Steps of the tick-borne encephalitis virus replication cycle that affect neuropathogenesis.

PubMed

Mandl, Christian W

2005-08-01

Tick-borne encephalitis virus (TBEV) is an important human pathogen that causes severe neurological illness in large areas of Europe and Asia. The neuropathogenesis of this disease agent is determined by its capacity to enter the central nervous system (CNS) after peripheral inoculation ("neuroinvasiveness") and its ability to replicate and cause damage within the CNS ("neurovirulence"). TBEV is a small, enveloped flavivirus with an unsegmented, positive-stranded RNA genome. Mutations affecting various steps of its natural replication cycle were shown to influence its neuropathogenic properties. This review describes experimental approaches and summarizes results on molecular determinants of neurovirulence and neuroinvasiveness that have been identified for this virus. It focuses on molecular mechanisms of three particular steps of the viral life cycle that have been studied in some detail for TBEV and two closely related tick-borne flaviviruses (Louping ill virus (LIV) and Langat virus (LGTV)), namely (i) the envelope protein E and its role in viral attachment to the cell surface, (ii) the 3'-noncoding region of the genome and its importance for viral RNA replication, and (iii) the capsid protein C and its role in the assembly process of infectious virus particles. Mutations affecting each of these three molecular targets significantly influence neuropathogenesis of TBEV, particularly its neuroinvasiveness. The understanding of molecular determinants of TBEV neuropathogenesis is relevant for vaccine development, also against other flaviviruses.

Replication enhancer elements within the open reading frame of tick-borne encephalitis virus and their evolution within the Flavivirus genus

PubMed Central

Tuplin, A.; Evans, D. J.; Buckley, A.; Jones, I. M.; Gould, E. A.; Gritsun, T. S.

2011-01-01

We provide experimental evidence of a replication enhancer element (REE) within the capsid gene of tick-borne encephalitis virus (TBEV, genus Flavivirus). Thermodynamic and phylogenetic analyses predicted that the REE folds as a long stable stem–loop (designated SL6), conserved among all tick-borne flaviviruses (TBFV). Homologous sequences and potential base pairing were found in the corresponding regions of mosquito-borne flaviviruses, but not in more genetically distant flaviviruses. To investigate the role of SL6, nucleotide substitutions were introduced which changed a conserved hexanucleotide motif, the conformation of the terminal loop and the base-paired dsRNA stacking. Substitutions were made within a TBEV reverse genetic system and recovered mutants were compared for plaque morphology, single-step replication kinetics and cytopathic effect. The greatest phenotypic changes were observed in mutants with a destabilized stem. Point mutations in the conserved hexanucleotide motif of the terminal loop caused moderate virus attenuation. However, all mutants eventually reached the titre of wild-type virus late post-infection. Thus, although not essential for growth in tissue culture, the SL6 REE acts to up-regulate virus replication. We hypothesize that this modulatory role may be important for TBEV survival in nature, where the virus circulates by non-viraemic transmission between infected and non-infected ticks, during co-feeding on local rodents. PMID:21622960

RNA viruses can hijack vertebrate microRNAs to suppress innate immunity

NASA Astrophysics Data System (ADS)

Trobaugh, Derek W.; Gardner, Christina L.; Sun, Chengqun; Haddow, Andrew D.; Wang, Eryu; Chapnik, Elik; Mildner, Alexander; Weaver, Scott C.; Ryman, Kate D.; Klimstra, William B.

2014-02-01

Currently, there is little evidence for a notable role of the vertebrate microRNA (miRNA) system in the pathogenesis of RNA viruses. This is primarily attributed to the ease with which these viruses mutate to disrupt recognition and growth suppression by host miRNAs. Here we report that the haematopoietic-cell-specific miRNA miR-142-3p potently restricts the replication of the mosquito-borne North American eastern equine encephalitis virus in myeloid-lineage cells by binding to sites in the 3' non-translated region of its RNA genome. However, by limiting myeloid cell tropism and consequent innate immunity induction, this restriction directly promotes neurologic disease manifestations characteristic of eastern equine encephalitis virus infection in humans. Furthermore, the region containing the miR-142-3p binding sites is essential for efficient virus infection of mosquito vectors. We propose that RNA viruses can adapt to use antiviral properties of vertebrate miRNAs to limit replication in particular cell types and that this restriction can lead to exacerbation of disease severity.

Inhibition of aldolase A blocks biogenesis of ATP and attenuates Japanese encephalitis virus production.

PubMed

Tien, Chih-Feng; Cheng, Shih-Ching; Ho, Yen-Peng; Chen, Yi-Shiuan; Hsu, Jung-Hsin; Chang, Ruey-Yi

2014-01-10

Viral replication depends on host proteins to supply energy and replication accessories for the sufficient production of viral progeny. In this study, we identified fructose-bisphosphate aldolase A as a binding partner of Japanese encephalitis virus (JEV) untranslated regions (UTRs) on the antigenome via RNA affinity capture and mass spectrometry. Direct interaction of aldolase A with JEV RNAs was confirmed by gel mobility shift assay and colocalization with active replication of double-stranded RNA in JEV-infected cells. Infection of JEV caused an increase in aldolase A expression of up to 33%. Knocking down aldolase A reduced viral translation, genome replication, and viral production significantly. Furthermore, JEV infection consumed 50% of cellular ATP, and the ATP level decreased by 70% in the aldolase A-knockdown cells. Overexpression of aldolase A in aldolase A-knockdown cells increased ATP levels significantly. Taken together, these results indicate that JEV replication requires aldolase A and consumes ATP. This is the first report of direct involvement of a host metabolic enzyme, aldolase A protein, in JEV replication. Copyright © 2013 Elsevier Inc. All rights reserved.

West Nile and St. Louis encephalitis viral genetic determinants of avian host competence

PubMed Central

Maharaj, Payal D.; Bosco-Lauth, Angela M.; Langevin, Stanley A.; Anishchenko, Michael; Bowen, Richard A.; Reisen, William K.

2018-01-01

West Nile virus (WNV) and St. Louis encephalitis (SLEV) virus are enzootically maintained in North America in cycles involving the same mosquito vectors and similar avian hosts. However, these viruses exhibit dissimilar viremia and virulence phenotypes in birds: WNV is associated with high magnitude viremias that can result in mortality in certain species such as American crows (AMCRs, Corvus brachyrhynchos) whereas SLEV infection yields lower viremias that have not been associated with avian mortality. Cross-neutralization of these viruses in avian sera has been proposed to explain the reduced circulation of SLEV since the introduction of WNV in North America; however, in 2015, both viruses were the etiologic agents of concurrent human encephalitis outbreaks in Arizona, indicating the need to re-evaluate host factors and cross-neutralization responses as factors potentially affecting viral co-circulation. Reciprocal chimeric WNV and SLEV viruses were constructed by interchanging the pre-membrane (prM)-envelope (E) genes, and viruses subsequently generated were utilized herein for the inoculation of three different avian species: house sparrows (HOSPs; Passer domesticus), house finches (Haemorhous mexicanus) and AMCRs. Cross-protective immunity between parental and chimeric viruses were also assessed in HOSPs. Results indicated that the prM-E genes did not modulate avian replication or virulence differences between WNV and SLEV in any of the three avian species. However, WNV-prME proteins did dictate cross-protective immunity between these antigenically heterologous viruses. Our data provides further evidence of the important role that the WNV / SLEV viral non-structural genetic elements play in viral replication, avian host competence and virulence. PMID:29447156

Lipids and flaviviruses, present and future perspectives for the control of dengue, Zika, and West Nile viruses.

PubMed

Martín-Acebes, Miguel A; Vázquez-Calvo, Ángela; Saiz, Juan-Carlos

2016-10-01

Flaviviruses are emerging arthropod-borne pathogens that cause life-threatening diseases such as yellow fever, dengue, West Nile encephalitis, tick-borne encephalitis, Kyasanur Forest disease, tick-borne encephalitis, or Zika disease. This viral genus groups >50 viral species of small enveloped plus strand RNA virus that are phylogenetically closely related to hepatitis C virus. Importantly, the flavivirus life cycle is intimately associated to host cell lipids. Along this line, flaviviruses rearrange intracellular membranes from the endoplasmic-reticulum of the infected cells to develop adequate platforms for viral replication and particle biogenesis. Moreover, flaviviruses dramatically orchestrate a profound reorganization of the host cell lipid metabolism to create a favorable environment for viral multiplication. Consistently, recent work has shown the importance of specific lipid classes in flavivirus infections. For instances, fatty acid synthesis is linked to viral replication, phosphatidylserine and phosphatidylethanolamine are involved on the entry of flaviviruses, sphingolipids (ceramide and sphingomyelin) play a key role on virus assembly and pathogenesis, and cholesterol is essential for innate immunity evasion in flavivirus-infected cells. Here, we revise the current knowledge on the interactions of the flaviviruses with the cellular lipid metabolism to identify potential targets for future antiviral development aimed to combat these relevant health-threatening pathogens. Copyright © 2016 Elsevier B.V. All rights reserved.

Tick-borne encephalitis virus and the immune response of the mammalian host.

PubMed

Dörrbecker, Bastian; Dobler, Gerhard; Spiegel, Martin; Hufert, Frank T

2010-07-01

Tick-borne encephalitis (TBE) is caused by Tick-borne encephalitis virus (TBEV), one of the most prevalent arboviruses in Europe and in many parts of Asia. Transmission of TBEV to humans usually occurs by bite of an infected tick or rarely by ingestion of unpasteurized milk products of infected livestock. TBEV infection induces an innate and adaptive immune response, nevertheless it is able to replicate in several cell types of the immune system at the same time which probably contributes to the spread of the virus in the human host. Furthermore, TBEV can enter the central nervous system (CNS) by yet not well understood mechanisms via the blood brain barrier (BBB) or the olfactory neurons which leads to serious neurological disorders like meningitis, encephalitis or even meningoencephalitis. In this article we review the known facts and possible hypotheses of interaction of TBEV with components of the mammalian immune system and their implications for TBEV-mediated pathogenesis. Copyright © 2010 Elsevier Ltd. All rights reserved.

Venezuelan Equine Encephalitis Virus replicon particles can induce rapid protection against Foot-and-Mouth Disease Virus

USDA-ARS?s Scientific Manuscript database

We have previously shown that swine pretreated with a replication-defective human adenovirus vector (Ad5) containing the porcine type I interferon gene (poIFN-alpha/Beta) are sterilely protected when challenged one day later with Foot-and-Mouth Disease Virus (FMDV), but the dose required is relativ...

Single-dose replication-defective VSV-based Nipah virus vaccines provide protection from lethal challenge in Syrian hamsters.

PubMed

Lo, Michael K; Bird, Brian H; Chattopadhyay, Anasuya; Drew, Clifton P; Martin, Brock E; Coleman, Joann D; Rose, John K; Nichol, Stuart T; Spiropoulou, Christina F

2014-01-01

Nipah virus (NiV) continues to cause outbreaks of fatal human encephalitis due to spillover from its bat reservoir. We determined that a single dose of replication-defective vesicular stomatitis virus (VSV)-based vaccine vectors expressing either the NiV fusion (F) or attachment (G) glycoproteins protected hamsters from over 1000 times LD50 NiV challenge. This highly effective single-dose protection coupled with an enhanced safety profile makes these candidates ideal for potential use in livestock and humans. Published by Elsevier B.V.

Mutational analysis of three predicted 5'-proximal stem-loop structures in the genome of tick-borne encephalitis virus indicates different roles in RNA replication and translation

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

Rouha, Harald; Hoenninger, Verena M.; Thurner, Caroline

2011-08-15

Flavivirus gene expression is modulated by RNA secondary structure elements at the terminal ends of the viral RNA molecule. For tick-borne encephalitis virus (TBEV), four stem-loop (SL) elements have been predicted in the first 180 nucleotides of the viral genome: 5'-SL1, 5'-SL2, 5'-SL3 and 5'-SL4. The last three of these appear to be unique to tick-borne flaviviruses. Here, we report their characterization by mutagenesis in a TBEV luciferase reporter system. By manipulating their thermodynamic properties, we found that an optimal stability of the 5'-SL2 is required for efficient RNA replication. 5'-SL3 formation is also important for viral RNA replication, butmore » although it contains the viral start codon, its formation is dispensable for RNA translation. 5'-SL4 appears to facilitate both RNA translation and replication. Our data suggest that maintenance of the balanced thermodynamic stability of these SL elements is important for temporal regulation of its different functions.« less

Replication of Japanese Encephalitis Virus.

DTIC Science & Technology

1980-12-10

persistently infected with JEV were studied. Over 200 cells were cloned from these cultures and all but four were nonproducers of infectious virus and viral...obtained for release of interfering particles by persis- tently infected cultures and clones , no new size classes of virus RNA could be demonstrated. iI...denaturing or non-dena- turing conditions. Both virus producer and non-producer cell clones were examined, and whether superinfected or not, they

Vesicular Stomatitis Virus Pseudotyped with Ebola Virus Glycoprotein Serves as a Highly Protective, Non-infectious Vaccine Against Ebola Virus Challenge

DTIC Science & Technology

2016-07-01

Single-Injection Trivalent Filovirus 428 Vaccine: Proof of Concept Study in Outbred Guinea Pigs . J Infect Dis. 429 29. Murin, C. D., M. L. Fusco, Z...Jahrling, and J. F. Smith. 2000. Recombinant RNA replicons derived from attenuated 442 Venezuelan equine encephalitis virus protect guinea pigs and...platform, 65 including ease of production and characterization, absence of virus replication concerns and the 66 robust immune stimulatory activity

Aedes albopictus (Diptera: Culicidae) as a potential vector of endemic and exotic arboviruses in Australia.

PubMed

Nicholson, J; Ritchie, S A; van den Hurk, A F

2014-05-01

In 2005, established populations of Aedes albopictus (Skuse) were discovered in the Torres Strait, the region that separates Papua New Guinea from northern Australia. This increased the potential for this species to be introduced to mainland Australia. Because it is an arbovirus vector elsewhere, we undertook laboratory-based infection and transmission experiments to determine the potential for Ae. albopictus from the Torres Strait to become infected with and transmit the four major Australian endemic arboviruses--Murray Valley encephalitis virus, West Nile virus Kunjin strain (WNV(KUN)), Ross River virus (RRV), and Barmah Forest virus--as well as the exotic Japanese encephalitis virus. Ae. albopictus is susceptible to infection with all viruses, with infection rates ranging between 8% for WNV(KUN) and 71% for RRV. Transmission rates of approximately 25% were observed for RRV and Barmah Forest virus, but these were < 17% for Murray Valley encephalitis virus, WNV(KUN), and Japanese encephalitis virus. Given its relative vector competence for alphaviruses, we also examined the replication kinetics and extrinsic incubation periods required for transmission of RRV and chikungunya virus. Despite lower body titers, more mosquitoes reared and maintained at 28 degrees C became infected with and transmitted the virus than those reared and maintained at 22 degrees C. The minimum time between Ae. albopictus consuming an infected bloodmeal and transmitting chikungunya virus was 2 d at 28 degrees C and 4 d at 22 degrees C, and for RRV, it was 4 d, irrespective of the temperature. Given its opportunistic feeding habits and aggressive biting behavior, the establishment of Ae. albopictus on the Australian mainland could have a considerable impact on alphavirus transmission.

