by the C5a peptidase. Molecular mimicry appears to play a role in autoimmune mechanisms involved in rheumatic fever, while nephritis strain-associated proteins may lead to immune-mediated acute glomerulonephritis. Vaccine strategies have focused on recombinant M protein and C5a peptidase vaccines, and mucosal vaccine delivery systems are under investigation. PMID:10885988

Arenavirus Diversity and Phylogeography of Mastomys natalensis Rodents, Nigeria

PubMed Central

Obadare, Adeoba; Oyeyiola, Akinlabi; Igbokwe, Joseph; Fasogbon, Ayobami; Igbahenah, Felix; Ortsega, Daniel; Asogun, Danny; Umeh, Prince; Vakkai, Innocent; Abejegah, Chukwuyem; Pahlman, Meike; Becker-Ziaja, Beate; Günther, Stephan; Fichet-Calvet, Elisabeth

2016-01-01

Mastomys natalensis rodents are natural hosts for Lassa virus (LASV). Detection of LASV in 2 mitochondrial phylogroups of the rodent near the Niger and Benue Rivers in Nigeria underlines the potential for LASV emergence in fresh phylogroups of this rodent. A Mobala-like sequence was also detected in eastern Nigeria. PMID:26982388

Macrophage inflammatory protein-1alpha: a link between innate immunity and familial Mediterranean fever?

PubMed

Dizdar, Omer; Kalyoncu, Umut; Karadag, Omer; Akdogan, Ali; Kiraz, Sedat; Ertenli, Ihsan; Barista, Ibrahim; Calguneri, Meral

2007-01-01

The aim of this study is to investigate the relationship between chemokines and the inflammation in Familial Mediterranean Fever (FMF). Forty-nine patients with FMF (41 in remission and 8 in acute attack period) and 20 healthy controls were included in the study. Serum levels of macrophage inflammatory protein-1alpha (MIP-1alpha) were assessed in the patients and the controls, along with other parameters of disease activity, i.e., fibrinogen, C-reactive protein and erythrocyte sedimentation rate. Serum MIP-1alpha levels of the patients with FMF in acute attack period were significantly higher than the patients in remission and healthy controls (p=0.02 and p=0.038, respectively). MIP-1alpha levels were weakly correlated with CRP (r=0.32, p=0.032) levels. MIP-1alpha may have a role in the pathogenesis of FMF attacks. MIP-1alpha and other chemokines may constitute a link between the innate immune system and FMF.

Development of a sheep challenge model for Rift Valley fever.

PubMed

Faburay, Bonto; Gaudreault, Natasha N; Liu, Qinfang; Davis, A Sally; Shivanna, Vinay; Sunwoo, Sun Young; Lang, Yuekun; Morozov, Igor; Ruder, Mark; Drolet, Barbara; Scott McVey, D; Ma, Wenjun; Wilson, William; Richt, Juergen A

2016-02-01

Rift Valley fever (RVF) is a zoonotic disease that causes severe epizootics in ruminants, characterized by mass abortion and high mortality rates in younger animals. The development of a reliable challenge model is an important prerequisite for evaluation of existing and novel vaccines. A study aimed at comparing the pathogenesis of RVF virus infection in US sheep using two genetically different wild type strains of the virus (SA01-1322 and Kenya-128B-15) was performed. A group of sheep was inoculated with both strains and all infected sheep manifested early-onset viremia accompanied by a transient increase in temperatures. The Kenya-128B-15 strain manifested higher virulence compared to SA01-1322 by inducing more severe liver damage, and longer and higher viremia. Genome sequence analysis revealed sequence variations between the two isolates, which potentially could account for the observed phenotypic differences. We conclude that Kenya-128B-15 sheep infection represents a good and virulent challenge model for RVF. Copyright © 2015 Elsevier Inc. All rights reserved.

Serum C-reactive protein in food protein-induced enterocolitis syndrome versus food protein-induced proctocolitis in Japan.

PubMed

Kimura, Mitsuaki; Shimomura, Masaki; Morishita, Hideaki; Meguro, Takaaki; Seto, Shiro

2016-09-01

Some infants with food protein-induced enterocolitis syndrome (FPIES) have increased serum C-reactive protein (CRP) and fever in Japan. The aim of this study was therefore to clarify and compare the incidence of this in patients with FPIES versus patients with food protein-induced proctocolitis (FPIP). One hundred and sixteen infants with non-IgE-mediated gastrointestinal food allergies were enrolled in this study and classified into three phenotypes: FPIES presenting with vomiting and/or diarrhea (n = 47); FPIP with bloody stool alone (n =19); and the mixed phenotype (MP), bloody stool with vomiting and/or diarrhea (n = 50). Serum CRP was increased in 55.3% of the FPIES group, similar to that in the MP group (54.0%), and significantly higher than in the FPIP group (15.8%; P < 0.01). Fever was observed in 29.8% of the FPIES group, significantly higher than in the MP group (8.0%; P < 0.01) and in the FPIP group (0%; P < 0.05). Patients with fever had significantly higher serum CRP than patients without fever (median, 12.8 vs <0.2 mg/dL, P < 0.00001). Serum CRP was significantly higher in the FPIES group than in the FPIP group. This suggests that serum CRP is a useful marker for differentiating the pathogenesis of FPIES from FPIP. From the perspective of serum CRP, the pathology of the intestinal inflammation in MP subjects is suggested to be similar to that of FPIES. © 2016 The Authors. Pediatrics International published by John Wiley & Sons Australia, Ltd on behalf of Japan Pediatric Society.

Identification of new protein interactions between dengue fever virus and its hosts, human and mosquito.

PubMed

Mairiang, Dumrong; Zhang, Huamei; Sodja, Ann; Murali, Thilakam; Suriyaphol, Prapat; Malasit, Prida; Limjindaporn, Thawornchai; Finley, Russell L

2013-01-01

The four divergent serotypes of dengue virus are the causative agents of dengue fever, dengue hemorrhagic fever and dengue shock syndrome. About two-fifths of the world's population live in areas where dengue is prevalent, and thousands of deaths are caused by the viruses every year. Dengue virus is transmitted from one person to another primarily by the yellow fever mosquito, Aedes aegypti. Recent studies have begun to define how the dengue viral proteins interact with host proteins to mediate viral replication and pathogenesis. A combined analysis of these studies, however, suggests that many virus-host protein interactions remain to be identified, especially for the mosquito host. In this study, we used high-throughput yeast two-hybrid screening to identify mosquito and human proteins that physically interact with dengue proteins. We tested each identified host protein against the proteins from all four serotypes of dengue to identify interactions that are conserved across serotypes. We further confirmed many of the interactions using co-affinity purification assays. As in other large-scale screens, we identified some previously detected interactions and many new ones, moving us closer to a complete host - dengue protein interactome. To help summarize and prioritize the data for further study, we combined our interactions with other published data and identified a subset of the host-dengue interactions that are now supported by multiple forms of evidence. These data should be useful for understanding the interplay between dengue and its hosts and may provide candidates for drug targets and vector control strategies.

Identification of New Protein Interactions between Dengue Fever Virus and Its Hosts, Human and Mosquito

PubMed Central

Mairiang, Dumrong; Zhang, Huamei; Sodja, Ann; Murali, Thilakam; Suriyaphol, Prapat; Malasit, Prida; Limjindaporn, Thawornchai; Finley, Russell L.