Innate immune response during herpes simplex virus encephalitis and development of immunomodulatory strategies.

PubMed

Piret, Jocelyne; Boivin, Guy

2015-09-01

Herpes simplex viruses are large double-stranded DNA viruses. These viruses have the ability to establish a lifelong latency in sensory ganglia and to invade and replicate in the CNS. Apart from relatively benign mucosal infections, HSV is responsible for severe illnesses including HSV encephalitis (HSE). HSE is the most common cause of sporadic, potentially fatal viral encephalitis in Western countries. If left untreated, the mortality rate associated with HSE is approximately 70%. Despite antiviral therapy, the mortality is still higher than 30%, and almost 60% of surviving individuals develop neurological sequelae. It is suggested that direct virus-related and indirect immune-mediated mechanisms contribute to the damages occurring in the CNS during HSE. In this manuscript, we describe the innate immune response to HSV, the development of HSE in mice knock-out for proteins of the innate immune system as well as inherited deficiencies in key components of the signaling pathways involved in the production of type I interferon that could predispose individuals to develop HSE. Finally, we review several immunomodulatory strategies aimed at modulating the innate immune response at a critical time after infection that were evaluated in mouse models and could be combined with antiviral therapy to improve the prognosis of HSE. In conclusion, the cerebral innate immune response that develops during HSE is a "double-edged sword" as it is critical to control viral replication in the brain early after infection, but, if left uncontrolled, may also result in an exaggerated inflammatory response that could be detrimental to the host. Copyright © 2015 John Wiley & Sons, Ltd.

Defining Hsp70 Subnetworks in Dengue Virus Replication Reveals Key Vulnerability in Flavivirus Infection

PubMed Central

Taguwa, Shuhei; Maringer, Kevin; Li, Xiaokai; Bernal-Rubio, Dabeiba; Rauch, Jennifer N.; Gestwicki, Jason E.; Andino, Raul; Fernandez-Sesma, Ana; Frydman, Judith

2015-01-01

Summary Viral protein homeostasis depends entirely on the machinery of the infected cell. Accordingly, viruses can illuminate the interplay between cellular proteostasis components and their distinct substrates. Here we define how the Hsp70 chaperone network mediates the dengue virus life cycle. Cytosolic Hsp70 isoforms are required at distinct steps of the viral cycle, including entry, RNA replication and virion biogenesis. Hsp70 function at each step is specified by nine distinct DNAJ cofactors. Of these, DnaJB11 relocalizes to virus-induced replication complexes to promote RNA synthesis, while DnaJB6 associates with capsid protein and facilitates virion biogenesis. Importantly, an allosteric Hsp70 inhibitor, JG40, potently blocks infection of different dengue serotypes in human primary blood cells without eliciting viral resistance or exerting toxicity to the host cells. JG40 also blocks replication of other medically-important flaviviruses including yellow fever, West Nile and Japanese encephalitis viruses. Thus, targeting host Hsp70 subnetworks provides a path for broad-spectrum antivirals. PMID:26582131

The Stress Granule Component TIA-1 Binds Tick-Borne Encephalitis Virus RNA and Is Recruited to Perinuclear Sites of Viral Replication To Inhibit Viral Translation

PubMed Central

Albornoz, Amelina; Carletti, Tea; Corazza, Gianmarco

2014-01-01

ABSTRACT Flaviviruses are a major cause of disease in humans and animals worldwide. Tick-borne encephalitis virus (TBEV) is the most important arthropod-borne flavivirus endemic in Europe and is the etiological agent of tick-borne encephalitis, a potentially fatal infection of the central nervous system. However, the contributions of host proteins during TBEV infection are poorly understood. In this work, we investigate the cellular protein TIA-1 and its cognate factor TIAR, which are stress-induced RNA-binding proteins involved in the repression of initiation of translation of cellular mRNAs and in the formation of stress granules. We show that TIA-1 and TIAR interact with viral RNA in TBEV-infected cells. During TBEV infection, cytoplasmic TIA-1 and TIAR are recruited at sites of viral replication with concomitant depletion from stress granules. This effect is specific, since G3BP1, another component of these cytoplasmic structures, remains localized to stress granules. Moreover, heat shock induction of stress granules containing TIA-1, but not G3BP1, is inhibited in TBEV-infected cells. Infection of cells depleted of TIA-1 or TIAR by small interfering RNA (siRNA) or TIA-1−/− mouse fibroblasts, leads to a significant increase in TBEV extracellular infectivity. Interestingly, TIAR−/− fibroblasts show the opposite effect on TBEV infection, and this phenotype appears to be related to an excess of TIA-1 in these cells. Taking advantage of a TBE-luciferase replicon system, we also observed increased luciferase activity in TIA-1−/− mouse fibroblasts at early time points, consistent with TIA-1-mediated inhibition at the level of the first round of viral translation. These results indicate that, in response to TBEV infection, TIA-1 is recruited to sites of virus replication to bind TBEV RNA and modulate viral translation independently of stress granule (SG) formation. IMPORTANCE This study (i) extends previous work that showed TIA-1/TIAR recruitment at sites of flavivirus replication, (ii) demonstrates that TIAR behaves like TIA-1 as an inhibitor of viral replication using an RNA interference (RNAi) approach in human cells that contradicts the previous hypothesis based on mouse embryonic fibroblast (MEF) knockouts only, (iii) demonstrates that tick-borne encephalitis virus (TBEV) is capable of inducing bona fide G3BP1/eIF3/eIF4B-positive stress granules, (iv) demonstrates a differential phenotype of stress response proteins following viral infection, and (v) implicates TIA-1 in viral translation and as a modulator of TBEV replication. PMID:24696465

The stress granule component TIA-1 binds tick-borne encephalitis virus RNA and is recruited to perinuclear sites of viral replication to inhibit viral translation.

PubMed

Albornoz, Amelina; Carletti, Tea; Corazza, Gianmarco; Marcello, Alessandro

2014-06-01

Flaviviruses are a major cause of disease in humans and animals worldwide. Tick-borne encephalitis virus (TBEV) is the most important arthropod-borne flavivirus endemic in Europe and is the etiological agent of tick-borne encephalitis, a potentially fatal infection of the central nervous system. However, the contributions of host proteins during TBEV infection are poorly understood. In this work, we investigate the cellular protein TIA-1 and its cognate factor TIAR, which are stress-induced RNA-binding proteins involved in the repression of initiation of translation of cellular mRNAs and in the formation of stress granules. We show that TIA-1 and TIAR interact with viral RNA in TBEV-infected cells. During TBEV infection, cytoplasmic TIA-1 and TIAR are recruited at sites of viral replication with concomitant depletion from stress granules. This effect is specific, since G3BP1, another component of these cytoplasmic structures, remains localized to stress granules. Moreover, heat shock induction of stress granules containing TIA-1, but not G3BP1, is inhibited in TBEV-infected cells. Infection of cells depleted of TIA-1 or TIAR by small interfering RNA (siRNA) or TIA-1(-/-) mouse fibroblasts, leads to a significant increase in TBEV extracellular infectivity. Interestingly, TIAR(-/-) fibroblasts show the opposite effect on TBEV infection, and this phenotype appears to be related to an excess of TIA-1 in these cells. Taking advantage of a TBE-luciferase replicon system, we also observed increased luciferase activity in TIA-1(-/-) mouse fibroblasts at early time points, consistent with TIA-1-mediated inhibition at the level of the first round of viral translation. These results indicate that, in response to TBEV infection, TIA-1 is recruited to sites of virus replication to bind TBEV RNA and modulate viral translation independently of stress granule (SG) formation. This study (i) extends previous work that showed TIA-1/TIAR recruitment at sites of flavivirus replication, (ii) demonstrates that TIAR behaves like TIA-1 as an inhibitor of viral replication using an RNA interference (RNAi) approach in human cells that contradicts the previous hypothesis based on mouse embryonic fibroblast (MEF) knockouts only, (iii) demonstrates that tick-borne encephalitis virus (TBEV) is capable of inducing bona fide G3BP1/eIF3/eIF4B-positive stress granules, (iv) demonstrates a differential phenotype of stress response proteins following viral infection, and (v) implicates TIA-1 in viral translation and as a modulator of TBEV replication. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Vesicular stomatitis virus infects resident cells of the central nervous system and induces replication-dependent inflammatory responses

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

Chauhan, Vinita S.; Furr, Samantha R.; Sterka, David G.

2010-05-10

Vesicular stomatitis virus (VSV) infection of mice via intranasal administration results in a severe encephalitis with rapid activation and proliferation of microglia and astrocytes. We have recently shown that these glial cells express RIG-I and MDA5, cytosolic pattern recognition receptors for viral RNA. However, it is unclear whether VSV can replicate in glial cells or if such replication is required for their inflammatory responses. Here we demonstrate that primary microglia and astrocytes are permissive for VSV infection and limited productive replication. Importantly, we show that viral replication is required for robust inflammatory mediator production by these cells. Finally, we havemore » confirmed that in vivo VSV administration can result in viral infection of glial cells in situ. These results suggest that viral replication within resident glial cells might play an important role in CNS inflammation following infection with VSV and possibly other neurotropic nonsegmented negative-strand RNA viruses.« less

p53 Is a Host Cell Regulator during Herpes Simplex Encephalitis.

PubMed

Maruzuru, Yuhei; Koyanagi, Naoto; Takemura, Naoki; Uematsu, Satoshi; Matsubara, Daisuke; Suzuki, Yutaka; Arii, Jun; Kato, Akihisa; Kawaguchi, Yasushi

2016-08-01

p53 is a critical host cell factor in the cellular response to a broad range of stress factors. We recently reported that p53 is required for efficient herpes simplex virus 1 (HSV-1) replication in cell culture. However, a defined role for p53 in HSV-1 replication and pathogenesis in vivo remains elusive. In this study, we examined the effects of p53 on HSV-1 infection in vivo using p53-deficient mice. Following intracranial inoculation, p53 knockout reduced viral replication in the brains of mice and led to significantly reduced rates of mortality due to herpes simplex encephalitis. These results suggest that p53 is an important host cell regulator of HSV-1 replication and pathogenesis in the central nervous system (CNS). HSV-1 causes sporadic cases of encephalitis, which, even with antiviral therapy, can result in severe neurological defects and even death. Many host cell factors involved in the regulation of CNS HSV-1 infection have been investigated using genetically modified mice. However, most of these factors are immunological regulators and act via immunological pathways in order to restrict CNS HSV-1 infection. They therefore provide limited information on intrinsic host cell regulators that may be involved in the facilitation of CNS HSV-1 infection. Here we demonstrate that a host cell protein, p53, which has generally been considered a host cell restriction factor for various viral infections, is required for efficient HSV-1 replication and pathogenesis in the CNS of mice. This is the first report showing that p53 positively regulates viral replication and pathogenesis in vivo and provides insights into its molecular mechanism, which may suggest novel clinical treatment options for herpes simplex encephalitis. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Functional Information Stored in the Conserved Structural RNA Domains of Flavivirus Genomes

PubMed Central

Fernández-Sanlés, Alba; Ríos-Marco, Pablo; Romero-López, Cristina; Berzal-Herranz, Alfredo

2017-01-01

The genus Flavivirus comprises a large number of small, positive-sense single-stranded, RNA viruses able to replicate in the cytoplasm of certain arthropod and/or vertebrate host cells. The genus, which has some 70 member species, includes a number of emerging and re-emerging pathogens responsible for outbreaks of human disease around the world, such as the West Nile, dengue, Zika, yellow fever, Japanese encephalitis, St. Louis encephalitis, and tick-borne encephalitis viruses. Like other RNA viruses, flaviviruses have a compact RNA genome that efficiently stores all the information required for the completion of the infectious cycle. The efficiency of this storage system is attributable to supracoding elements, i.e., discrete, structural units with essential functions. This information storage system overlaps and complements the protein coding sequence and is highly conserved across the genus. It therefore offers interesting potential targets for novel therapeutic strategies. This review summarizes our knowledge of the features of flavivirus genome functional RNA domains. It also provides a brief overview of the main achievements reported in the design of antiviral nucleic acid-based drugs targeting functional genomic RNA elements. PMID:28421048

Defining Hsp70 Subnetworks in Dengue Virus Replication Reveals Key Vulnerability in Flavivirus Infection.

PubMed

Taguwa, Shuhei; Maringer, Kevin; Li, Xiaokai; Bernal-Rubio, Dabeiba; Rauch, Jennifer N; Gestwicki, Jason E; Andino, Raul; Fernandez-Sesma, Ana; Frydman, Judith

2015-11-19

Viral protein homeostasis depends entirely on the machinery of the infected cell. Accordingly, viruses can illuminate the interplay between cellular proteostasis components and their distinct substrates. Here, we define how the Hsp70 chaperone network mediates the dengue virus life cycle. Cytosolic Hsp70 isoforms are required at distinct steps of the viral cycle, including entry, RNA replication, and virion biogenesis. Hsp70 function at each step is specified by nine distinct DNAJ cofactors. Of these, DnaJB11 relocalizes to virus-induced replication complexes to promote RNA synthesis, while DnaJB6 associates with capsid protein and facilitates virion biogenesis. Importantly, an allosteric Hsp70 inhibitor, JG40, potently blocks infection of different dengue serotypes in human primary blood cells without eliciting viral resistance or exerting toxicity to the host cells. JG40 also blocks replication of other medically-important flaviviruses including yellow fever, West Nile and Japanese encephalitis viruses. Thus, targeting host Hsp70 subnetworks provides a path for broad-spectrum antivirals. Copyright © 2015 Elsevier Inc. All rights reserved.

Inhibition of West Nile Virus replication by retrovirus-delivered small interfering RNA in human neuroblastoma cells.

PubMed

Yang, Yongbo; Wu, Chengxiang; Wu, Jianguo; Nerurkar, Vivek R; Yanagihara, Richard; Lu, Yuanan

2008-05-01

West Nile virus (WNV) has been responsible for the largest outbreaks of arboviral encephalitis in U.S. history. No specific drug is currently available for the effective treatment of WNV infection. To exploit RNA interference as a potential therapeutic approach, a Moloney murine leukemia virus-based retrovirus vector was used to effectively deliver WNV-specific small interfering RNA (siRNA) into human neuroblastoma HTB-11 cells. Viral plaque assays demonstrated that transduced cells were significantly refractory to WNV replication, as compared to untransduced control cells (P < 0.05), which correlated with the reduced expression of target viral genes and respective viral proteins. Therefore, retrovirus-mediated delivery of siRNA for gene silencing can be used to study the specific functions of viral genes associated with replication and may have potential therapeutic applications.

Complete inactivation of Venezuelan equine encephalitis virus by 1,5-iodonaphthylazide

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

Sharma, Anuj; Birla Institute of Technology and Science, Pilani; Raviv, Yossef

2007-06-29

Hydrophobic alkylating compounds like 1,5-iodonaphthylazide (INA) partitions into biological membranes and accumulates selectively into the hydrophobic domain of the lipid bilayer. Upon irradiation with far UV light, INA binds selectively to transmembrane proteins in the viral envelope and renders them inactive. Such inactivation does not alter the ectodomains of the membrane proteins thus preserving the structural and conformational integrity of immunogens on the surface of the virus. In this study, we have used INA to inactivate Venezuelan equine encephalitis virus (VEEV). Treatment of VEEV with INA followed by irradiation with UV light resulted in complete inactivation of the virus. Immuno-fluorescencemore » for VEEV and virus titration showed no virus replication in-vitro. Complete loss of infectivity was also achieved in mice infected with INA treated plus irradiated preparations of VEEV. No change in the structural integrity of VEEV particles were observed after treatment with INA plus irradiation as assessed by electron microscopy. This data suggest that such inactivation strategies can be used for developing vaccine candidates for VEEV and other enveloped viruses.« less

Experimental infection and natural contact exposure of ferrets with canine influenza virus (H3N2).

PubMed

Lee, Yu-Na; Lee, Dong-Hun; Park, Jae-Keun; Yuk, Seong-Su; Kwon, Jung-Hoon; Nahm, Sang-Soep; Lee, Joong-Bok; Park, Seung-Yong; Choi, In-Soo; Song, Chang-Seon

2013-02-01

Epidemics of H3N2 canine influenza virus (CIV) among dogs in South Korea and southern China have raised concern over the potential for zoonotic transmission of these viruses. Here, we analysed the pathogenesis and transmissibility of H3N2 CIV in ferret. H3N2 CIV replicated efficiently in the respiratory system of inoculated ferrets and caused acute necrotizing bronchioalveolitis and non-suppurative encephalitis. Transmission of H3N2 CIV was detected in three of six ferrets co-housed with inoculated ferrets, but no viruses were detected in second-contact ferrets. These findings show that H3N2 CIV has the capacity to replicate in and transmit partially among co-housed ferrets and underscore the need for continued public health surveillance.

Vectors expressing chimeric Japanese encephalitis dengue 2 viruses.

PubMed

Wei, Y; Wang, S; Wang, X

2014-01-01

Vectors based on self-replicating RNAs (replicons) of flaviviruses are becoming powerful tool for expression of heterologous genes in mammalian cells and development of novel antiviral and anticancer vaccines. We constructed two vectors expressing chimeric viruses consisting of attenuated SA14-14-2 strain of Japanese encephalitis virus (JEV) in which the PrM/M-E genes were replaced fully or partially with those of dengue 2 virus (DENV-2). These vectors, named pJED2 and pJED2-1770 were transfected to BHK-21 cells and produced chimeric viruses JED2V and JED2-1770V, respectively. The chimeric viruses could be passaged in C6/36 but not BHK-21 cells. The chimeric viruses produced in C6/36 cells CPE 4-5 days after infection and RT-PCR, sequencing, immunofluorescence assay (IFA) and Western blot analysis confirmed the chimeric nature of produced viruses. The immunogenicity of chimeric viruses in mice was proved by detecting DENV-2 E protein-specific serum IgG antibodies with neutralization titer of 10. Successful preparation of infectious clones of chimeric JEV-DENV-2 viruses showed that JEV-based expression vectors are fully functional.

Purification and crystallization of Kokobera virus helicase

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

De Colibus, Luigi; Speroni, Silvia; Coutard, Bruno

2007-03-01

Kokobera virus is a mosquito-borne flavivirus belonging, like West Nile virus, to the Japanese encephalitis virus serocomplex. Crystals of the Kokobera virus helicase domain were obtained by the hanging-drop vapour-diffusion method and exhibit a diffraction limit of 2.3 Å. Kokobera virus is a mosquito-borne flavivirus belonging, like West Nile virus, to the Japanese encephalitis virus serocomplex. The flavivirus genus is characterized by a positive-sense single-stranded RNA genome. The unique open reading frame of the viral RNA is transcribed and translated as a single polyprotein which is post-translationally cleaved to yield three structural and seven nonstructural proteins, one of which ismore » the NS3 gene that encodes a C-terminal helicase domain consisting of 431 amino acids. Helicase inhibitors are potential antiviral drugs as the helicase is essential to viral replication. Crystals of the Kokobera virus helicase domain were obtained by the hanging-drop vapour-diffusion method. The crystals belong to space group P3{sub 1}21 (or P3{sub 2}21), with unit-cell parameters a = 88.6, c = 138.6 Å, and exhibit a diffraction limit of 2.3 Å.« less

Interaction of Flaviviruses with Reproduction Inhibitors Binding in β-OG Pocket: Insights from Molecular Dynamics Simulations.

PubMed

Dueva, Evgenia V; Osolodkin, Dmitry I; Kozlovskaya, Liubov I; Palyulin, Vladimir A; Pentkovski, Vladimir M; Zefirov, Nikolay S

2014-10-01

Flaviviral diseases, including dengue fever, West Nile fever, yellow fever, tick-borne encephalitis, Omsk haemorrhagic fever, and Powassan encephalitis, threaten human health all over the world. Lack of effective antivirals targeting replication cycle of flaviviruses makes the search of such compounds a challenging task. Recently we have identified a reproduction inhibitor effective against tick-borne encephalitis virus and Powassan virus (POWV) (ACS Med. Chem. Lett., 2013, 4, 869-874). To enable using this inhibitor as a template for 3D pharmacophore search, a biologically active conformation of this molecule should have been established. Here we performed molecular dynamics simulations of the complexes between the different enantiomers of the inhibitor and POWV envelope (E) proteins, putative targets of the inhibitor, in the different protonation states corresponding to the different stages of membrane fusion process. Several stable conformations of the inhibitor were identified, opening routes for further design of more advanced molecules. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

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

Zhao, Baoyu; Yi, Guanghui; Du, Fenglei

The recent outbreak of Zika virus (ZIKV) has infected over 1 million people in over 30 countries. ZIKV replicates its RNA genome using virally encoded replication proteins. Nonstructural protein 5 (NS5) contains a methyltransferase for RNA capping and a polymerase for viral RNA synthesis. Here we report the crystal structures of full-length NS5 and its polymerase domain at 3.0 Å resolution. The NS5 structure has striking similarities to the NS5 protein of the related Japanese encephalitis virus. The methyltransferase contains in-line pockets for substrate binding and the active site. Key residues in the polymerase are located in similar positions tomore » those of the initiation complex for the hepatitis C virus polymerase. The polymerase conformation is affected by the methyltransferase, which enables a more efficiently elongation of RNA synthesis in vitro. Altogether, our results will contribute to future studies on ZIKV infection and the development of inhibitors of ZIKV replication.« less

Crystal structure of full-length Zika virus NS5 protein reveals a conformation similar to Japanese encephalitis virus NS5

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

Upadhyay, Anup K.; Cyr, Matthew; Longenecker, Kenton

The rapid spread of the recentZika virus(ZIKV) epidemic across various countries in the American continent poses a major health hazard for the unborn fetuses of pregnant women. To date, there is no effective medical intervention. The nonstructural protein 5 ofZika virus(ZIKV-NS5) is critical for ZIKV replication through the 5'-RNA capping and RNA polymerase activities present in its N-terminal methyltransferase (MTase) and C-terminal RNA-dependent RNA polymerase (RdRp) domains, respectively. The crystal structure of the full-length ZIKV-NS5 protein has been determined at 3.05 Å resolution from a crystal belonging to space groupP2 12 12 and containing two protein molecules in the asymmetricmore » unit. The structure is similar to that reported for the NS5 protein fromJapanese encephalitis virusand suggests opportunities for structure-based drug design targeting either its MTase or RdRp domain.« less

The efficient packaging of Venezuelan equine encephalitis virus-specific RNAs into viral particles is determined by nsP1–3 synthesis

PubMed Central

Volkova, Eugenia; Gorchakov, Rodion; Frolov, Ilya

2008-01-01

Alphaviruses are regarded as attractive systems for expression of heterologous genes and development of recombinant vaccines. Venezuelan equine encephalitis virus (VEE)-based vectors are particularly promising because of their specificity to lymphoid tissues and strong resistance to interferon. To improve understanding of the VEE genome packaging and optimize application of this virus as a vector, we analyzed in more detail the mechanism of packaging of the VEE-specific RNAs. The presence of the RNAs in the VEE particles during serial passaging in tissue culture was found to depend not only on the presence of packaging signal(s), but also on the ability of these RNAs to express in cis nsP1, nsP2 and nsP3 in the form of a P123 precursor. Packaging of VEE genomes into infectious virions was also found to be more efficient compared to that of Sindbis virus, in spite of lower levels of RNA replication and structural protein production. PMID:16239019

A Genome-Wide RNA Interference Screen Identifies a Role for Wnt/β-Catenin Signaling during Rift Valley Fever Virus Infection.

PubMed

Harmon, Brooke; Bird, Sara W; Schudel, Benjamin R; Hatch, Anson V; Rasley, Amy; Negrete, Oscar A

2016-08-15

Rift Valley fever virus (RVFV) is an arbovirus within the Bunyaviridae family capable of causing serious morbidity and mortality in humans and livestock. To identify host factors involved in bunyavirus replication, we employed genome-wide RNA interference (RNAi) screening and identified 381 genes whose knockdown reduced infection. The Wnt pathway was the most represented pathway when gene hits were functionally clustered. With further investigation, we found that RVFV infection activated Wnt signaling, was enhanced when Wnt signaling was preactivated, was reduced with knockdown of β-catenin, and was blocked using Wnt signaling inhibitors. Similar results were found using distantly related bunyaviruses La Crosse virus and California encephalitis virus, suggesting a conserved role for Wnt signaling in bunyaviral infection. We propose a model where bunyaviruses activate Wnt-responsive genes to regulate optimal cell cycle conditions needed to promote efficient viral replication. The findings in this study should aid in the design of efficacious host-directed antiviral therapeutics. RVFV is a mosquito-borne bunyavirus that is endemic to Africa but has demonstrated a capacity for emergence in new territories (e.g., the Arabian Peninsula). As a zoonotic pathogen that primarily affects livestock, RVFV can also cause lethal hemorrhagic fever and encephalitis in humans. Currently, there are no treatments or fully licensed vaccines for this virus. Using high-throughput RNAi screening, we identified canonical Wnt signaling as an important host pathway regulating RVFV infection. The beneficial role of Wnt signaling was observed for RVFV, along with other disparate bunyaviruses, indicating a conserved bunyaviral replication mechanism involving Wnt signaling. These studies supplement our knowledge of the fundamental mechanisms of bunyavirus infection and provide new avenues for countermeasure development against pathogenic bunyaviruses. Copyright © 2016 Harmon et al.

A genome-wide RNA interference screen identifies a role for Wnt/β-catenin signaling during Rift Valley Fever Virus infection

DOE PAGES

Harmon, Brooke; Bird, Sara W.; Schudel, Benjamin R.; ...

2016-05-25

Rift Valley fever virus (RVFV) is an arbovirus within the Bunyaviridae family capable of causing serious morbidity and mortality in humans and livestock. To identify host factors involved in bunyavirus replication, we employed genome-wide RNA interference (RNAi) screening and identified 381 genes whose knockdown reduced infection. The Wnt pathway was the most represented pathway when gene hits were functionally clustered. With further investigation, we found that RVFV infection activated Wnt signaling, was enhanced when Wnt signaling was preactivated, was reduced with knockdown of β-catenin, and was blocked using Wnt signaling inhibitors. Similar results were found using distantly related bunyaviruses Lamore » Crosse virus and California encephalitis virus, suggesting a conserved role for Wnt signaling in bunyaviral infection. We propose a model where bunyaviruses activate Wnt-responsive genes to regulate optimal cell cycle conditions needed to promote efficient viral replication. The findings in this study should aid in the design of efficacious host-directed antiviral therapeutics. IMPORTANCE RVFV is a mosquito-borne bunyavirus that is endemic to Africa but has demonstrated a capacity for emergence in new territories (e.g., the Arabian Peninsula). As a zoonotic pathogen that primarily affects livestock, RVFV can also cause lethal hemorrhagic fever and encephalitis in humans. Currently, there are no treatments or fully licensed vaccines for this virus. Using high-throughput RNAi screening, we identified canonical Wnt signaling as an important host pathway regulating RVFV infection. The beneficial role of Wnt signaling was observed for RVFV, along with other disparate bunyaviruses, indicating a conserved bunyaviral replication mechanism involving Wnt signaling. Lastly, these studies supplement our knowledge of the fundamental mechanisms of bunyavirus infection and provide new avenues for countermeasure development against pathogenic bunyaviruses.« less

Low-fidelity Venezuelan equine encephalitis virus polymerase mutants to improve live-attenuated vaccine safety and efficacy

PubMed Central

Kautz, Tiffany F; Guerbois, Mathilde; Khanipov, Kamil; Yun, Ruimei; Warmbrod, Kelsey L; Fofanov, Yuriy; Weaver, Scott C; Forrester, Naomi L

2018-01-01

Abstract During RNA virus replication, there is the potential to incorporate mutations that affect virulence or pathogenesis. For live-attenuated vaccines, this has implications for stability, as replication may result in mutations that either restore the wild-type phenotype via reversion or compensate for the attenuating mutations by increasing virulence (pseudoreversion). Recent studies have demonstrated that altering the mutation rate of an RNA virus is an effective attenuation tool. To validate the safety of low-fidelity mutations to increase vaccine attenuation, several mutations in the RNA-dependent RNA-polymerase (RdRp) were tested in the live-attenuated Venezuelan equine encephalitis virus vaccine strain, TC-83. Next generation sequencing after passage in the presence of mutagens revealed a mutant containing three mutations in the RdRp, TC-83 3x, to have decreased replication fidelity, while a second mutant, TC-83 4x displayed no change in fidelity, but shared many phenotypic characteristics with TC-83 3x. Both mutants exhibited increased, albeit inconsistent attenuation in an infant mouse model, as well as increased immunogenicity and complete protection against lethal challenge of an adult murine model compared with the parent TC-83. During serial passaging in a highly permissive model, the mutants increased in virulence but remained less virulent than the parent TC-83. These results suggest that the incorporation of low-fidelity mutations into the RdRp of live-attenuated vaccines for RNA viruses can confer increased immunogenicity whilst showing some evidence of increased attenuation. However, while in theory such constructs may result in more effective vaccines, the instability of the vaccine phenotype decreases the likelihood of this being an effective vaccine strategy. PMID:29593882

A genome-wide RNA interference screen identifies a role for Wnt/β-catenin signaling during Rift Valley Fever Virus infection

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

Harmon, Brooke; Bird, Sara W.; Schudel, Benjamin R.