2013-01-01

The four divergent serotypes of dengue virus are the causative agents of dengue fever, dengue hemorrhagic fever and dengue shock syndrome. About two-fifths of the world's population live in areas where dengue is prevalent, and thousands of deaths are caused by the viruses every year. Dengue virus is transmitted from one person to another primarily by the yellow fever mosquito, Aedes aegypti. Recent studies have begun to define how the dengue viral proteins interact with host proteins to mediate viral replication and pathogenesis. A combined analysis of these studies, however, suggests that many virus-host protein interactions remain to be identified, especially for the mosquito host. In this study, we used high-throughput yeast two-hybrid screening to identify mosquito and human proteins that physically interact with dengue proteins. We tested each identified host protein against the proteins from all four serotypes of dengue to identify interactions that are conserved across serotypes. We further confirmed many of the interactions using co-affinity purification assays. As in other large-scale screens, we identified some previously detected interactions and many new ones, moving us closer to a complete host – dengue protein interactome. To help summarize and prioritize the data for further study, we combined our interactions with other published data and identified a subset of the host-dengue interactions that are now supported by multiple forms of evidence. These data should be useful for understanding the interplay between dengue and its hosts and may provide candidates for drug targets and vector control strategies. PMID:23326450

Bacterial-based Systems for Expression and Purification of Recombinant Lassa Virus Proteins of Immunological Relevance

DTIC Science & Technology

2008-06-06

sites. Abbreviations include: MBP gene (malE), MBP promoter (Ptac), philamentous phage origin of replication ( M13 ori), bacterial origin of replica...notwithstanding any other provision of law, no person shall be subject to a penalty for failing to comply with a collection of information if it does not display

Characterization and pathogenesis of aerosolized eastern equine encephalitis in the common marmoset (Callithrix jacchus).

PubMed

Porter, Aimee I; Erwin-Cohen, Rebecca A; Twenhafel, Nancy; Chance, Taylor; Yee, Steven B; Kern, Steven J; Norwood, David; Hartman, Laurie J; Parker, Michael D; Glass, Pamela J; DaSilva, Luis

2017-02-07

Licensed antiviral therapeutics and vaccines to protect against eastern equine encephalitis virus (EEEV) in humans currently do not exist. Animal models that faithfully recapitulate the clinical characteristics of human EEEV encephalitic disease, including fever, drowsiness, anorexia, and neurological signs such as seizures, are needed to satisfy requirements of the Food and Drug Administration (FDA) for clinical product licensing under the Animal Rule. In an effort to meet this requirement, we estimated the median lethal dose and described the pathogenesis of aerosolized EEEV in the common marmoset (Callithrix jacchus). Five marmosets were exposed to aerosolized EEEV FL93-939 in doses ranging from 2.4 × 10 1 PFU to 7.95 × 10 5 PFU. The median lethal dose was estimated to be 2.05 × 10 2 PFU. Lethality was observed as early as day 4 post-exposure in the highest-dosed marmoset but animals at lower inhaled doses had a protracted disease course where humane study endpoint was not met until as late as day 19 post-exposure. Clinical signs were observed as early as 3 to 4 days post-exposure, including fever, ruffled fur, decreased grooming, and leukocytosis. Clinical signs increased in severity as disease progressed to include decreased body weight, subdued behavior, tremors, and lack of balance. Fever was observed as early as day 2-3 post-exposure in the highest dose groups and hypothermia was observed in several cases as animals became moribund. Infectious virus was found in several key tissues, including brain, liver, kidney, and several lymph nodes. Clinical hematology results included early neutrophilia, lymphopenia, and thrombocytopenia. Key pathological changes included meningoencephalitis and retinitis. Immunohistochemical staining for viral antigen was positive in the brain, retina, and lymph nodes. More intense and widespread IHC labeling occurred with increased aerosol dose. We have estimated the medial lethal dose of aerosolized EEEV and described the pathology of clinical disease in the marmoset model. The results demonstrate that the marmoset is an animal model suitable for emulation of human EEEV disease in the development of medical countermeasures.

A Systematic Screen of FDA-Approved Drugs for Inhibitors of Biological Threat Agents

PubMed Central

Madrid, Peter B.; Chopra, Sidharth; Manger, Ian D.; Gilfillan, Lynne; Keepers, Tiffany R.; Shurtleff, Amy C.; Green, Carol E.; Iyer, Lalitha V.; Dilks, Holli Hutcheson; Davey, Robert A.; Kolokoltsov, Andrey A.; Carrion, Ricardo; Patterson, Jean L.; Bavari, Sina; Panchal, Rekha G.; Warren, Travis K.; Wells, Jay B.; Moos, Walter H.; Burke, RaeLyn L.; Tanga, Mary J.

2013-01-01

Background The rapid development of effective medical countermeasures against potential biological threat agents is vital. Repurposing existing drugs that may have unanticipated activities as potential countermeasures is one way to meet this important goal, since currently approved drugs already have well-established safety and pharmacokinetic profiles in patients, as well as manufacturing and distribution networks. Therefore, approved drugs could rapidly be made available for a new indication in an emergency. Methodology/Principal Findings A large systematic effort to determine whether existing drugs can be used against high containment bacterial and viral pathogens is described. We assembled and screened 1012 FDA-approved drugs for off-label broad-spectrum efficacy against Bacillus anthracis; Francisella tularensis; Coxiella burnetii; and Ebola, Marburg, and Lassa fever viruses using in vitro cell culture assays. We found a variety of hits against two or more of these biological threat pathogens, which were validated in secondary assays. As expected, antibiotic compounds were highly active against bacterial agents, but we did not identify any non-antibiotic compounds with broad-spectrum antibacterial activity. Lomefloxacin and erythromycin were found to be the most potent compounds in vivo protecting mice against Bacillus anthracis challenge. While multiple virus-specific inhibitors were identified, the most noteworthy antiviral compound identified was chloroquine, which disrupted entry and replication of two or more viruses in vitro and protected mice against Ebola virus challenge in vivo. Conclusions/Significance The feasibility of repurposing existing drugs to face novel threats is demonstrated and this represents the first effort to apply this approach to high containment bacteria and viruses. PMID:23577127

The clinically approved drugs amiodarone, dronedarone and verapamil inhibit filovirus cell entry.

PubMed

Gehring, Gerrit; Rohrmann, Katrin; Atenchong, Nkacheh; Mittler, Eva; Becker, Stephan; Dahlmann, Franziska; Pöhlmann, Stefan; Vondran, Florian W R; David, Sascha; Manns, Michael P; Ciesek, Sandra; von Hahn, Thomas

2014-08-01

Filoviruses such as Ebola virus and Marburg virus cause a severe haemorrhagic fever syndrome in humans for which there is no specific treatment. Since filoviruses use a complex route of cell entry that depends on numerous cellular factors, we hypothesized that there may be drugs already approved for human use for other indications that interfere with signal transduction or other cellular processes required for their entry and hence have anti-filoviral properties. We used authentic filoviruses and lentiviral particles pseudotyped with filoviral glycoproteins to identify and characterize such compounds. We discovered that amiodarone, a multi-ion channel inhibitor and adrenoceptor antagonist, is a potent inhibitor of filovirus cell entry at concentrations that are routinely reached in human serum during anti-arrhythmic therapy. A similar effect was observed with the amiodarone-related agent dronedarone and the L-type calcium channel blocker verapamil. Inhibition by amiodarone was concentration dependent and similarly affected pseudoviruses as well as authentic filoviruses. Inhibition of filovirus entry was observed with most but not all cell types tested and was accentuated by the pre-treatment of cells, indicating a host cell-directed mechanism of action. The New World arenavirus Guanarito was also inhibited by amiodarone while the Old World arenavirus Lassa and members of the Rhabdoviridae (vesicular stomatitis virus) and Bunyaviridae (Hantaan) families were largely resistant. The ion channel blockers amiodarone, dronedarone and verapamil inhibit filoviral cell entry. © The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

[Current status of anthrax or black fever].