Rift Valley fever virus (RVFV) is an arbovirus within the Bunyaviridae family capable of causing serious morbidity and mortality in humans and livestock. To identify host factors involved in bunyavirus replication, we employed genome-wide RNA interference (RNAi) screening and identified 381 genes whose knockdown reduced infection. The Wnt pathway was the most represented pathway when gene hits were functionally clustered. With further investigation, we found that RVFV infection activated Wnt signaling, was enhanced when Wnt signaling was preactivated, was reduced with knockdown of β-catenin, and was blocked using Wnt signaling inhibitors. Similar results were found using distantly related bunyaviruses Lamore » Crosse virus and California encephalitis virus, suggesting a conserved role for Wnt signaling in bunyaviral infection. We propose a model where bunyaviruses activate Wnt-responsive genes to regulate optimal cell cycle conditions needed to promote efficient viral replication. The findings in this study should aid in the design of efficacious host-directed antiviral therapeutics. IMPORTANCE RVFV is a mosquito-borne bunyavirus that is endemic to Africa but has demonstrated a capacity for emergence in new territories (e.g., the Arabian Peninsula). As a zoonotic pathogen that primarily affects livestock, RVFV can also cause lethal hemorrhagic fever and encephalitis in humans. Currently, there are no treatments or fully licensed vaccines for this virus. Using high-throughput RNAi screening, we identified canonical Wnt signaling as an important host pathway regulating RVFV infection. The beneficial role of Wnt signaling was observed for RVFV, along with other disparate bunyaviruses, indicating a conserved bunyaviral replication mechanism involving Wnt signaling. Lastly, these studies supplement our knowledge of the fundamental mechanisms of bunyavirus infection and provide new avenues for countermeasure development against pathogenic bunyaviruses.« less

Structure and function of the Zika virus full-length NS5 protein

DOE PAGES

Zhao, Baoyu; Yi, Guanghui; Du, Fenglei; ...

2017-03-27

The recent outbreak of Zika virus (ZIKV) has infected over 1 million people in over 30 countries. ZIKV replicates its RNA genome using virally encoded replication proteins. Nonstructural protein 5 (NS5) contains a methyltransferase for RNA capping and a polymerase for viral RNA synthesis. Here we report the crystal structures of full-length NS5 and its polymerase domain at 3.0 Å resolution. The NS5 structure has striking similarities to the NS5 protein of the related Japanese encephalitis virus. The methyltransferase contains in-line pockets for substrate binding and the active site. Key residues in the polymerase are located in similar positions tomore » those of the initiation complex for the hepatitis C virus polymerase. The polymerase conformation is affected by the methyltransferase, which enables a more efficiently elongation of RNA synthesis in vitro. Altogether, our results will contribute to future studies on ZIKV infection and the development of inhibitors of ZIKV replication.« less

Herpes simplex virus serotype and entry receptor availability alter CNS disease in a mouse model of neonatal HSV.

PubMed

Kopp, Sarah J; Ranaivo, Hantamalala R; Wilcox, Douglas R; Karaba, Andrew H; Wainwright, Mark S; Muller, William J

2014-12-01

Outcomes of neonates with herpes simplex virus (HSV) encephalitis are worse after infection with HSV-2 when compared with HSV-1. The proteins herpes virus entry mediator (HVEM) and nectin-1 mediate HSV entry into susceptible cells. Prior studies have shown receptor-dependent differences in pathogenesis that depend on route of inoculation and host developmental age. We investigated serotype-related differences in HSV disease and their relationship to entry receptor availability in a mouse model of encephalitis. Mortality was attenuated in 7-d-old, wild-type (WT) mice inoculated with HSV-1(F) when compared with HSV-2(333). No serotype-specific differences were seen after inoculation of adult mice. HSV-1 pathogenesis was also attenuated relative to HSV-2 in newborn but not adult mice lacking HVEM or nectin-1. HSV-2 requires nectin-1 for encephalitis in adult but not newborn mice; in contrast, nectin-1 was important for HSV-1 pathogenesis in both age groups. Early viral replication was independent of age, viral serotype, or mouse genotype, suggesting host responses influence outcomes. In this regard, significantly greater amounts of inflammatory mediators were detected in brain homogenates from WT newborns 2 d after infection compared with adults and receptor-knockout newborns. Dysregulation of inflammatory responses induced by infection may influence the severity of HSV encephalitis.

Host Translation Shutoff Mediated by Non-structural Protein 2 is a Critical Factor in the Antiviral State Resistance of Venezuelan Equine Encephalitis Virus

PubMed Central

Bhalla, Nishank; Sun, Chengqun; Lam, L. K. Metthew; Gardner, Christina L.; Ryman, Kate D.; Klimstra, William B.

2016-01-01

Most previous studies of interferon-alpha/beta (IFN-α/β) response antagonism by alphaviruses have focused upon interruption of IFN-α/β induction and/or receptor signaling cascades. Infection of mice with Venezuelan equine encephalitis alphavirus (VEEV) or Sindbis virus (SINV) induces serum IFN-α/β, that elicits a systemic antiviral state in uninfected cells successfully controlling SINV but not VEEV replication. Furthermore, VEEV replication is more resistant than that of SINV to a pre-existing antiviral state in vitro. While host macromolecular shutoff is proposed as a major antagonist of IFN-α/β induction, the underlying mechanisms of alphavirus resistance to a pre-existing antiviral state are not fully defined, nor is the mechanism for the greater resistance of VEEV. Here, we have separated viral transcription and translation shutoff with multiple alphaviruses, identified the viral proteins that induce each activity, and demonstrated that VEEV nonstructural protein 2-induced translation shutoff is likely a critical factor in enhanced antiviral state resistance of this alphavirus. PMID:27318152

Molecular targets for flavivirus drug discovery

PubMed Central

Sampath, Aruna; Padmanabhan, R.

2009-01-01

Flaviviruses are a major cause of infectious disease in humans. Dengue virus causes an estimated 50 million cases of febrile illness each year, including an increasing number of cases of hemorrhagic fever. West Nile virus, which recently spread from the Mediterranean basin to the Western Hemisphere, now causes thousands of sporadic cases of encephalitis annually. Despite the existence of licensed vaccines, yellow fever, Japanese encephalitis and tick-borne encephalitis also claim many thousands of victims each year across their vast endemic areas. Antiviral therapy could potentially reduce morbidity and mortality from flavivirus infections, but no effective drugs are currently available. This article introduces a collection of papers in Antiviral Research on molecular targets for flavivirus antiviral drug design and murine models of dengue virus disease that aims to encourage drug development efforts. After reviewing the flavivirus replication cycle, we discuss the envelope glycoprotein, NS3 protease, NS3 helicase, NS5 methyltransferase and NS5 RNA-dependent RNA polymerase as potential drug targets, with special attention being given to the viral protease. The other viral proteins are the subject of individual articles in the journal. Together, these papers highlight current status of drug discovery efforts for flavivirus diseases and suggest promising areas for further research. PMID:18796313

Adaptation of tick-borne encephalitis virus from human brain to different cell cultures induces multiple genomic substitutions.

PubMed

Ponomareva, Eugenia P; Ternovoi, Vladimir A; Mikryukova, Tamara P; Protopopova, Elena V; Gladysheva, Anastasia V; Shvalov, Alexander N; Konovalova, Svetlana N; Chausov, Eugene V; Loktev, Valery B

2017-10-01

The C11-13 strain from the Siberian subtype of tick-borne encephalitis virus (TBEV) was isolated from human brain using pig embryo kidney (PEK), 293, and Neuro-2a cells. Analysis of the complete viral genome of the C11-13 variants during six passages in these cells revealed that the cell-adapted C11-13 variants had multiple amino acid substitutions as compared to TBEV from human brain. Seven out of eight amino acids substitutions in the high-replicating C11-13(PEK) variant mapped to non-structural proteins; 13 out of 14 substitutions in the well-replicating C11-13(293) variant, and all four substitutions in the low-replicating C11-13(Neuro-2a) variant were also localized in non-structural proteins, predominantly in the NS2a (2), NS3 (6) and NS5 (3) proteins. The substitutions NS2a 1067 (Asn → Asp), NS2a 1168 (Leu → Val) in the N-terminus of NS2a and NS3 1745 (His → Gln) in the helicase domain of NS3 were found in all selected variants. We postulate that multiple substitutions in the NS2a, NS3 and NS5 genes play a key role in adaptation of TBEV to different cells.

Adaptor protein complexes-1 and 3 are involved at distinct stages of flavivirus life-cycle

PubMed Central

Agrawal, Tanvi; Schu, Peter; Medigeshi, Guruprasad R.

2013-01-01

Intracellular protein trafficking pathways are hijacked by viruses at various stages of viral life-cycle. Heterotetrameric adaptor protein complexes (APs) mediate vesicular trafficking at distinct intracellular sites and are essential for maintaining the organellar homeostasis. In the present study, we studied the effect of AP-1 and AP-3 deficiency on flavivirus infection in cells functionally lacking these proteins. We show that AP-1 and AP-3 participate in flavivirus life-cycle at distinct stages. AP-3-deficient cells showed delay in initiation of Japanese encephalitis virus and dengue virus RNA replication, which resulted in reduction of infectious virus production. AP-3 was found to colocalize with RNA replication compartments in infected wild-type cells. AP-1 deficiency affected later stages of dengue virus infection where increased intracellular accumulation of infectious virus was observed. Therefore, our results propose a novel role for AP-1 and AP-3 at distinct stages of infection of some of the RNA viruses. PMID:23657274

Adaptor protein complexes-1 and 3 are involved at distinct stages of flavivirus life-cycle.

PubMed

Agrawal, Tanvi; Schu, Peter; Medigeshi, Guruprasad R

2013-01-01

Intracellular protein trafficking pathways are hijacked by viruses at various stages of viral life-cycle. Heterotetrameric adaptor protein complexes (APs) mediate vesicular trafficking at distinct intracellular sites and are essential for maintaining the organellar homeostasis. In the present study, we studied the effect of AP-1 and AP-3 deficiency on flavivirus infection in cells functionally lacking these proteins. We show that AP-1 and AP-3 participate in flavivirus life-cycle at distinct stages. AP-3-deficient cells showed delay in initiation of Japanese encephalitis virus and dengue virus RNA replication, which resulted in reduction of infectious virus production. AP-3 was found to colocalize with RNA replication compartments in infected wild-type cells. AP-1 deficiency affected later stages of dengue virus infection where increased intracellular accumulation of infectious virus was observed. Therefore, our results propose a novel role for AP-1 and AP-3 at distinct stages of infection of some of the RNA viruses.

Tick-borne flavivirus infection in Ixodes scapularis larvae: development of a novel method for synchronous viral infection of ticks

PubMed Central

Mitzel, Dana N.; Wolfinbarger, James B.; Daniel Long, R.; Masnick, Max; Best, Sonja M.; Bloom, Marshall E.

2007-01-01

Following a bite from an infected tick, tick-borne flaviviruses cause encephalitis, meningitis and hemorrhagic fever in humans. Although these viruses spend most of their time in the tick, little is known regarding the virus-vector interactions. We developed a simple method for synchronously infecting Ixodes scapularis larvae with Langat virus (LGTV) by immersion in media containing the virus. This technique resulted in approximately 96% of ticks becoming infected. LGTV infection and replication were demonstrated by both viral antigen expression and the accumulation of viral RNA. Furthermore, ticks transmitted LGTV to 100% of the mice and maintained the virus through molting into the next life stage. This technique circumvents limitations present in the current methods by mimicking the natural route of infection and by using attenuated virus strains to infect ticks; thereby, making this technique a powerful tool to study both virus and tick determinants of replication, pathogenesis and transmission. PMID:17490700

Activation/proliferation and apoptosis of bystander goat lymphocytes induced by a macrophage-tropic chimeric caprine arthritis encephalitis virus expressing SIV Nef

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

Bouzar, Baya Amel; Rea, Angela; Hoc-Villet, Stephanie

Caprine arthritis encephalitis virus (CAEV) is the natural lentivirus of goats, well known for its tropism for macrophages and its inability to cause infection in lymphocytes. The viral genome lacks nef, tat, vpu and vpx coding sequences. To test the hypothesis that when nef is expressed by the viral genome, the virus became toxic for lymphocytes during replication in macrophages, we inserted the SIVsmm PBj14 nef coding sequences into the genome of CAEV thereby generating CAEV-nef. This recombinant virus is not infectious for lymphocytes but is fully replication competent in goat macrophages in which it constitutively expresses the SIV Nef.more » We found that goat lymphocytes cocultured with CAEV-nef-infected macrophages became activated, showing increased expression of the interleukin-2 receptor (IL-2R). Activation correlated with increased proliferation of the cells. Interestingly, a dual effect in terms of apoptosis regulation was observed in exposed goat lymphocytes. Nef was found first to induce a protection of lymphocytes from apoptosis during the first few days following exposure to infected macrophages, but later it induced increased apoptosis in the activated lymphocytes. This new recombinant virus provides a model to study the functions of Nef in the context of infection of macrophages, but in absence of infection of T lymphocytes and brings new insights into the biological effects of Nef on lymphocytes.« less

Effects of RNA interference therapy against herpes simplex virus type 1 encephalitis.

PubMed

da Silva, Alexandre S; Raposo, Jéssica V; Pereira, Tiago C; Pinto, Marcelo A; de Paula, Vanessa S

2016-01-01

Herpetic encephalitis (HSE) is caused mainly by herpes simplex virus type 1 (HSV-1) with an annual incidence of 1-4 cases/million inhabitants. Currently, HSE treatment faces difficulties such as the use of antivirals with elevated toxicity, metabolic side effects and HSV-1 resistance. An alternative to antivirals is the use of small interfering RNA (siRNA) as a viral replication inhibitor. In this work, siRNA targeting the UL-39 region was evaluated for HSE treatment in vivo. BALB/c mice were inoculated with HSV-1 and treated with siRNA. The treatment was evaluated through kinetics of HSV-1 replication inhibition, number of siRNA doses administered and treatment with siRNA plus acyclovir. All groups were evaluated for signs of HSE, mortality and HSV-1 replication inhibition. The treated group of the kinetic experiment demonstrated a reduction of HSE signs and an HSV-1 replication inhibition of 43.6-99.9% in the brain and 53-98% in trigeminal ganglia (TG). Animals treated with one or two doses of siRNA had a prolonged survival time, reduced clinical signs of HSE and HSV-1 replication inhibition of 67.7% in brains and 85.7% in TG of animals treated with two doses of siRNA. Also, animals treated with siRNA plus acyclovir demonstrated reduced signs of HSE and mortality, as well as HSV-1 replication inhibition in the brain (83.2%) and TG (74.5%). These findings demonstrated that siRNA was capable of reducing HSE clinical signs, prolonging survival time and inhibiting HSV-1 replication in mice. Thus, siRNA can be a potential alternative to the standard HSE treatment especially to reduce clinical signs and extend survival time in vivo.

Antiviral macrophage responses in flavivirus encephalitis

PubMed Central

Ashhurst, Thomas Myles; van Vreden, Caryn; Munoz-Erazo, Luis; Niewold, Paula; Watabe, Kanami; Terry, Rachael L.; Deffrasnes, Celine; Getts, Daniel R.; King, Nicholas Jonathan Cole

2013-01-01

Mosquito-borne flaviviruses are a major current and emerging threat, affecting millions of people worldwide. Global climate change, combined with increasing proximity of humans to animals and mosquito vectors by expansion into natural habitats, coupled with the increase in international travel, have resulted in significant spread and concomitant increase in the incidence of infection and severe disease. Although neuroinvasive disease has been well described for some viral infections such as Japanese Encephalitis virus (JEV) and West Nile virus (WNV), others such as dengue virus (DENV) have recently displayed an emerging pattern of neuroinvasive disease, distinct from the previously observed, systemically-induced encephalomyelopathy. In this setting, the immune response is a crucial component of host defence, in preventing viral dissemination and invasion of the central nervous system (CNS). However, subversion of the anti-viral activities of macrophages by flaviviruses can facilitate viral replication and spread, enhancing the intensity of immune responses, leading to severe immune-mediated disease which may be further exacerbated during the subsequent infection with some flaviviruses. Furthermore, in the CNS myeloid cells may be responsible for inducing specific inflammatory changes, which can lead to significant pathological damage during encephalitis. The interaction of virus and cells of the myeloid lineage is complex, and this interaction is likely responsible at least in part, for crucial differences between viral clearance and pathology. Recent studies on the role of myeloid cells in innate immunity and viral control, and the mechanisms of evasion and subversion used by flaviviruses are rapidly advancing our understanding of the immunopathological mechanisms involved in flavivirus encephalitis and will lead to the development of therapeutic strategies previously not considered. PMID:24434318

Tick-Borne Encephalitis (TBE)

MedlinePlus

... virus, Siberian tick-borne encephalitis virus, and Far eastern Tick-borne encephalitis virus (formerly known as Russian ... viruses are closely related to TBEV and Far-eastern TBE, and include Omsk hemorrhagic fever virus in ...

Combined treatment of adenosine nucleoside inhibitor NITD008 and histone deacetylase inhibitor vorinostat represents an immunotherapy strategy to ameliorate West Nile virus infection.

PubMed

Nelson, Jacob; Roe, Kelsey; Orillo, Beverly; Shi, Pei-Yong; Verma, Saguna

2015-10-01

West Nile virus (WNV), a member of the Flaviviridae family, is the leading cause of viral encephalitis in the United States. Despite efforts to control the spread of WNV, there has been an increase in the number of outbreaks and clinical cases with neurological problems. There are no antiviral compounds currently in trials for WNV. NITD008 is an adenosine analogue inhibitor that interrupts the RNA-dependent RNA polymerase of flaviviruses. Previous studies demonstrated NITD008 as a potent antiviral for dengue virus, however this drug was associated with preclinical toxicity. The ability of NITD008 to block WNV replication is only shown in Vero cells. Neuroinflammation is also a major cause of the WNV-associated pathology, therefore we evaluated the effect of NITD008 and a newly characterized anti-inflammatory drug vorinostat (SAHA), a histone deacetylase inhibitor, on WNV replication and disease progression in a mouse model. When administered at 10 and 25mg/kg at days 1-6 after WNV infection in C57BL/6 mice, NITD008 conferred complete protection from clinical symptoms and death, which correlated with reduced viral load in the serum and restriction of virus-CNS entry. Delay of NITD008 treatment to days 3-6 and days 5-9 after infection, when WNV replication was high in the periphery and brain, resulted in the gradual loss of protection against WNV infection. However, co-treatment with SAHA and NITD008 during the CNS phase of disease improved disease outcome significantly by reducing inflammation and neuronal death. Our results support potential synergistic effect of combination therapy of NITD008 with SAHA for the treatment of WNV encephalitis. Copyright © 2015 Elsevier B.V. All rights reserved.

Integrin αvβ3 promotes infection by Japanese encephalitis virus.

PubMed

Fan, Wenchun; Qian, Ping; Wang, Dandan; Zhi, Xianwei; Wei, Yanming; Chen, Huanchun; Li, Xiangmin

2017-04-01

Japanese encephalitis virus (JEV) is a mosquito-borne flavivirus that is one of the major causes of viral encephalitis diseases worldwide. The JEV envelope protein facilitates viral entry, and its domain III contains an Arg-Gly-Asp (RGD) motif, that may modulate JEV entry through the RGD-binding integrin. In this study, the roles of integrin αv and β3 on the infection of JEV were evaluated. Reduced expression of integrin αv/β3 by special shRNA confers 2 to 4-fold inhibition of JEV replication in BHK-21 cells. Meanwhile, antibodies specific for integrin αv/β3 displayed ~58% and ~33% inhibition of JEV infectivity and RGD-specific peptides produced ~36% of inhibition. Expression of E protein and JEV RNA loads were clearly increased in CHO cells transfected with cDNA encoding human integrin β3. Moreover, integrin αv mediates JEV infection in viral binding stage of life cycle. Therefore, our study suggested that integrin αv and β3 serve as a host factor associated with JEV entry into the target cells. Copyright © 2016 Elsevier Ltd. All rights reserved.

miR-370 mimic inhibits replication of Japanese encephalitis virus in glioblastoma cells.

PubMed

Li, Wenjuan; Cheng, Peng; Nie, Shangdan; Cui, Wen

2016-01-01

Japanese encephalitis (JE) is one of the most severe viral infections of the central nervous system. No effective treatment for JE currently exists, because its pathogenesis remains largely unknown. The present study was designed to screen the potential microRNAs (miRNAs) involved in JE. Glioblastoma cells were collected, after being infected with the Japanese encephalitis virus (JEV). Total miRNAs were extracted and analyzed using an miRNA chip. One of the most severely affected miRNAs was selected, and the role of miR-370 in JEV infection was investigated. Cell viability and apoptosis of the host cells were evaluated. JEV replication was detected via analysis of gene E expression. Real-time polymerase chain reaction was used to determine the levels of endogenous miR-370 and expression of innate immunity-related genes. Following JEV infection, 114 miRNAs were affected, as evidenced by the miRNA chip. Among them, 30 miRNAs were upregulated and 84 were downregulated. The changes observed in five miRNAs were confirmed by real-time polymerase chain reaction. One of the significantly downregulated miRNAs was miR-370. Therefore, miR-370 mimic was transfected into the cells, following which the levels of endogenous miR-370 were significantly elevated. Concurrently, JEV replication was significantly reduced 24 hours after transfection of miR-370 mimic. Functionally, miR-370 mimic mitigated both JEV-induced apoptosis and the inhibition of host cell proliferation. Following JEV infection, interferon-β and nuclear factor-kappa B were upregulated, whereas miR-370 mimic prevented the upregulation of the genes induced by JEV infection. The present study demonstrated that miR-370 expression in host cells is downregulated following JEV infection, which further mediates innate immunity-related gene expression. Taken together, miR-370 mimic might be useful to prevent viral replication and infection-induced host cell injury.

Flavivirus NS3 and NS5 proteins interaction network: a high-throughput yeast two-hybrid screen

PubMed Central

2011-01-01

Background The genus Flavivirus encompasses more than 50 distinct species of arthropod-borne viruses, including several major human pathogens, such as West Nile virus, yellow fever virus, Japanese encephalitis virus and the four serotypes of dengue viruses (DENV type 1-4). Each year, flaviviruses cause more than 100 million infections worldwide, some of which lead to life-threatening conditions such as encephalitis or haemorrhagic fever. Among the viral proteins, NS3 and NS5 proteins constitute the major enzymatic components of the viral replication complex and are essential to the flavivirus life cycle. Results We report here the results of a high-throughput yeast two-hybrid screen to identify the interactions between human host proteins and the flavivirus NS3 and NS5 proteins. Using our screen results and literature curation, we performed a global analysis of the NS3 and NS5 cellular targets based on functional annotation with the Gene Ontology features. We finally created the first flavivirus NS3 and NS5 proteins interaction network and analysed the topological features of this network. Our proteome mapping screen identified 108 human proteins interacting with NS3 or NS5 proteins or both. The global analysis of the cellular targets revealed the enrichment of host proteins involved in RNA binding, transcription regulation, vesicular transport or innate immune response regulation. Conclusions We proposed that the selective disruption of these newly identified host/virus interactions could represent a novel and attractive therapeutic strategy in treating flavivirus infections. Our virus-host interaction map provides a basis to unravel fundamental processes about flavivirus subversion of the host replication machinery and/or immune defence strategy. PMID:22014111

Flavivirus NS3 and NS5 proteins interaction network: a high-throughput yeast two-hybrid screen.

PubMed

Le Breton, Marc; Meyniel-Schicklin, Laurène; Deloire, Alexandre; Coutard, Bruno; Canard, Bruno; de Lamballerie, Xavier; Andre, Patrice; Rabourdin-Combe, Chantal; Lotteau, Vincent; Davoust, Nathalie

2011-10-20

The genus Flavivirus encompasses more than 50 distinct species of arthropod-borne viruses, including several major human pathogens, such as West Nile virus, yellow fever virus, Japanese encephalitis virus and the four serotypes of dengue viruses (DENV type 1-4). Each year, flaviviruses cause more than 100 million infections worldwide, some of which lead to life-threatening conditions such as encephalitis or haemorrhagic fever. Among the viral proteins, NS3 and NS5 proteins constitute the major enzymatic components of the viral replication complex and are essential to the flavivirus life cycle. We report here the results of a high-throughput yeast two-hybrid screen to identify the interactions between human host proteins and the flavivirus NS3 and NS5 proteins. Using our screen results and literature curation, we performed a global analysis of the NS3 and NS5 cellular targets based on functional annotation with the Gene Ontology features. We finally created the first flavivirus NS3 and NS5 proteins interaction network and analysed the topological features of this network. Our proteome mapping screen identified 108 human proteins interacting with NS3 or NS5 proteins or both. The global analysis of the cellular targets revealed the enrichment of host proteins involved in RNA binding, transcription regulation, vesicular transport or innate immune response regulation. We proposed that the selective disruption of these newly identified host/virus interactions could represent a novel and attractive therapeutic strategy in treating flavivirus infections. Our virus-host interaction map provides a basis to unravel fundamental processes about flavivirus subversion of the host replication machinery and/or immune defence strategy.

Encephalitis

MedlinePlus

... due to some viruses, including: Measles Mumps Polio Rabies Rubella Varicella (chickenpox) Other viruses that cause encephalitis ... Vaccinate animals to prevent encephalitis caused by the rabies virus.

Cross-neutralisation of viruses of the tick-borne encephalitis complex following tick-borne encephalitis vaccination and/or infection.

PubMed

McAuley, Alexander J; Sawatsky, Bevan; Ksiazek, Thomas; Torres, Maricela; Korva, Miša; Lotrič-Furlan, Stanka; Avšič-Županc, Tatjana; von Messling, Veronika; Holbrook, Michael R; Freiberg, Alexander N; Beasley, David W C; Bente, Dennis A

2017-01-01

The tick-borne encephalitis complex contains a number of flaviviruses that share close genetic homology, and are responsible for significant human morbidity and mortality with widespread geographical range. Although many members of this complex have been recognised for decades, licenced human vaccines with broad availability are only available for tick-borne encephalitis virus. While tick-borne encephalitis virus vaccines have been demonstrated to induce significant protective immunity, as determined by virus-neutralisation titres, vaccine breakthrough (clinical infection following complete vaccination), has been described. The aim of this study was to confirm the cross-neutralisation of tick-borne flaviviruses using mouse immune ascitic fluids, and to determine the magnitude of cross-neutralising antibody titres in sera from donors following tick-borne encephalitis vaccination, infection, and vaccine breakthrough. The results demonstrate that there is significant cross-neutralisation of representative members of the tick-borne encephalitis complex following vaccination and/or infection, and that the magnitude of immune responses varies based upon the exposure type. Donor sera successfully neutralised most of the viruses tested, with 85% of vaccinees neutralising Kyasanur forest disease virus and 73% of vaccinees neutralising Alkhumra virus. By contrast, only 63% of vaccinees neutralised Powassan virus, with none of these neutralisation titres exceeding 1:60. Taken together, the data suggest that tick-borne encephalitis virus vaccination may protect against most of the members of the tick-borne encephalitis complex including Kyasanur forest disease virus and Alkhumra virus, but that the neutralisation of Powassan virus following tick-borne encephalitis vaccination is minimal.

Recent Progress in Understanding Coxsackievirus Replication, Dissemination, and Pathogenesis

PubMed Central

Sin, Jon; Mangale, Vrushali; Thienphrapa, Wdee; Gottlieb, Roberta A.; Feuer, Ralph

2015-01-01

Coxsackieviruses (CVs) are relatively common viruses associated with a number of serious human diseases, including myocarditis and meningo-encephalitis. These viruses are considered cytolytic yet can persist for extended periods of time within certain host tissues requiring evasion from the host immune response and a greatly reduced rate of replication. A member of Picornaviridae family, CVs have been historically considered non-enveloped viruses – although recent evidence suggest that CV and other picornaviruses hijack host membranes and acquire an envelope. Acquisition of an envelope might provide distinct benefits to CV virions, such as resistance to neutralizing antibodies and efficient nonlytic viral spread. CV exhibits a unique tropism for progenitor cells in the host which may help to explain the susceptibility of the young host to infection and the establishment of chronic disease in adults. CVs have also been shown to exploit autophagy to maximize viral replication and assist in unconventional release from target cells. In this article, we review recent progress in clarifying virus replication and dissemination within the host cell, identifying determinants of tropism, and defining strategies utilized by the virus to evade the host immune response. Also, we will highlight unanswered questions and provide future perspectives regarding the potential mechanisms of CV pathogenesis. PMID:26142496

Exposure-based screening for Nipah virus encephalitis, Bangladesh.