PubMed

Chantal, J

1997-01-01

Although anthrax is one of the oldest recognized infectious diseases in the world, it remains widespread particularly in tropical zones such as Africa. The impact of this major zoonoses is further enhanced by the fact that the pulmonary form can be used for biological warfare. Recently there has been a revival of interest in anthrax and research has benefited greatly from advances in molecular biology. The main factors accounting for the virulence of Bacillus anthracis have been elucidated. The author reports current data concerning pathogenesis, epidemiology and diagnosis and reviews progress made in the field of prophylaxis especially with regard to vaccines.

Time to revise the paradigm of hantavirus syndromes? Hantavirus pulmonary syndrome caused by European hantavirus.

PubMed

Rasmuson, J; Andersson, C; Norrman, E; Haney, M; Evander, M; Ahlm, C

2011-05-01

Hantaviruses have previously been recognised to cause two separate syndromes: hemorrhagic fever with renal syndrome in Eurasia, and hantavirus pulmonary syndrome (HPS) in the Americas. However, increasing evidence suggests that this dichotomy is no longer fruitful when recognising human hantavirus disease and understanding the pathogenesis. Herein are presented three cases of severe European Puumala hantavirus infection that meet the HPS case definition. The clinical and pathological findings were similar to those found in American hantavirus patients. Consequently, hantavirus infection should be considered as a cause of acute respiratory distress in all endemic areas worldwide.

Sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease): two case reports.

PubMed

El Kohen, A; Planquart, X; Al Hamany, Z; Bienvenu, L; Kzadri, M; Herman, D

2001-12-01

Sinus histiocytosis with massive lymphadenopathy or Destombes-Rosai-Dorfman's syndrome is a rare benign disease of unknown etiology, usually seen in younger patients. The cases reported concerned a 15-month old Caucasian boy and an 8 year old black boy with unilateral cervical enlargement, occasional fever and without any extranodal involvement. Diagnosis was performed by superficial lymph node biopsy. No immunodeficiency was found. The patients received no therapy and a complete spontaneous resolution was seen after a few months in the two cases. The clinical presentation, histologic characteristics, pathogenesis and treatment of the Destombes-Rosai-Dorfman's syndrome are discussed.

[Research progress on ebola virus glycoprotein].

PubMed

Ding, Guo-Yong; Wang, Zhi-Yu; Gao, Lu; Jiang, Bao-Fa

2013-03-01

Ebola virus (EBOV) causes outbreaks of a highly lethal hemorrhagic fever in humans and there are no effective therapeutic or prophylactic treatments available. The glycoprotein (GP) of EBOV is a transmembrane envelope protein known to play multiple functions including virus attachment and entry, cell rounding and cytotoxicity, down-regulation of host surface proteins, and enhancement of virus assembly and budding. GP is the primary target of protective immunity and the key target for developing neutralizing antibodies. In this paper, the research progress on genetic structure, pathogenesis and immunogenicity of EBOV GP in the last 5 years is reviewed.

Molecular Determinants of Ebola Virus Virulence in Mice

PubMed Central

Ebihara, Hideki; Takada, Ayato; Kobasa, Darwyn; Jones, Steven; Neumann, Gabriele; Theriault, Steven; Bray, Mike; Feldmann, Heinz; Kawaoka, Yoshihiro

2006-01-01

Zaire ebolavirus (ZEBOV) causes severe hemorrhagic fever in humans and nonhuman primates, with fatality rates in humans of up to 90%. The molecular basis for the extreme virulence of ZEBOV remains elusive. While adult mice resist ZEBOV infection, the Mayinga strain of the virus has been adapted to cause lethal infection in these animals. To understand the pathogenesis underlying the extreme virulence of Ebola virus (EBOV), here we identified the mutations responsible for the acquisition of the high virulence of the adapted Mayinga strain in mice, by using reverse genetics. We found that mutations in viral protein 24 and in the nucleoprotein were primarily responsible for the acquisition of high virulence. Moreover, the role of these proteins in virulence correlated with their ability to evade type I interferon-stimulated antiviral responses. These findings suggest a critical role for overcoming the interferon-induced antiviral state in the pathogenicity of EBOV and offer new insights into the pathogenesis of EBOV infection. PMID:16848640

[Hyperimmunoglobulin D syndrome].

PubMed

Drenth, J P; Denecker, N E; Prieur, A M; Van der Meer, J W

1995-09-16

The hyper-IgD syndrome is a rare entity characterized by early onset of attacks of periodic fever. All patients have an elevated serum IgD (> 100 U/ml). Symptoms during attacks include joint involvements (arthralgias/arthritis), abdominal complaints (vomiting, pain, diarrhoea), skin lesions, swollen lymph nodes, and headache. In 1992 an International hyper-IgD study group was established, and to date the diagnosis has been made in 60, mainly European patients; 14 come from France. The disorder occurs in families and is transmitted by autosomal recessive inheritance. Linkage studies indicate that the gene encoding for familial Mediterranean fever is different from the gene for the hyper-IgD syndrome. In children the hyper-IgD syndrome should be distinguished from two other periodic febrile disorders. CINCA (chronic inflammatory, neurological, cutaneous and articular syndrome) and FAPA (periodic fever, adenopathies, pharyngitis, and aphtous stomatitis) share some symptoms with the hyper-IgD syndrome but in these syndromes serum IgD is normal. The pathogenesis remains to be elucidated but during attacks all patients have an acute-phase response with elevated C-reactive protein concentrations. During the febrile episodes, the inflammatory cytokines such as IL-6 TNF alpha, IFN gamma are increased together with natural occurring inhibitors such as IL-1ra and sTNFr. There is no therapy for the syndrome and patients will experience attacks during their entire life although frequency and severity tend to diminish with age.

Nitric oxide inhibits establishment of macroschizont-infected cell lines and is produced by macrophages of calves undergoing bovine tropical theileriosis or East Coast fever.

PubMed

Visser, A E; Abraham, A; Sakyi, L J; Brown, C G; Preston, P M

1995-02-01

Nitric oxide (NO) was produced when bovine peripheral blood mononuclear cells (PBMC) or purified, adherent PBMC (macrophages) were incubated in vitro with bovine recombinant interferon gamma (Bo rIFN-gamma). NO was produced by cells from naive, uninfected calves as well as by cells from cattle either infected with or recovered from infection with Theileria annulata or Theileria parva. PBMC of cattle undergoing tropical theileriosis (T. annulata infection) or East Coast fever (T. parva infection) synthesized NO spontaneously in vitro. NO was also induced when PBMC of immune, but not of naive, cattle were cultured with T. annulata macroschizont-infected cell lines. Macrophages alone were not stimulated to produce NO by such infected cells. In vitro establishment of macroschizont-infected cell lines was suppressed either by incubating sporozoites with S-nitroso-N-acetyl-DL-penicillamine (SNAP), a NO releasing molecule, prior to invasion of PBMC or by pulsing developing cultures of trophozoite-infected cells with SNAP. Proliferation of established macroschizont-infected cell lines was not affected by SNAP. Taken together with the well documented roles of NO in neutrotransmission, vasodilatation, cell and tissue damage and immunosuppression, the results presented here indicate that NO may not only protect cattle against T. annulata and T. parva but, if produced in excess, play a prominent role in the pathogenesis of tropical theileriosis and East Coast fever.

Immune Response to Dengue and Zika.

PubMed

Ngono, Annie Elong; Shresta, Sujan

2018-04-26

Flaviviruses such as dengue (DENV), yellow fever (YFV), West Nile (WNV), and Zika (ZIKV) are human pathogens of global significance. In particular, DENV causes the most prevalent mosquito-borne viral diseases in humans, and ZIKV emerged from obscurity into the spotlight in 2016 as the etiologic agent of congenital Zika syndrome. Owing to the recent emergence of ZIKV as a global pandemic threat, the roles of the immune system during ZIKV infections are as yet unclear. In contrast, decades of DENV research implicate a dual role for the immune system in protection against and pathogenesis of DENV infection. As DENV and ZIKV are closely related, knowledge based on DENV studies has been used to prioritize investigation of ZIKV immunity and pathogenesis, and to accelerate ZIKV diagnostic, therapeutic, and vaccine design. This review discusses the following topics related to innate and adaptive immune responses to DENV and ZIKV: the interferon system as the key mechanism of host defense and viral target for immune evasion, antibody-mediated protection versus antibody-dependent enhancement, and T cell-mediated protection versus original T cell antigenic sin. Understanding the mechanisms that regulate the balance between immune-mediated protection and pathogenesis during DENV and ZIKV infections is critical toward development of safe and effective DENV and ZIKV therapeutics and vaccines.

Pathogenesis of chronic active Epstein-Barr virus infection: is this an infectious disease, lymphoproliferative disorder, or immunodeficiency?

PubMed

Kimura, Hiroshi

2006-01-01

Chronic active Epstein-Barr virus infection (CAEBV) is characterised by chronic or recurrent infectious mononucleosis-like symptoms, such as fever, hepatosplenomegaly, persistent hepatitis and extensive lymphadenopathy. Patients with CAEBV have high viral loads in their peripheral blood and/or an unusual pattern of EBV-related antibodies. This disease is rare but severe with high morbidity and mortality. Nearly three decades have passed since this disease was first identified, and recent advances in technology have increased our understanding of CAEBV pathophysiology. There is accumulating evidence that the clonal expansion of EBV-infected T or natural killer (NK) cells plays a central role in the pathogenesis of CAEBV. However, it remains unclear whether CAEBV is truly a monoclonal lymphoproliferative disorder. EBV-infected T or NK cells are able to evade the host cellular immune system due to the limited expression of viral proteins of reduced antigenicity. Recent studies suggest that infection of T or NK cells is a common event during primary EBV infection. A defect or single nucleotide polymorphism in host immune-modulating genes may allow for the expansion of virus infected cells giving rise to CAEBV. In this review, I summarise our current understanding of the pathogenesis of CAEBV and propose a model of CAEBV pathogenicity.

Novel Arenavirus Sequences in Hylomyscus sp. and Mus (Nannomys) setulosus from Côte d'Ivoire: Implications for Evolution of Arenaviruses in Africa

PubMed Central

Kouassi, Stéphane K.; Fichet-Calvet, Elisabeth; Becker-Ziaja, Beate; Rieger, Toni; Ölschläger, Stephan; Dosso, Hernri; Denys, Christiane; ter Meulen, Jan; Akoua-Koffi, Chantal; Günther, Stephan

2011-01-01

This study aimed to identify new arenaviruses and gather insights in the evolution of arenaviruses in Africa. During 2003 through 2005, 1,228 small mammals representing 14 different genera were trapped in 9 villages in south, east, and middle west of Côte d'Ivoire. Specimens were screened by pan-Old World arenavirus RT-PCRs targeting S and L RNA segments as well as immunofluorescence assay. Sequences of two novel tentative species of the family Arenaviridae, Menekre and Gbagroube virus, were detected in Hylomyscus sp. and Mus (Nannomys) setulosus, respectively. Arenavirus infection of Mus (Nannomys) setulosus was also demonstrated by serological testing. Lassa virus was not found, although 60% of the captured animals were Mastomys natalensis. Complete S RNA and partial L RNA sequences of the novel viruses were recovered from the rodent specimens and subjected to phylogenetic analysis. Gbagroube virus is a closely related sister taxon of Lassa virus, while Menekre virus clusters with the Ippy/Mobala/Mopeia virus complex. Reconstruction of possible virus–host co-phylogeny scenarios suggests that, within the African continent, signatures of co-evolution might have been obliterated by multiple host-switching events. PMID:21695269

Dengue fever with diffuse cerebral hemorrhages, subdural hematoma and cranial diabetes insipidus.

PubMed

Jayasinghe, Nayomi Shermila; Thalagala, Eranga; Wattegama, Milanka; Thirumavalavan, Kanapathipillai

2016-05-10

Neurological manifestations in dengue fever occur in <1 % of the patients and known to be due to multisystem dysfunction secondary to vascular leakage. Occurrence of wide spread cerebral haemorrhages with subdural hematoma during the leakage phase without profound thrombocytopenia and occurrence of cranial diabetes insipidus are extremely rare and had not been reported in published literature earlier, thus we report the first case. A 24 year old previously healthy lady was admitted on third day of fever with thrombocytopenia. Critical phase started on fifth day with evidence of pleural effusion and moderate ascites. Thirty one hours into critical phase she developed headache, altered level of consciousness, limb rigidity and respiratory depression without definite seizures. Non-contrast CT brain done at tertiary care level revealed diffuse intracranial haemorrhages and sub arachnoid haemorrhages in right frontal, parietal, occipital lobes and brainstem, cerebral oedema with an acute subdural hematoma in right temporo- parietal region. Her platelet count was 40,000 at this time with signs of vascular leakage. She was intubated and ventilated with supportive care. Later on she developed features of cranial diabetes insipidus and it responded to intranasal desmopressin therapy. In spite of above measures signs of brainstem herniation developed and she succumbed to the illness on day 8. Dengue was confirmed serologically. Exact pathophysiological mechanism of diffuse cerebral haemorrhages without profound thrombocytopenia is not well understood. Increased awareness and high degree of clinical suspicion is needed among clinicians for timely diagnosis of this extremely rare complication of dengue fever. We postulate that immunological mechanisms may play a role in pathogenesis. However further comprehensive research and studies are needed to understand the pathophysiological mechanisms leading to this complication.

Host biomarkers are associated with progression to dengue haemorrhagic fever: a nested case-control study.

PubMed

Conroy, Andrea L; Gélvez, Margarita; Hawkes, Michael; Rajwans, Nimerta; Tran, Vanessa; Liles, W Conrad; Villar-Centeno, Luis Angel; Kain, Kevin C

2015-11-01

Dengue represents the most important arboviral infection worldwide. Onset of circulatory collapse can be unpredictable. Biomarkers that can identify individuals at risk of plasma leakage may facilitate better triage and clinical management. Using a nested case-control design, we randomly selected subjects from a prospective cohort study of dengue in Colombia (n=1582). Using serum collected within 96 hours of fever onset, we tested 19 biomarkers by ELISA in cases (developed dengue hemorrhagic fever or dengue shock syndrome (DHF/DSS); n=46), and controls (uncomplicated dengue fever (DF); n=65) and healthy controls (HC); n=15. Ang-1 levels were lower and angptl3, sKDR, sEng, sICAM-1, CRP, CXCL10/IP-10, IL-18 binding protein, CHI3L1, C5a and Factor D levels were increased in dengue compared to HC. sICAM-1, sEng and CXCL10/IP-10 were further elevated in subjects who subsequently developed DHF/DSS (p=0.008, p=0.028 and p=0.025, respectively). In a logistic regression model, age (odds ratio (OR) (95% CI): 0.95 (0.92-0.98), p=0.001), hyperesthesia/hyperalgesia (OR; 3.8 (1.4-10.4), p=0.008) and elevated sICAM-1 (>298ng/mL: OR; 6.3 (1.5-25.7), p=0.011) at presentation were independently associated with progression to DHF/DSS. These results suggest that inflammation and endothelial activation are important pathways in the pathogenesis of dengue and sICAM-1 levels may identify individuals at risk of plasma leakage. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Invariant NKT Cell Response to Dengue Virus Infection in Human