PubMed

Sazzad, Hossain M S; Luby, Stephen P; Ströher, Ute; Daszak, Peter; Sultana, Sharmin; Afroj, Sayma; Rahman, Mahmudur; Gurley, Emily S

2015-02-01

We measured the performance of exposure screening questions to identify Nipah virus encephalitis in hospitalized encephalitis patients during the 2012-13 Nipah virus season in Bangladesh. The sensitivity (93%), specificity (82%), positive predictive value (37%), and negative predictive value (99%) results suggested that screening questions could more quickly identify persons with Nipah virus encephalitis.

St. Louis encephalitis virus possibly transmitted through blood transfusion-Arizona, 2015.

PubMed

Venkat, Heather; Adams, Laura; Sunenshine, Rebecca; Krow-Lucal, Elisabeth; Levy, Craig; Kafenbaum, Tammy; Sylvester, Tammy; Smith, Kirk; Townsend, John; Dosmann, Melissa; Kamel, Hany; Patron, Roberto; Kuehnert, Matthew; Annambhotla, Pallavi; Basavaraju, Sridhar V; Rabe, Ingrid B

2017-12-01

St. Louis encephalitis virus is a mosquito-borne flavivirus that infrequently causes epidemic central nervous system infections. In the United States, blood donors are not screened for St. Louis encephalitis virus infection, and transmission through blood transfusion has not been reported. During September 2015, St. Louis encephalitis virus infection was confirmed in an Arizona kidney transplant recipient. An investigation was initiated to determine the infection source. The patient was interviewed, and medical records were reviewed. To determine the likelihood of mosquito-borne infection, mosquito surveillance data collected at patient and blood donor residences in timeframes consistent with their possible exposure periods were reviewed. To investigate other routes of exposure, organ and blood donor and recipient specimens were obtained and tested for evidence of St. Louis encephalitis virus infection. The patient presented with symptoms of central nervous system infection. Recent St. Louis encephalitis virus infection was serologically confirmed. The organ donor and three other organ recipients showed no laboratory or clinical evidence of St. Louis encephalitis virus infection. Among four donors of blood products received by the patient via transfusion, one donor had a serologically confirmed, recent St. Louis encephalitis virus infection. Exposure to an infected mosquito was unlikely based on the patient's minimal outdoor exposure. In addition, no St. Louis encephalitis virus-infected mosquito pools were identified around the patient's residence. This investigation provides evidence of the first reported possible case of St. Louis encephalitis virus transmission through blood product transfusion. Health care providers and public health professionals should maintain heightened awareness for St. Louis encephalitis virus transmission through blood transfusion in settings where outbreaks are identified. © 2017 AABB.

The pathogenesis of bornaviral diseases in mammals.

PubMed

Tizard, Ian; Ball, Judith; Stoica, George; Payne, Susan

2016-12-01

Natural bornavirus infections and their resulting diseases are largely restricted to horses and sheep in Central Europe. The disease also occurs naturally in cats, and can be induced experimentally in laboratory rodents and numerous other mammals. Borna disease virus-1 (BoDV-1), the cause of most cases of mammalian Borna disease, is a negative-stranded RNA virus that replicates within the nucleus of target cells. It causes severe, often lethal, encephalitis in susceptible species. Recent events, especially the discovery of numerous new species of bornaviruses in birds and a report of an acute, lethal bornaviral encephalitis in humans, apparently acquired from squirrels, have revived interest in this remarkable family of viruses. The clinical manifestations of the bornaviral diseases are highly variable. Thus, in addition to acute lethal encephalitis, they can cause persistent neurologic disease associated with diverse behavioral changes. They also cause a severe retinitis resulting in blindness. In this review, we discuss both the pathological lesions observed in mammalian bornaviral disease and the complex pathogenesis of the neurologic disease. Thus infected neurons may be destroyed by T-cell-mediated cytotoxicity. They may die as a result of excessive inflammatory cytokine release from microglia. They may also die as a result of a 'glutaminergic storm' due to a failure of infected astrocytes to regulate brain glutamate levels.

Force Protection Technologies for the 2010-2020 Timeframe

DTIC Science & Technology

2003-11-01

virus V12. Monkey pox virus Viruses V13. Rift Valley fever virus V14. Tick-borne encephalitis virus (Russian Spring-Summer... virus Viruses V20. Japanese encephalitis virus R1. Coxiella burnetti R2. Bartonella Quintana (Rochlimea quintana, Rickettsia quintana) R3...fever virus WV5. Oropouche virus WV6. Powassan virus WV7. Rocio virus Viruses (Warning List) WV8. St Louis encephalitis virus WB1.

Protein Interactions during the Flavivirus and Hepacivirus Life Cycle*

PubMed Central

Bruening, Janina; Weigel, Bettina; Pietschmann, Thomas

2017-01-01

Protein–protein interactions govern biological functions in cells, in the extracellular milieu, and at the border between cells and extracellular space. Viruses are small intracellular parasites and thus rely on protein interactions to produce progeny inside host cells and to spread from cell to cell. Usage of host proteins by viruses can have severe consequences e.g. apoptosis, metabolic disequilibria, or altered cell proliferation and mobility. Understanding protein interactions during virus infection can thus educate us on viral infection and pathogenesis mechanisms. Moreover, it has led to important clinical translations, including the development of new therapeutic and vaccination strategies. Here, we will discuss protein interactions of members of the Flaviviridae family, which are small enveloped RNA viruses. Dengue virus, Zika virus and hepatitis C virus belong to the most prominent human pathogenic Flaviviridae. With a genome of roughly ten kilobases encoding only ten viral proteins, Flaviviridae display intricate mechanisms to engage the host cell machinery for their purpose. In this review, we will highlight how dengue virus, hepatitis C virus, Japanese encephalitis virus, tick-borne encephalitis virus, West Nile virus, yellow fever virus, and Zika virus proteins engage host proteins and how this knowledge helps elucidate Flaviviridae infection. We will specifically address the protein composition of the virus particle as well as the protein interactions during virus entry, replication, particle assembly, and release from the host cell. Finally, we will give a perspective on future challenges in Flaviviridae interaction proteomics and why we believe these challenges should be met. PMID:28077444

Cyclophilin B facilitates the replication of Orf virus.

PubMed

Zhao, Kui; Li, Jida; He, Wenqi; Song, Deguang; Zhang, Ximu; Zhang, Di; Zhou, Yanlong; Gao, Feng

2017-06-15

Viruses interact with host cellular factors to construct a more favourable environment for their efficient replication. Expression of cyclophilin B (CypB), a cellular peptidyl-prolyl cis-trans isomerase (PPIase), was found to be significantly up-regulated. Recently, a number of studies have shown that CypB is important in the replication of several viruses, including Japanese encephalitis virus (JEV), hepatitis C virus (HCV) and human papillomavirus type 16 (HPV 16). However, the function of cellular CypB in ORFV replication has not yet been explored. Suppression subtractive hybridization (SSH) technique was applied to identify genes differentially expressed in the ORFV-infected MDBK cells at an early phase of infection. Cellular CypB was confirmed to be significantly up-regulated by quantitative reverse transcription-PCR (qRT-PCR) analysis and Western blotting. The role of CypB in ORFV infection was further determined using Cyclosporin A (CsA) and RNA interference (RNAi). Effect of CypB gene silencing on ORFV replication by 50% tissue culture infectious dose (TCID 50 ) assay and qRT-PCR detection. In the present study, CypB was found to be significantly up-regulated in the ORFV-infected MDBK cells at an early phase of infection. Cyclosporin A (CsA) exhibited suppressive effects on ORFV replication through the inhibition of CypB. Silencing of CypB gene inhibited the replication of ORFV in MDBK cells. In conclusion, these data suggest that CypB is critical for the efficient replication of the ORFV genome. Cellular CypB was confirmed to be significantly up-regulated in the ORFV-infected MDBK cells at an early phase of infection, which could effectively facilitate the replication of ORFV.

[Role of Powassan virus in the etiological structure of tick-borne encephalitis in the Primorsky Kray].

PubMed

Leonova, G N; Isachkova, L M; Baranov, N I; Krugliak, S P

1980-01-01

Composite studies conducted annually in the Primorsky kray showed the tick-borne encephalitis virus to play the main etiological role in the group of encephalites with the spring-summer incidence. In 1976--1978, virological studies of 69 cases of the disease yielded 11 strains of tick-borne encephalitis virus. In 1978, from the blood of clinically normal woman after a tick bite strain 555 was first isolated which was identified as Powassan virus, and antigenemia was observed for 53 days using the fluorescent antibody technique. In the same period, serological examinations of the blood sera from 117 patients demonstrated antibody to tick-borne encephalitis virus in 69.2%, to Powassan virus in 4,3% and to both viruses simultaneously in 4.3%. Besides, antibody to tick-borne encephalitis virus, Powassan virus and both viruses simultaneously was found in patients with progredient forms of tick-borne encephalitis and in subjects with the history of tick attachment.

Last 20 aa of the West Nile virus NS1' protein are responsible for its retention in cells and the formation of unique heat-stable dimers.

PubMed

Young, Lucy B; Melian, Ezequiel Balmori; Setoh, Yin Xiang; Young, Paul R; Khromykh, Alexander A

2015-05-01

West Nile virus (WNV), a mosquito-borne flavivirus, is the major cause of arboviral encephalitis in the USA. As with other members of the Japanese encephalitis virus serogroup, WNV produces an additional non-structural protein, NS1', a C-terminal extended product of NS1 generated as the result of a -1 programmed ribosomal frameshift (PRF). We have previously shown that mutations abolishing the PRF, and consequently NS1', resulted in reduced neuroinvasiveness. However, whether this was caused by the PRF event itself or by the lack of a PRF product, NS1', or a combination of both, remains undetermined. Here, we showed that WNV NS1' formed a unique subpopulation of heat- and low-pH-stable dimers. C-terminal truncations and mutational analysis employing an NS1'-expressing plasmid showed that stability of NS1' dimers was linked to the penultimate 10 aa. To examine the role of NS1' heat-stable dimers in virus replication and pathogenicity, a stop codon mutation was introduced into NS1' to create a WNV producing a truncated version of NS1' lacking the last 20 aa, but not affecting the PRF. NS1' protein produced by this mutant virus was secreted more efficiently than WT NS1', indicating that the sequence of the last 20 aa of NS1' was responsible for its cellular retention. Further analysis of this mutant showed growth kinetics in cells and virulence in weanling mice after peripheral infection similar to the WT WNVKUN, suggesting that full-length NS1' was not essential for virus replication in vitro and for virulence in mice. © 2015 The Authors.

Helicase Domain of West Nile Virus NS3 Protein Plays a Role in Inhibition of Type I Interferon Signalling.

PubMed

Setoh, Yin Xiang; Periasamy, Parthiban; Peng, Nias Yong Gao; Amarilla, Alberto A; Slonchak, Andrii; Khromykh, Alexander A

2017-11-02

West Nile virus (WNV) is a neurotropic flavivirus that can cause encephalitis in mammalian and avian hosts. In America, the virulent WNV strain (NY99) is causing yearly outbreaks of encephalitis in humans and horses, while in Australia the less virulent Kunjin strain of WNV strain has not been associated with significant disease outbreaks until a recent 2011 large outbreak in horses (but not in humans) caused by NSW2011 strain. Using chimeric viruses between NY99 and NSW2011 strains we previously identified a role for the non-structural proteins of NY99 strain and especially the NS3 protein, in enhanced virus replication in type I interferon response-competent cells and increased virulence in mice. To further define the role of NY99 NS3 protein in inhibition of type I interferon response, we have generated and characterised additional chimeric viruses containing the protease or the helicase domains of NY99 NS3 on the background of the NSW2011 strain. The results identified the role for the helicase but not the protease domain of NS3 protein in the inhibition of type I interferon signalling and showed that helicase domain of the more virulent NY99 strain performs this function more efficiently than helicase domain of the less virulent NSW2011 strain. Further analysis with individual amino acid mutants identified two amino acid residues in the helicase domain primarily responsible for this difference. Using chimeric replicons, we also showed that the inhibition of type I interferon (IFN) signalling was independent of other known functions of NS3 in RNA replication and assembly of virus particles.

Helicase Domain of West Nile Virus NS3 Protein Plays a Role in Inhibition of Type I Interferon Signalling

PubMed Central

Periasamy, Parthiban; Peng, Nias Yong Gao; Amarilla, Alberto A.; Slonchak, Andrii; Khromykh, Alexander A.

2017-01-01

West Nile virus (WNV) is a neurotropic flavivirus that can cause encephalitis in mammalian and avian hosts. In America, the virulent WNV strain (NY99) is causing yearly outbreaks of encephalitis in humans and horses, while in Australia the less virulent Kunjin strain of WNV strain has not been associated with significant disease outbreaks until a recent 2011 large outbreak in horses (but not in humans) caused by NSW2011 strain. Using chimeric viruses between NY99 and NSW2011 strains we previously identified a role for the non-structural proteins of NY99 strain and especially the NS3 protein, in enhanced virus replication in type I interferon response-competent cells and increased virulence in mice. To further define the role of NY99 NS3 protein in inhibition of type I interferon response, we have generated and characterised additional chimeric viruses containing the protease or the helicase domains of NY99 NS3 on the background of the NSW2011 strain. The results identified the role for the helicase but not the protease domain of NS3 protein in the inhibition of type I interferon signalling and showed that helicase domain of the more virulent NY99 strain performs this function more efficiently than helicase domain of the less virulent NSW2011 strain. Further analysis with individual amino acid mutants identified two amino acid residues in the helicase domain primarily responsible for this difference. Using chimeric replicons, we also showed that the inhibition of type I interferon (IFN) signalling was independent of other known functions of NS3 in RNA replication and assembly of virus particles. PMID:29099073

Tick-borne encephalitis.