PubMed Central

Matangkasombut, Ponpan; Chan-in, Wilawan; Opasawaschai, Anunya; Pongchaikul, Pisut; Tangthawornchaikul, Nattaya; Vasanawathana, Sirijitt; Limpitikul, Wannee; Malasit, Prida; Duangchinda, Thaneeya; Screaton, Gavin; Mongkolsapaya, Juthathip

2014-01-01

Background Dengue viral infection is a global health threat without vaccine or specific treatment. The clinical outcome varies from asymptomatic, mild dengue fever (DF) to severe dengue hemorrhagic fever (DHF). While adaptive immune responses were found to be detrimental in the dengue pathogenesis, the roles of earlier innate events remain largely uninvestigated. Invariant natural killer T (iNKT) cells represent innate-like T cells that could dictate subsequent adaptive response but their role in human dengue virus infection is not known. We hypothesized that iNKT cells play a role in human dengue infection. Methods Blood samples from a well-characterized cohort of children with DF, DHF, in comparison to non-dengue febrile illness (OFI) and healthy controls at various time points were studied. iNKT cells activation were analyzed by the expression of CD69 by flow cytometry. Their cytokine production was then analyzed after α-GalCer stimulation. Further, the CD1d expression on monocytes, and CD69 expression on conventional T cells were measured. Results iNKT cells were activated during acute dengue infection. The level of iNKT cell activation associates with the disease severity. Furthermore, these iNKT cells had altered functional response to subsequent ex vivo stimulation with α-GalCer. Moreover, during acute dengue infection, monocytic CD1d expression was also upregulated and conventional T cells also became activated. Conclusion iNKT cells might play an early and critical role in the pathogenesis of severe dengue viral infection in human. Targeting iNKT cells and CD1d serve as a potential therapeutic strategy for severe dengue infection in the future. PMID:24945350

Proteomics Analysis of the Causative Agent of Typhoid Fever

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

Ansong, Charles; Yoon, Hyunjin; Norbeck, Angela D.

2008-02-01

Typhoid fever is a potentially fatal disease caused by the bacterial pathogen Salmonella enterica serovar Typhi (S. typhi). S. typhi infection is a complex process that involves numerous bacterially-encoded virulence determinants, and these are thought to confer both stringent human host specificity and a high mortality rate. In the present study we used a liquid chromatography-mass spectrometry (LC-MS) based proteomics strategy to investigate the proteome of logarithmic, stationary phase, and low pH/low magnesium (MgM) S. typhi cultures. This represents the first large scale comprehensive characterization of the S. typhi proteome. Our analysis identified a total of 2066 S. typhi proteins.more » In an effort to identify putative S. typhi-specific virulence factors, we then compared our S. typhi results to those obtained in a previously published study of the S. typhimurium proteome under similar conditions (Adkins J.N. et al (2006) Mol Cell Prot). Comparative proteomic analysis of S. typhi (strain Ty2) and S. typhimurium (strains LT2 and 14028) revealed a subset of highly expressed proteins unique to S. typhi that were exclusively detected under conditions that mimic the infective state in macrophage cells. These proteins included CdtB, HlyE, and a conserved protein encoded by t1476. The differential expression of selected proteins was confirmed by Western blot analysis. Taken together with the current literature, our observations suggest that this subset of proteins may play a role in S. typhi pathogenesis and human host specificity. In addition, we observed products of the biotin (bio) operon displayed a higher abundance in the more virulent strains S. typhi-Ty2 and S. typhimurium-14028 compared to the virulence attenuated S. typhimurium strain LT2, suggesting bio proteins may contribute to Salmonella pathogenesis.« less

A case of thyroid storm with a markedly elevated level of circulating soluble interleukin-2 receptor complicated by multiple organ failure and disseminated intravascular coagulation syndrome.

PubMed

Shimoda, Yoko; Satoh, Tetsurou; Takahashi, Hiroki; Katano-Toki, Akiko; Ozawa, Atsushi; Tomaru, Takuya; Horiguchi, Norio; Kaira, Kyoichi; Nishioka, Masaki; Shibusawa, Nobuyuki; Hashimoto, Koshi; Wakino, Shu; Mori, Masatomo; Yamada, Masanobu

2014-01-01

Thyroid storm (TS) is a life-threatening endocrine emergency. However, the pathogenesis of TS is poorly understood. A 40-year-old man was admitted to a nearby hospital with body weight loss and jaundice. Five days after a contrasted abdominal computerized tomography (CT) scan, he exhibited high fever and disturbance of consciousness. He was diagnosed with TS originating from untreated Graves' disease and was transferred to the intensive care unit (ICU) of our hospital. The patient exhibited impaired consciousness (E4V1M4 in Glasgow coma scale), high fever (39.3°C), and atrial flutter with a pulse rate 162/min, and was complicated by heart failure, acute hepatic failure, and disseminated intravascular coagulation syndrome (DIC). His circulating level of soluble interleukin-2 receptor (sIL-2R), a serum marker of an activated immune response, was highly elevated (7,416 U/mL, reference range: 135-483). Multiple organ failure (MOF) and DIC were successfully managed by multimodality treatments using inorganized iodide, glucocorticoids, anti-thyroid drugs, beta-blockers, and diuretics as well as an anticoagulant agent and the transfusion of platelet concentrate and fresh frozen plasma. sIL-2R levels gradually decreased during the initial treatment, but were still above the reference range even after thyroidectomy. Mild elevations in serum levels of sIL-2R have previously been correlated with thyroid hormone levels in non-storm Graves' disease. The present study demonstrated, for the first time, that circulating sIL-2R levels could be markedly elevated in TS. The marked increase in sIL-2R levels was speculated to represent an inappropriate generalized immune response that plays an unknown role in the pathogenesis of TS.

Interacting roles of immune mechanisms and viral load in the pathogenesis of crimean-congo hemorrhagic fever.

PubMed

Saksida, Ana; Duh, Darja; Wraber, Branka; Dedushaj, Isuf; Ahmeti, Salih; Avsic-Zupanc, Tatjana

2010-07-01

Until now, the pathogenesis of Crimean-Congo hemorrhagic fever (CCHF) has not been well described. However, it has been hypothesized that it could be a result of the direct injury of virus-infected tissues in combination with the indirect effects of host immune responses, including cytokines. To shed more light on the role of viral load and cytokines, differential influences of CCHF virus (CCHFV) RNA load, antibody response, and cytokine production on severity and outcome of the disease were studied in sera of 46 patients with confirmed acute CCHF from Kosovo. In this study, viral load proved to be strongly related to the severity and outcome of the disease, with higher viral loads detected in patients with fatal outcomes than in surviving patients. Also, patients with fatal outcome had on average a weaker antibody response, if one was present at all. High levels of interleukin-10 (IL-10), gamma interferon (IFN-gamma), and tumor necrosis factor alpha (TNF-alpha) were associated with poor outcome, since detected concentrations were highest in patients with fatal outcome and lowest in patients with moderate disease course. Additionally, a positive linear dependence between viral load and these cytokines was observed. Interestingly, reduced levels of IL-12 were detected in all CCHF patients. Our study favors the hypothesis that CCHF could be a result of a delayed and downregulated immune response caused by IL-10, which leads to an increased replication and spread of CCHFV throughout the body. This consequently triggers increased production of IFN-gamma and TNF-alpha, cytokines mediating vascular dysfunction, disseminated intravascular coagulation, organ failure, and shock.

Rheumatic fever & rheumatic heart disease: The last 50 years

PubMed Central

Kumar, R. Krishna; Tandon, R.

2013-01-01

Rheumatic fever (RF) and rheumatic heart disease (RHD) continue to be a major health hazard in most developing countries as well as sporadically in developed economies. Despite reservations about the utility, echocardiographic and Doppler (E&D) studies have identified a massive burden of RHD suggesting the inadequacy of the Jones’ criteria updated by the American Heart Association in 1992. Subclinical carditis has been recognized by E&D in patients with acute RF without clinical carditis as well as by follow up of RHD patients presenting as isolated chorea or those without clinical evidence of carditis. Over the years, the medical management of RF has not changed. Paediatric and juvenile mitral stenosis (MS), upto the age of 12 and 20 yr respectively, severe enough to require operative treatement was documented. These negate the belief that patients of RHD become symptomatic ≥20 years after RF as well as the fact that congestive cardiac failure in childhood indicates active carditis and RF. Non-surgical balloon mitral valvotomy for MS has been initiated. Mitral and/or aortic valve replacement during active RF in patients not responding to medical treatment has been found to be life saving as well as confirming that congestive heart failure in acute RF is due to an acute haemodynamic overload. Pathogenesis as well as susceptibility to RF continue to be elusive. Prevention of RF morbidity depends on secondary prophylaxis which cannot reduce the burden of diseases. Primary prophylaxis is not feasible in the absence of a suitable vaccine. Attempts to design an antistreptococcal vaccine utilizing the M-protein has not succeeded in the last 40 years. Besides pathogenesis many other questions remain unanswered. PMID:23703332

The High Degree of Sequence Plasticity of the Arenavirus Noncoding Intergenic Region (IGR) Enables the Use of a Nonviral Universal Synthetic IGR To Attenuate Arenaviruses

PubMed Central

Iwasaki, Masaharu; Cubitt, Beatrice; Sullivan, Brian M.

2016-01-01

ABSTRACT Hemorrhagic fever arenaviruses (HFAs) pose important public health problems in regions where they are endemic. Concerns about human-pathogenic arenaviruses are exacerbated because of the lack of FDA-licensed arenavirus vaccines and because current antiarenaviral therapy is limited to an off-label use of ribavirin that is only partially effective. We have recently shown that the noncoding intergenic region (IGR) present in each arenavirus genome segment, the S and L segments (S-IGR and L-IGR, respectively), plays important roles in the control of virus protein expression and that this knowledge could be harnessed for the development of live-attenuated vaccine strains to combat HFAs. In this study, we further investigated the sequence plasticity of the arenavirus IGR. We demonstrate that recombinants of the prototypic arenavirus lymphocytic choriomeningitis virus (rLCMVs), whose S-IGRs were replaced by the S-IGR of Lassa virus (LASV) or an entirely nonviral S-IGR-like sequence (Ssyn), are viable, indicating that the function of S-IGR tolerates a high degree of sequence plasticity. In addition, rLCMVs whose L-IGRs were replaced by Ssyn or S-IGRs of the very distantly related reptarenavirus Golden Gate virus (GGV) were viable and severely attenuated in vivo but able to elicit protective immunity against a lethal challenge with wild-type LCMV. Our findings indicate that replacement of L-IGR by a nonviral Ssyn could serve as a universal molecular determinant of arenavirus attenuation. IMPORTANCE Hemorrhagic fever arenaviruses (HFAs) cause high rates of morbidity and mortality and pose important public health problems in regions where they are endemic. Implementation of live-attenuated vaccines (LAVs) will represent a major step to combat HFAs. Here we document that the arenavirus noncoding intergenic region (IGR) has a high degree of plasticity compatible with virus viability. This observation led us to generate recombinant LCMVs containing nonviral synthetic IGRs. These rLCMVs were severely attenuated in vivo but able to elicit protective immunity against a lethal challenge with wild-type LCMV. These nonviral synthetic IGRs can be used as universal molecular determinants of arenavirus attenuation for the rapid development of safe and effective, as well as stable, LAVs to combat HFA. PMID:26739049

Ebola hemorrhagic Fever and the current state of vaccine development.

PubMed

Hong, Joo Eun; Hong, Kee-Jong; Choi, Woo Young; Lee, Won-Ja; Choi, Yeon Hwa; Jeong, Chung-Hyeon; Cho, Kwang-Il

2014-12-01

Current Ebola virus outbreak in West Africa already reached the total number of 1,323 including 729 deaths by July 31st. the fatality is around 55% in the southeastern area of Guinea, Sierra Leone, Liberia, and Nigeria. The number of patients with Ebola Hemorrhagic Fever (EHF) was continuously increasing even though the any effective therapeutics or vaccines has not been developed yet. The Ebola virus in Guinea showed 98% homology with Zaire Ebola Virus. Study of the pathogenesis of Ebola virus infection and assess of the various candidates of vaccine have been tried for a long time, especially in United States and some European countries. Even though the attenuated live vaccine and DNA vaccine containing Ebola viral genes were tested and showed efficacy in chimpanzees, those candidates still need clinical tests requiring much longer time than the preclinical development to be approved for the practical treatment. It can be expected to eradicate Ebola virus by a safe and efficient vaccine development similar to the case of smallpox virus which was extinguished from the world by the variola vaccine.

Serum Metabolomic Profiling of Piglets Infected with Virulent Classical Swine Fever Virus

PubMed Central

Gong, Wenjie; Jia, Junjie; Zhang, Bikai; Mi, Shijiang; Zhang, Li; Xie, Xiaoming; Guo, Huancheng; Shi, Jishu; Tu, Changchun

2017-01-01

Classical swine fever (CSF) is a highly contagious swine infectious disease and causes significant economic losses for the pig industry worldwide. The objective of this study was to determine whether small molecule metabolites contribute to the pathogenesis of CSF. Birefly, serum metabolomics of CSFV Shimen strain-infected piglets were analyzed by ultraperformance liquid chromatography/electrospray ionization time-of-flight mass spectrometry (UPLC/ESI-Q-TOF/MS) in combination with multivariate statistical analysis. In CSFV-infected piglets at days 3 and 7 post-infection changes were found in metabolites associated with several key metabolic pathways, including tryptophan catabolism and the kynurenine pathway, phenylalanine metabolism, fatty acid and lipid metabolism, the tricarboxylic acid and urea cycles, branched-chain amino acid metabolism, and nucleotide metabolism. Several pathways involved in energy metabolism including fatty acid biosynthesis and β-oxidation, branched-chain amino acid metabolism, and the tricarboxylic acid cycle were significantly inhibited. Changes were also observed in several metabolites exclusively associated with gut microbiota. The metabolomic profiles indicate that CSFV-host gut microbiome interactions play a role in the development of CSF. PMID:28496435

Mosquito Bite Delivery of Dengue Virus Enhances Immunogenicity and Pathogenesis in Humanized Mice

PubMed Central

Cox, Jonathan; Mota, Javier; Sukupolvi-Petty, Soila; Diamond, Michael S.