PubMed

Gritsun, T S; Lashkevich, V A; Gould, E A

2003-01-01

Tick-borne encephalitis (TBE) is one of the most dangerous human infections occurring in Europe and many parts of Asia. The etiological agent Tick-borne encephalitis virus (TBEV), is a member of the virus genus Flavivirus, of the family Flaviviridae. TBEV is believed to cause at least 11,000 human cases of encephalitis in Russia and about 3000 cases in the rest of Europe annually. Related viruses within the same group, Louping ill virus (LIV), Langat virus (LGTV) and Powassan virus (POWV), also cause human encephalitis but rarely on an epidemic scale. Three other viruses within the same group, Omsk hemorrhagic fever virus (OHFV), Kyasanur Forest disease virus (KFDV) and Alkhurma virus (ALKV), are closely related to the TBEV complex viruses and tend to cause fatal hemorrhagic fevers rather than encephalitis. This review describes the clinical manifestations associated with TBEV infections, the main molecular-biological properties of these viruses, and the different factors that define the incidence and severity of disease. The role of ticks and their local hosts in the emergence of new virus variants with different pathogenic characteristics is also discussed. This review also contains a brief history of vaccination against TBE including trials with live attenuated vaccine and modern tendencies in developing of vaccine virus strains.

Viral Vectors for Use in the Development of Biodefense Vaccines

DTIC Science & Technology

2005-06-17

vaccinia virus, and Venezuelan equine encephalitis virus, as vaccine vectors has enabled researchers to develop effective means for countering the...biowarfare. The use of viruses, for example adenovirus, vaccinia virus, and Venezuelan equine encephalitis virus, as vaccine -vectors has enabled researchers to... vaccines . . . . . . . . . . . . . . . . . . . 1298 2.1.3. Vaccinia virus-vectored Venezuelan equine encephalitis vaccines

Characterization of infectious Murray Valley encephalitis virus derived from a stably cloned genome-length cDNA.

PubMed

Hurrelbrink, R J; Nestorowicz, A; McMinn, P C

1999-12-01

An infectious cDNA clone of Murray Valley encephalitis virus prototype strain 1-51 (MVE-1-51) was constructed by stably inserting genome-length cDNA into the low-copy-number plasmid vector pMC18. Designated pMVE-1-51, the clone consisted of genome-length cDNA of MVE-1-51 under the control of a T7 RNA polymerase promoter. The clone was constructed by using existing components of a cDNA library, in addition to cDNA of the 3' terminus derived by RT-PCR of poly(A)-tailed viral RNA. Upon comparison with other flavivirus sequences, the previously undetermined sequence of the 3' UTR was found to contain elements conserved throughout the genus FLAVIVIRUS: RNA transcribed from pMVE-1-51 and subsequently transfected into BHK-21 cells generated infectious virus. The plaque morphology, replication kinetics and antigenic profile of clone-derived virus (CDV-1-51) was similar to the parental virus in vitro. Furthermore, the virulence properties of CDV-1-51 and MVE-1-51 (LD(50) values and mortality profiles) were found to be identical in vivo in the mouse model. Through site-directed mutagenesis, the infectious clone should serve as a valuable tool for investigating the molecular determinants of virulence in MVE virus.

Evaluation of chimeric yellow fever 17D/dengue viral replication in ticks.

PubMed

Kazimírová, Mária; Mantel, Nathalie; Raynaud, Sandrine; Slovák, Mirko; Ustaniková, Katarína; Lang, Jean; Guy, Bruno; Barban, Veronique; Labuda, Milan

2012-11-01

Chimeric yellow fever 17D/DENV-1-4 viruses (CYD-1-4) have been developed as a tetravalent dengue vaccine candidate which is currently being evaluated in efficacy trials in Asia and America. While YF 17D and DENV are mosquito-borne flaviviruses, it has been shown that CYD-1-4 do not replicate after oral infection in mosquitoes and are not transmitted to new hosts. To further document the risk of environmental dissemination of these viruses, we evaluated the replication of CYD-1-4 in ticks, the vector of tick-borne encephalitis virus (TBEV), another member of the flavivirus family. Females of two hard tick species, Ixodes ricinus and Rhipicephalus appendiculatus, were inoculated intracoelomically with CYD-1-4 viruses and parent viruses (DENV-1-4 and YF 17D). Virus persistence and replication was assessed 2, 16, and 44 days post-inoculation by plaque titration and qRT-PCR. CYD-1-4 viruses were detected in I. ricinus ticks at early time points post-inoculation, but with infectious titers at least 100-fold lower than those observed in TBEV-infected ticks. Unlike TBEV, complete viral clearance occurred by day 44 in most ticks except for CYD-2, which had a tendency to decline. In addition, while about 70% of TBEV-infected I. ricinus nymphs acquired infection by co-feeding with infected tick females on non-viremic hosts, no co-feeding transmission of CYD-2 virus was detected. Based on these results, we conclude that the risk of dissemination of the candidate vaccine viruses by tick bite is highly unlikely.

A Novel Self-Replicating Chimeric Lentivirus-Like Particle

PubMed Central

Young, Kelly R.; Madden, Victoria J.; Johnson, Philip R.; Johnston, Robert E.

2012-01-01

Successful live attenuated vaccines mimic natural exposure to pathogens without causing disease and have been successful against several viruses. However, safety concerns prevent the development of attenuated human immunodeficiency virus (HIV) as a vaccine candidate. If a safe, replicating virus vaccine could be developed, it might have the potential to offer significant protection against HIV infection and disease. Described here is the development of a novel self-replicating chimeric virus vaccine candidate that is designed to provide natural exposure to a lentivirus-like particle and to incorporate the properties of a live attenuated virus vaccine without the inherent safety issues associated with attenuated lentiviruses. The genome from the alphavirus Venezuelan equine encephalitis virus (VEE) was modified to express SHIV89.6P genes encoding the structural proteins Gag and Env. Expression of Gag and Env from VEE RNA in primate cells led to the assembly of particles that morphologically and functionally resembled lentivirus virions and that incorporated alphavirus RNA. Infection of CD4+ cells with chimeric lentivirus-like particles was specific and productive, resulting in RNA replication, expression of Gag and Env, and generation of progeny chimeric particles. Further genome modifications designed to enhance encapsidation of the chimeric virus genome and to express an attenuated simian immunodeficiency virus (SIV) protease for particle maturation improved the ability of chimeric lentivirus-like particles to propagate in cell culture. This study provides proof of concept for the feasibility of creating chimeric virus genomes that express lentivirus structural proteins and assemble into infectious particles for presentation of lentivirus immunogens in their native and functional conformation. PMID:22013035

A novel self-replicating chimeric lentivirus-like particle.

PubMed

Jurgens, Christy K; Young, Kelly R; Madden, Victoria J; Johnson, Philip R; Johnston, Robert E

2012-01-01

Successful live attenuated vaccines mimic natural exposure to pathogens without causing disease and have been successful against several viruses. However, safety concerns prevent the development of attenuated human immunodeficiency virus (HIV) as a vaccine candidate. If a safe, replicating virus vaccine could be developed, it might have the potential to offer significant protection against HIV infection and disease. Described here is the development of a novel self-replicating chimeric virus vaccine candidate that is designed to provide natural exposure to a lentivirus-like particle and to incorporate the properties of a live attenuated virus vaccine without the inherent safety issues associated with attenuated lentiviruses. The genome from the alphavirus Venezuelan equine encephalitis virus (VEE) was modified to express SHIV89.6P genes encoding the structural proteins Gag and Env. Expression of Gag and Env from VEE RNA in primate cells led to the assembly of particles that morphologically and functionally resembled lentivirus virions and that incorporated alphavirus RNA. Infection of CD4⁺ cells with chimeric lentivirus-like particles was specific and productive, resulting in RNA replication, expression of Gag and Env, and generation of progeny chimeric particles. Further genome modifications designed to enhance encapsidation of the chimeric virus genome and to express an attenuated simian immunodeficiency virus (SIV) protease for particle maturation improved the ability of chimeric lentivirus-like particles to propagate in cell culture. This study provides proof of concept for the feasibility of creating chimeric virus genomes that express lentivirus structural proteins and assemble into infectious particles for presentation of lentivirus immunogens in their native and functional conformation.

Provenance and geographic spread of St. Louis encephalitis virus.

PubMed

Kopp, Anne; Gillespie, Thomas R; Hobelsberger, Daniel; Estrada, Alejandro; Harper, James M; Miller, Richard A; Eckerle, Isabella; Müller, Marcel A; Podsiadlowski, Lars; Leendertz, Fabian H; Drosten, Christian; Junglen, Sandra

2013-06-11

St. Louis encephalitis virus (SLEV) is the prototypic mosquito-borne flavivirus in the Americas. Birds are its primary vertebrate hosts, but amplification in certain mammals has also been suggested. The place and time of SLEV emergence remain unknown. In an ecological investigation in a tropical rainforest in Palenque National Park, Mexico, we discovered an ancestral variant of SLEV in Culex nigripalpus mosquitoes. Those SLEV-Palenque strains form a highly distinct phylogenetic clade within the SLEV species. Cell culture studies of SLEV-Palenque versus epidemic SLEV (MSI-7) revealed no growth differences in insect cells but a clear inability of SLEV-Palenque to replicate in cells from birds, cotton rats, and free-tailed bats permissive for MSI-7 replication. Only cells from nonhuman primates and neotropical fruit bats were moderately permissive. Phylogeographic reconstruction identified the common ancestor of all epidemic SLEV strains to have existed in an area between southern Mexico and Panama ca. 330 years ago. Expansion of the epidemic lineage occurred in two waves, the first representing emergence near the area of origin and the second involving almost parallel appearances of the virus in the lower Mississippi and Amazon delta regions. Early diversification events overlapped human habitat invasion during the post-Columbian era. Several documented SLEV outbreaks, such as the 1964 Houston epidemic or the 1990 Tampa epidemic, were predated by the arrival of novel strains between 1 and 4 years before the outbreaks. Collectively, our data provide insight into the putative origins of SLEV, suggesting that virus emergence was driven by human invasion of primary rainforests. IMPORTANCE St. Louis encephalitis virus (SLEV) is the prototypic mosquito-transmitted flavivirus of the Americas. Unlike the West Nile virus, which we know was recently introduced into North America from the Old World, the provenience of SLEV is obscure. In an ecological investigation in a primary rainforest area of Palenque National Park, Mexico, we have discovered an ancestral variant of SLEV. The ancestral virus was much less active than the epidemic virus in cell cultures, reflecting its incomplete adaptation to hosts encountered outside primary rainforests. Knowledge of this virus enabled a spatiotemporal reconstruction of the common ancestor of all SLEVs and how the virus spread from there. We can infer that the cosmopolitan SLEV lineage emerged from Central America in the 17th century, a period of post-Columbian colonial history marked by intense human invasion of primary rainforests. Further spread followed major bird migration pathways over North and South America.

Alpha-Synuclein Expression Restricts RNA Viral Infections in the Brain.

PubMed

Beatman, Erica L; Massey, Aaron; Shives, Katherine D; Burrack, Kristina S; Chamanian, Mastooreh; Morrison, Thomas E; Beckham, J David

2015-12-30

We have discovered that native, neuronal expression of alpha-synuclein (Asyn) inhibits viral infection, injury, and disease in the central nervous system (CNS). Enveloped RNA viruses, such as West Nile virus (WNV), invade the CNS and cause encephalitis, yet little is known about the innate neuron-specific inhibitors of viral infections in the CNS. Following WNV infection of primary neurons, we found that Asyn protein expression is increased. The infectious titer of WNV and Venezuelan equine encephalitis virus (VEEV) TC83 in the brains of Asyn-knockout mice exhibited a mean increase of 10(4.5) infectious viral particles compared to the titers in wild-type and heterozygote littermates. Asyn-knockout mice also exhibited significantly increased virus-induced mortality compared to Asyn heterozygote or homozygote control mice. Virus-induced Asyn localized to perinuclear, neuronal regions expressing viral envelope protein and the endoplasmic reticulum (ER)-associated trafficking protein Rab1. In Asyn-knockout primary neuronal cultures, the levels of expression of ER signaling pathways, known to support WNV replication, were significantly elevated before and during viral infection compared to those in Asyn-expressing primary neuronal cultures. We propose a model in which virus-induced Asyn localizes to ER-derived membranes, modulates virus-induced ER stress signaling, and inhibits viral replication, growth, and injury in the CNS. These data provide a novel and important functional role for the expression of native alpha-synuclein, a protein that is closely associated with the development of Parkinson's disease. Neuroinvasive viruses such as West Nile virus are able to infect neurons and cause severe disease, such as encephalitis, or infection of brain tissue. Following viral infection in the central nervous system, only select neurons are infected, implying that neurons exhibit innate resistance to viral infections. We discovered that native neuronal expression of alpha-synuclein inhibited viral infection in the central nervous system. When the gene for alpha-synuclein was deleted, mice exhibited significantly decreased survival, markedly increased viral growth in the brain, and evidence of increased neuron injury. Virus-induced alpha-synuclein localized to intracellular neuron membranes, and in the absence of alpha-synuclein expression, specific endoplasmic reticulum stress signaling events were significantly increased. We describe a new neuron-specific inhibitor of viral infections in the central nervous system. Given the importance of alpha-synuclein as a cause of Parkinson's disease, these data also ascribe a novel functional role for the native expression of alpha-synuclein in the CNS. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

9 CFR 121.4 - Overlap select agents and toxins.

Code of Federal Regulations, 2011 CFR

2011-01-01

...; Hendra virus; Nipah virus; Rift Valley fever virus; Venezuelan equine encephalitis virus. (c) Genetic... melitensis, Hendra virus, Nipah virus, Rift Valley fever virus, and Venezuelan equine encephalitis virus...

High-Resolution Functional Mapping of the Venezuelan Equine Encephalitis Virus Genome by Insertional Mutagenesis and Massively Parallel Sequencing

DTIC Science & Technology

2010-10-14

High-Resolution Functional Mapping of the Venezuelan Equine Encephalitis Virus Genome by Insertional Mutagenesis and Massively Parallel Sequencing...Venezuelan equine encephalitis virus (VEEV) genome. We initially used a capillary electrophoresis method to gain insight into the role of the VEEV...Smith JM, Schmaljohn CS (2010) High-Resolution Functional Mapping of the Venezuelan Equine Encephalitis Virus Genome by Insertional Mutagenesis and

Replication of Many Human Viruses Is Refractory to Inhibition by Endogenous Cellular MicroRNAs

PubMed Central

Bogerd, Hal P.; Skalsky, Rebecca L.; Kennedy, Edward M.; Furuse, Yuki; Whisnant, Adam W.; Flores, Omar; Schultz, Kimberly L. W.; Putnam, Nicole; Barrows, Nicholas J.; Sherry, Barbara; Scholle, Frank; Garcia-Blanco, Mariano A.; Griffin, Diane E.