2012-01-01

Dengue viruses (DENV) are transmitted to humans by the bite of Aedes aegypti or Aedes albopictus mosquitoes, with millions of infections annually in over 100 countries. The diseases they produce, which occur exclusively in humans, are dengue fever (DF) and dengue hemorrhagic fever (DHF). We previously developed a humanized mouse model of DF in which mice transplanted with human hematopoietic stem cells produced signs of DENV disease after injection with low-passage, wild-type isolates. Using these mice, but now allowing infected A. aegypti to transmit dengue virus during feeding, we observed signs of more severe disease (higher and more sustained viremia, erythema, and thrombocytopenia). Infected mice mounted innate (gamma interferon [IFN-γ] and soluble interleukin 2 receptor alpha [sIL-2Rα]) and adaptive (anti-DENV antibodies) immune responses that failed to clear viremia until day 56, while a mosquito bite alone induced strong immunomodulators (tumor necrosis factor alpha [TNF-α], IL-4, and IL-10) and thrombocytopenia. This is the first animal model that allows an evaluation of human immunity to DENV infection after mosquito inoculation. PMID:22573866

The Complement System in Flavivirus Infections

PubMed Central

Conde, Jonas N.; Silva, Emiliana M.; Barbosa, Angela S.; Mohana-Borges, Ronaldo

2017-01-01

The incidence of flavivirus infections has increased dramatically in recent decades in tropical and sub-tropical climates worldwide, affecting hundreds of millions of people each year. The Flaviviridae family includes dengue, West Nile, Zika, Japanese encephalitis, and yellow fever viruses that are typically transmitted by mosquitoes or ticks, and cause a wide range of symptoms, such as fever, shock, meningitis, paralysis, birth defects, and death. The flavivirus genome is composed of a single positive-sense RNA molecule encoding a single viral polyprotein. This polyprotein is further processed by viral and host proteases into three structural proteins (C, prM/M, E) and seven non-structural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, NS5) that are involved in viral replication and pathogenicity. The complement system has been described to play an important role in flavivirus infection either by protecting the host and/or by influencing disease pathogenesis. In this mini-review, we will explore the role of complement system inhibition and/or activation against infection by the Flavivirus genus, with an emphasis on dengue and West Nile viruses. PMID:28261172

The role of granulocyte macrophage-colony stimulating factor in gastrointestinal immunity to salmonellosis.

PubMed

Coon, C; Beagley, K W; Bao, S

2009-08-01

Human Salmonella infection, in particular, typhoid fever is a highly infectious disease that remains a major public health problem causing significant morbidity and mortality. The outcome of these infections depends on the host's immune response, particularly the actions of granulocytes and macrophages. Using a mouse model of human typhoid fever, with Salmonella typhimurium infection of wild type and granulocyte macrophage-colony stimulating factor (GM-CSF) knock out mice we show a delay in the onset of immune-mediated tissue damage in the spleens and livers of GM-CSF(-/-) mice. Furthermore, GM-CSF(-/-) mice have a prolonged sequestration of S. typhimurium in affected tissues despite an increased production of F4/80+ effector cells. Moreover in the absence of GM-CSF, a decrease in pro-inflammatory cytokine expression of tumor necrosis factor-alpha, interleukin-12 (IL-12) and IL-18 was found, which may alter the host's immune response to infection. GM-CSF appears to play an important role in the pathogenesis of Salmonellosis, and may contribute significantly to the development of protective gastrointestinal mucosal immune responses against oral pathogens.

Leukopenia in familial Mediterranean fever: case series and literature review with special emphasis on pathogenesis.

PubMed

Aslan, Deniz

2014-03-01

Leukopenia is a blood disease in which the number of circulating white blood cells diminishes. All underlying causes of leukopenia are not yet known. The subjects of this study are 15 leukopenic patients who were assessed by a systemic workup, including physical examination, blood tests, and molecular analysis. A common and unusual cause was revealed in all patients. This cause was a disorder with a laboratory characteristic of leukocytosis, namely familial Mediterranean fever (FMF). It was discussed that leukopenia arising in the context of FMF is mainly due to autophagy and apoptosis processes. These two pathophysiological characteristics of FMF were thought to explain the particular (episodic and self-limited) leukopenia in this disorder. Based on the results of this study in conjunction with the currently existing literature data, we suggest that FMF causes leukopenia. Leukopenic cases should be investigated for FMF, particularly if the leukopenia is episodic in nature. Early recognition of FMF would help to skip unnecessary invasive procedures and to prevent the development of amyloidosis, the devastating complication of FMF.

Classical Swine Fever-An Updated Review.

PubMed

Blome, Sandra; Staubach, Christoph; Henke, Julia; Carlson, Jolene; Beer, Martin

2017-04-21

Classical swine fever (CSF) remains one of the most important transboundary viral diseases of swine worldwide. The causative agent is CSF virus, a small, enveloped RNA virus of the genus Pestivirus. Based on partial sequences, three genotypes can be distinguished that do not, however, directly correlate with virulence. Depending on both virus and host factors, a wide range of clinical syndromes can be observed and thus, laboratory confirmation is mandatory. To this means, both direct and indirect methods are utilized with an increasing degree of commercialization. Both infections in domestic pigs and wild boar are of great relevance; and wild boars are a reservoir host transmitting the virus sporadically also to pig farms. Control strategies for epidemic outbreaks in free countries are mainly based on classical intervention measures; i.e., quarantine and strict culling of affected herds. In these countries, vaccination is only an emergency option. However, live vaccines are used for controlling the disease in endemically infected regions in Asia, Eastern Europe, the Americas, and some African countries. Here, we will provide a concise, updated review on virus properties, clinical signs and pathology, epidemiology, pathogenesis and immune responses, diagnosis and vaccination possibilities.

Development and characterization of polyclonal peptide antibodies for the detection of Yellow fever virus proteins.

PubMed

Stock, N K; Escadafal, C; Achazi, K; Cissé, M; Niedrig, M

2015-09-15

There is still a considerable need for development of new tools and methods detecting specific viral proteins for the diagnosis and pathogenesis study of the Yellow fever virus (YFV). This study aimed to develop and characterize polyclonal peptide antisera for detection of YFV-C and -NS1 proteins. The antisera were used further to investigate NS1 protein expression during YFV infection in mammalian cells. YFV target proteins were detected by all antisera in western blot and immunofluorescence assays. No cross-reactivity was observed with Dengue virus, West Nile virus, Tick-borne encephalitis virus and Japanese encephalitis virus. Nuclear localization of the YFV-C protein was demonstrated for the first time. Experiments investigating NS1 expression suggested a potential use of the YFV-NS1 antisera for development of diagnostic approaches targeting the secreted form of the NS1 protein. The antisera described in this study offer new possibilities for use in YFV research and for the development of novel diagnostic tests. Copyright © 2015 Elsevier B.V. All rights reserved.

Expression of interferon-induced antiviral genes is delayed in a STAT1 knockout mouse model of Crimean-Congo hemorrhagic fever.

PubMed

Bowick, Gavin C; Airo, Adriana M; Bente, Dennis A

2012-06-19

Crimean Congo hemorrhagic fever (CCHF) is a tick-borne hemorrhagic zoonosis associated with high mortality. Pathogenesis studies and the development of vaccines and antivirals against CCHF have been severely hampered by the lack of suitable animal model. We recently developed and characterized a mature mouse model for CCHF using mice carrying STAT1 knockout (KO). Given the importance of interferons in controlling viral infections, we investigated the expression of interferon pathway-associated genes in KO and wild-type (WT) mice challenged with CCHF virus. We expected that the absence of the STAT1 protein would result in minimal expression of IFN-related genes. Surprisingly, the KO mice showed high levels of IFN-stimulated gene expression, beginning on day 2 post-infection, while in WT mice challenged with virus the same genes were expressed at similar levels on day 1. We conclude that CCHF virus induces similar type I IFN responses in STAT1 KO and WT mice, but the delayed response in the KO mice permits rapid viral dissemination and fatal illness.

Genetic polymorphisms of molecules involved in host immune response to dengue virus infection.

PubMed

Fang, Xin; Hu, Zhen; Shang, Weilong; Zhu, Junmin; Xu, Chuanshan; Rao, Xiancai

2012-11-01

The dengue virus (DENV) belongs to the flavivirus family. Each of the four distinct serotypes of this virus is capable of causing human disease, especially in tropical and subtropical areas. The majority of people infected with DENV manifest asymptomatic or dengue fever with flu-like self-limited symptoms. However, a small portion of patients emerge with severe manifestations referred to as dengue hemorrhagic fever, which has a high mortality rate if not treated promptly. The host immune system, which plays important roles throughout the whole process of DENV infection, has been confirmed to have double-edged effects on DENV infection. Recently, much attention has been paid to the genetic heterogeneity of molecules involved in the host immune response to DENV infection. This heterogeneity has been proved to be the determining factor for DENV disease orientation. The present review discusses the primary functions and single nucleotide polymorphisms of some critical molecules in the human DENV immunological defense, especially the polymorphism locus associated with the DENV pathogenesis and disease susceptibility. © 2012 Federation of European Microbiological Societies. Published by Blackwell Publishing Ltd. All rights reserved.

Investigation of type-I interferon dysregulation by arenaviruses : a multidisciplinary approach.

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

Kozina, Carol L.; Moorman, Matthew Wallace; Branda, Catherine

2011-09-01

This report provides a detailed overview of the work performed for project number 130781, 'A Systems Biology Approach to Understanding Viral Hemorrhagic Fever Pathogenesis.' We report progress in five key areas: single cell isolation devices and control systems, fluorescent cytokine and transcription factor reporters, on-chip viral infection assays, molecular virology analysis of Arenavirus nucleoprotein structure-function, and development of computational tools to predict virus-host protein interactions. Although a great deal of work remains from that begun here, we have developed several novel single cell analysis tools and knowledge of Arenavirus biology that will facilitate and inform future publications and funding proposals.

Hemophagocytic syndromes and infection.

PubMed Central

Fisman, D. N.

2000-01-01

Hemophagocytic lymphohistiocytosis (HLH) is an unusual syndrome characterized by fever, splenomegaly, jaundice, and the pathologic finding of hemophagocytosis (phagocytosis by macrophages of erythrocytes, leukocytes, platelets, and their precursors) in bone marrow and other tissues. HLH may be diagnosed in association with malignant, genetic, or autoimmune diseases but is also prominently linked with Epstein-Barr (EBV) virus infection. Hyperproduction of cytokines, including interferon-gamma and tumor necrosis factor-alpha, by EBV- infected T lymphocytes may play a role in the pathogenesis of HLH. EBV-associated HLH may mimic T-cell lymphoma and is treated with cytotoxic chemotherapy, while hemophagocytic syndromes associated with nonviral pathogens often respond to treatment of the underlying infection. PMID:11076718

Study of the pathogenesis of Ebola fever in laboratory animals with different sensitivity to this virus.

PubMed

Chepurnov, A A; Dadaeva, A A; Kolesnikov, S I

2001-12-01

Pathophysiological parameters were compared in animals with different sensitivity to Ebola virus infected with this virus. Analysis of the results showed the differences in immune reactions underlying the difference between Ebola-sensitive and Ebola-resistant animals. No neutrophil activation in response to Ebola virus injection was noted in Ebola-sensitive animal. Phagocytic activity of neutrophils in these animals inversely correlated with animal sensitivity to Ebola virus. Animal susceptibility to Ebola virus directly correlated with the decrease in the number of circulating T and B cells. We conclude that the immune system plays the key role in animal susceptibility and resistance to Ebola virus.

[Analysis of clinical characteristic of 158 inpatients with dengue fever in Guangzhou area during the 2014 epidemic].

PubMed

Ye, Zi; Huang, Yingxiong; Jiang, Peng; Zheng, Ziyu; Xiong, Yan; Xu, Jia; Xiao, Xiaoyong; Zhan, Hong

2015-04-01

To investigate the clinical characteristics of the inpatients suffering from dengue fever in order to provide references for better diagnosis and treatment. The clinical data of 158 dengue fever patients admitted to the First Affiliated Hospital of Sun Yat-Sen University from July 23rd to October 31st, 2014 during the 2014 epidemic in Guangzhou area were retrospectively analyzed, including general clinical manifestations, conventional examinations, pathogenesis, and prognosis. The mean age of the 158 patients was ( 56 ± 20 ) years, with half of them over 60 years old (79 cases). Among them, 94 (59.49%) were male. (1) The common manifestations included fever (100%), headache (70.89%), myalgia/bone soreness (62.03%), and skin rash (54.43%). Bleeding and plasma leakage were found in 25.95% and 14.56% of the patients respectively. (2) Laboratory examination: leucopenia (75.32%) and thrombocytopenia (77.85%) were found, and alanine aminotransferase (ALT) and aspartate aminotransferase ( AST ) were elevated in 57.59% and 77.85% of the patients respectively. However, elevation of blood hematocrit was rare (1.27% ). (3) It was found that in the acute phase (0 - 5 days of the onset), serum dengue virus antibody IgM (DF-IgM) was positive in 63.54% of the patients (61/96), and 92.62% (113/122) of patients were dengue virus RNA ( DENA-RNA ) positive. (4) The rate of comorbidity in this study was 55.06% ( 87/158 ), including hypertension (27.22%) and type 2 diabetes (15.82%), which were the two most common co-morbidities. (5) All the patients were given supportive therapy to prevent complications. They were also isolated for more than 5 days after onset, and at least for 24 hours after subsidence of fever in addition. (6) The criteria for the diagnosis of severe dengue were fulfilled in 18 patients (11.39%). One patient died of massive hemorrhage from gastro-intestinal tract, and 1 patient voluntarily left hospital with untreated multiple organ dysfunction syndrome (MODS). Another 2 patients of dengue fever died from primary cardio-cerebrovascular disease, and the remaining 154 patients (97.47%) fully recovered with supportive therapy and complication prevention measures. The clinical manifestations of inpatients with dengue fever in this study were typical, and they manifested a higher incidence of severe illness. DENA-RNA could be a sensitive indicator for early pathogenic diagnosis. With symptomatic and supportive therapy, most patients had a good outcome. However, early diagnosis and clinical interventions of severe dengue still need further studies.

Interactome analysis of the lymphocytic choriomeningitis virus nucleoprotein in infected cells reveals ATPase Na+/K+ transporting subunit Alpha 1 and prohibitin as host-cell factors involved in the life cycle of mammarenaviruses

PubMed Central

Iwasaki, Masaharu; Caì, Yíngyún; de la Torre, Juan C.

2018-01-01

Several mammalian arenaviruses (mammarenaviruses) cause hemorrhagic fevers in humans and pose serious public health concerns in their endemic regions. Additionally, mounting evidence indicates that the worldwide-distributed, prototypic mammarenavirus, lymphocytic choriomeningitis virus (LCMV), is a neglected human pathogen of clinical significance. Concerns about human-pathogenic mammarenaviruses are exacerbated by of the lack of licensed vaccines, and current anti-mammarenavirus therapy is limited to off-label use of ribavirin that is only partially effective. Detailed understanding of virus/host-cell interactions may facilitate the development of novel anti-mammarenavirus strategies by targeting components of the host-cell machinery that are required for efficient virus multiplication. Here we document the generation of a recombinant LCMV encoding a nucleoprotein (NP) containing an affinity tag (rLCMV/Strep-NP) and its use to capture the NP-interactome in infected cells. Our proteomic approach combined with genetics and pharmacological validation assays identified ATPase Na+/K+ transporting subunit alpha 1 (ATP1A1) and prohibitin (PHB) as pro-viral factors. Cell-based assays revealed that ATP1A1 and PHB are involved in different steps of the virus life cycle. Accordingly, we observed a synergistic inhibitory effect on LCMV multiplication with a combination of ATP1A1 and PHB inhibitors. We show that ATP1A1 inhibitors suppress multiplication of Lassa virus and Candid#1, a live-attenuated vaccine strain of Junín virus, suggesting that the requirement of ATP1A1 in virus multiplication is conserved among genetically distantly related mammarenaviruses. Our findings suggest that clinically approved inhibitors of ATP1A1, like digoxin, could be repurposed to treat infections by mammarenaviruses pathogenic for humans. PMID:29462184