2014-01-01

ABSTRACT The issue of whether viruses are subject to restriction by endogenous microRNAs (miRNAs) and/or by virus-induced small interfering RNAs (siRNAs) in infected human somatic cells has been controversial. Here, we address this question in two ways. First, using deep sequencing, we demonstrate that infection of human cells by the RNA virus dengue virus (DENV) or West Nile virus (WNV) does not result in the production of any virus-derived siRNAs or viral miRNAs. Second, to more globally assess the potential of small regulatory RNAs to inhibit virus replication, we used gene editing to derive human cell lines that lack a functional Dicer enzyme and that therefore are unable to produce miRNAs or siRNAs. Infection of these cells with a wide range of viruses, including DENV, WNV, yellow fever virus, Sindbis virus, Venezuelan equine encephalitis virus, measles virus, influenza A virus, reovirus, vesicular stomatitis virus, human immunodeficiency virus type 1, or herpes simplex virus 1 (HSV-1), failed to reveal any enhancement in the replication of any of these viruses, although HSV-1, which encodes at least eight Dicer-dependent viral miRNAs, did replicate somewhat more slowly in the absence of Dicer. We conclude that most, and perhaps all, human viruses have evolved to be resistant to inhibition by endogenous human miRNAs during productive replication and that dependence on a cellular miRNA, as seen with hepatitis C virus, is rare. How viruses have evolved to avoid inhibition by endogenous cellular miRNAs, which are generally highly conserved during metazoan evolution, remains to be determined. IMPORTANCE Eukaryotic cells express a wide range of small regulatory RNAs, including miRNAs, that have the potential to inhibit the expression of mRNAs that show sequence complementarity. Indeed, previous work has suggested that endogenous miRNAs have the potential to inhibit viral gene expression and replication. Here, we demonstrate that the replication of a wide range of pathogenic viruses is not enhanced in human cells engineered to be unable to produce miRNAs, indicating that viruses have evolved to be resistant to inhibition by miRNAs. This result is important, as it implies that manipulation of miRNA levels is not likely to prove useful in inhibiting virus replication. It also focuses attention on the question of how viruses have evolved to resist inhibition by miRNAs and whether virus mutants that have lost this resistance might prove useful, for example, in the development of attenuated virus vaccines. PMID:24807715

A Brief Review of West Nile Virus Biology.

PubMed

Londono-Renteria, Berlin; Colpitts, Tonya M

2016-01-01

West Nile virus (WNV) is an arbovirus with increased global incidence in the last decade. It is also a major cause of human encephalitis in the USA. WNV is an arthropod-transmitted virus that mainly affects birds but humans become infected as incidental dead-end hosts which can cause outbreaks in naïve populations. The main vectors of WNV are mosquitoes of the genus Culex, which preferentially feed on birds. As in many other arboviruses, the characteristics that allow Flaviviruses like WNV to replicate and transmit to different hosts are encrypted in their genome, which also contains information for the production of structural and nonstructural proteins needed for host cell infection. WNV and other Flaviviruses have developed different strategies to establish infection, replication, and successful transmission. Most of these strategies include the diversion of the host's immune responses away from the virus. In this review, we describe the molecular structure and protein function of WNV with emphasis on protein involvement in the modulation of antiviral immune responses.

Temperature-sensitive mutations for live-attenuated Rift Valley fever vaccines: implications from other RNA viruses

PubMed Central

Nishiyama, Shoko; Ikegami, Tetsuro

2015-01-01

Rift Valley fever (RVF) is a mosquito-borne zoonotic disease endemic to the African continent. RVF is characterized by high rate of abortions in ruminants and hemorrhagic fever, encephalitis, or blindness in humans. RVF is caused by the Rift Valley fever virus (RVFV: genus Phlebovirus, family Bunyaviridae). Vaccination is the only known effective strategy to prevent the disease, but there are no licensed RVF vaccines available for humans. A live-attenuated vaccine candidate derived from the wild-type pathogenic Egyptian ZH548 strain, MP-12, has been conditionally licensed for veterinary use in the U.S. MP-12 displays a temperature-sensitive (ts) phenotype and does not replicate at 41°C. The ts mutation limits viral replication at a specific body temperature and may lead to an attenuation of the virus. Here we will review well-characterized ts mutations for RNA viruses, and further discuss the potential in designing novel live-attenuated vaccines for RVF. PMID:26322023

A MicroRNA Screen Identifies the Wnt Signaling Pathway as a Regulator of the Interferon Response during Flavivirus Infection

PubMed Central

Smith, Jessica L.; Jeng, Sophia; McWeeney, Shannon K.

2017-01-01

ABSTRACT The impact of mosquito-borne flavivirus infections worldwide is significant, and many critical aspects of these viruses' biology, including virus-host interactions, host cell requirements for replication, and how virus-host interactions impact pathology, remain to be fully understood. The recent reemergence and spread of flaviviruses, including dengue virus (DENV), West Nile virus (WNV), and Zika virus (ZIKV), highlight the importance of performing basic research on this important group of pathogens. MicroRNAs (miRNAs) are small, noncoding RNAs that modulate gene expression posttranscriptionally and have been demonstrated to regulate a broad range of cellular processes. Our research is focused on identifying pro- and antiflaviviral miRNAs as a means of characterizing cellular pathways that support or limit viral replication. We have screened a library of known human miRNA mimics for their effect on the replication of three flaviviruses, DENV, WNV, and Japanese encephalitis virus (JEV), using a high-content immunofluorescence screen. Several families of miRNAs were identified as inhibiting multiple flaviviruses, including the miRNA miR-34, miR-15, and miR-517 families. Members of the miR-34 family, which have been extensively characterized for their ability to repress Wnt/β-catenin signaling, demonstrated strong antiflaviviral effects, and this inhibitory activity extended to other viruses, including ZIKV, alphaviruses, and herpesviruses. Previous research suggested a possible link between the Wnt and type I interferon (IFN) signaling pathways. Therefore, we investigated the role of type I IFN induction in the antiviral effects of the miR-34 family and confirmed that these miRNAs potentiate interferon regulatory factor 3 (IRF3) phosphorylation and translocation to the nucleus, the induction of IFN-responsive genes, and the release of type I IFN from transfected cells. We further demonstrate that the intersection between the Wnt and IFN signaling pathways occurs at the point of glycogen synthase kinase 3β (GSK3β)–TANK-binding kinase 1 (TBK1) binding, inducing TBK1 to phosphorylate IRF3 and initiate downstream IFN signaling. In this way, we have identified a novel cellular signaling network with a critical role in regulating the replication of multiple virus families. These findings highlight the opportunities for using miRNAs as tools to discover and characterize unique cellular factors involved in supporting or limiting virus replication, opening up new avenues for antiviral research. IMPORTANCE MicroRNAs are a class of small regulatory RNAs that modulate cellular processes through the posttranscriptional repression of multiple transcripts. We hypothesized that individual miRNAs may be capable of inhibiting viral replication through their effects on host proteins or pathways. To test this, we performed a high-content screen for miRNAs that inhibit the replication of three medically relevant members of the flavivirus family: West Nile virus, Japanese encephalitis virus, and dengue virus 2. The results of this screen identify multiple miRNAs that inhibit one or more of these viruses. Extensive follow-up on members of the miR-34 family of miRNAs, which are active against all three viruses as well as the closely related Zika virus, demonstrated that miR-34 functions through increasing the infected cell's ability to respond to infection through the interferon-based innate immune pathway. Our results not only add to the knowledge of how viruses interact with cellular pathways but also provide a basis for more extensive data mining by providing a comprehensive list of miRNAs capable of inhibiting flavivirus replication. Finally, the miRNAs themselves or cellular pathways identified as modulating virus infection may prove to be novel candidates for the development of therapeutic interventions. PMID:28148804

A MicroRNA Screen Identifies the Wnt Signaling Pathway as a Regulator of the Interferon Response during Flavivirus Infection.

PubMed

Smith, Jessica L; Jeng, Sophia; McWeeney, Shannon K; Hirsch, Alec J

2017-04-15

The impact of mosquito-borne flavivirus infections worldwide is significant, and many critical aspects of these viruses' biology, including virus-host interactions, host cell requirements for replication, and how virus-host interactions impact pathology, remain to be fully understood. The recent reemergence and spread of flaviviruses, including dengue virus (DENV), West Nile virus (WNV), and Zika virus (ZIKV), highlight the importance of performing basic research on this important group of pathogens. MicroRNAs (miRNAs) are small, noncoding RNAs that modulate gene expression posttranscriptionally and have been demonstrated to regulate a broad range of cellular processes. Our research is focused on identifying pro- and antiflaviviral miRNAs as a means of characterizing cellular pathways that support or limit viral replication. We have screened a library of known human miRNA mimics for their effect on the replication of three flaviviruses, DENV, WNV, and Japanese encephalitis virus (JEV), using a high-content immunofluorescence screen. Several families of miRNAs were identified as inhibiting multiple flaviviruses, including the miRNA miR-34, miR-15, and miR-517 families. Members of the miR-34 family, which have been extensively characterized for their ability to repress Wnt/β-catenin signaling, demonstrated strong antiflaviviral effects, and this inhibitory activity extended to other viruses, including ZIKV, alphaviruses, and herpesviruses. Previous research suggested a possible link between the Wnt and type I interferon (IFN) signaling pathways. Therefore, we investigated the role of type I IFN induction in the antiviral effects of the miR-34 family and confirmed that these miRNAs potentiate interferon regulatory factor 3 (IRF3) phosphorylation and translocation to the nucleus, the induction of IFN-responsive genes, and the release of type I IFN from transfected cells. We further demonstrate that the intersection between the Wnt and IFN signaling pathways occurs at the point of glycogen synthase kinase 3β (GSK3β)-TANK-binding kinase 1 (TBK1) binding, inducing TBK1 to phosphorylate IRF3 and initiate downstream IFN signaling. In this way, we have identified a novel cellular signaling network with a critical role in regulating the replication of multiple virus families. These findings highlight the opportunities for using miRNAs as tools to discover and characterize unique cellular factors involved in supporting or limiting virus replication, opening up new avenues for antiviral research. IMPORTANCE MicroRNAs are a class of small regulatory RNAs that modulate cellular processes through the posttranscriptional repression of multiple transcripts. We hypothesized that individual miRNAs may be capable of inhibiting viral replication through their effects on host proteins or pathways. To test this, we performed a high-content screen for miRNAs that inhibit the replication of three medically relevant members of the flavivirus family: West Nile virus, Japanese encephalitis virus, and dengue virus 2. The results of this screen identify multiple miRNAs that inhibit one or more of these viruses. Extensive follow-up on members of the miR-34 family of miRNAs, which are active against all three viruses as well as the closely related Zika virus, demonstrated that miR-34 functions through increasing the infected cell's ability to respond to infection through the interferon-based innate immune pathway. Our results not only add to the knowledge of how viruses interact with cellular pathways but also provide a basis for more extensive data mining by providing a comprehensive list of miRNAs capable of inhibiting flavivirus replication. Finally, the miRNAs themselves or cellular pathways identified as modulating virus infection may prove to be novel candidates for the development of therapeutic interventions. Copyright © 2017 American Society for Microbiology.

Etiology and prognosis of acute viral encephalitis and meningitis in Chinese children: a multicentre prospective study.

PubMed

Ai, Junhong; Xie, Zhengde; Liu, Gang; Chen, Zongbo; Yang, Yong; Li, Yuning; Chen, Jing; Zheng, Guo; Shen, Kunling

2017-07-14

In China, there were few studies about the pathogens of acute viral encephalitis and meningitis in children in recent years. The aims of this study were to characterize the etiology and prognosis of acute viral encephalitis and meningitis in Chinese children. This was a multicentre prospective study. Two hundred and sixty one viral encephalitis patients and 285 viral meningitis patients were enrolled. The mean age of viral encephalitis and meningitis were 5.88 ± 3.60 years and 6.39 ± 3.57 years, respectively. Real-time reverse transcription PCR and multiplex PCR were used to detect human enteroviruses and herpes viruses in cerebrospinal fluid (CSF) of patients with encephalitis or meningitis. The enzyme-linked immune absorbent assay (ELISA) was used for detecting IgM antibody against Japanese encephalitis virus (JEV) in CSF and against mumps virus, tick-borne encephalitis virus (TBEV), dengue virus and rubella virus in acute serum. The clinical and outcome data were collected during patients' hospitalization. The etiology of viral encephalitis was confirmed in 52.5% patients. The primary pathogen was human enteroviruses (27.7%) in viral encephalitis. The incidence of sequelae and the fatality rate of viral encephalitis with confirmed etiology were 7.5% and 0.8%, respectively. The etiology of viral meningitis was identified in 42.8% cases. The leading pathogen was also human enteroviruses (37.7%) in viral meningitis. The prognosis of viral meningitis was favorable with only 0.7% patients had neurological sequelae. Human enteroviruses were the leading cause both in acute viral encephalitis and viral meningitis in children. The incidence of sequelae and fatality rate of viral encephalitis with confirmed etiology were 7.5% and 0.8%, respectively. The prognosis of viral meningitis was favorable compared to viral encephalitis.

Interferons and Alphavirus Pathogenesis: Implications for Developing Medical Countermeasures

DTIC Science & Technology

2005-12-01

respiratory tract with Venezuelan equine encephalomyelitis virus in normal and operated Macaca rhesus monkeys. II. Results of histological examination... respiratory tract with Venezuelan equine encephalomyelitis virus in normal and operated Macaca rhesus monkeys. I. Results of virological examination. Acta...alphavirus family: Venezuelan equine encephalitis virus (VEEV), eastern equine encephalitis virus (EEEV), and western equine encephalitis virus (WEEV). I

Protein Interactions during the Flavivirus and Hepacivirus Life Cycle.

PubMed

Gerold, Gisa; Bruening, Janina; Weigel, Bettina; Pietschmann, Thomas

2017-04-01

Protein-protein interactions govern biological functions in cells, in the extracellular milieu, and at the border between cells and extracellular space. Viruses are small intracellular parasites and thus rely on protein interactions to produce progeny inside host cells and to spread from cell to cell. Usage of host proteins by viruses can have severe consequences e.g. apoptosis, metabolic disequilibria, or altered cell proliferation and mobility. Understanding protein interactions during virus infection can thus educate us on viral infection and pathogenesis mechanisms. Moreover, it has led to important clinical translations, including the development of new therapeutic and vaccination strategies. Here, we will discuss protein interactions of members of the Flaviviridae family, which are small enveloped RNA viruses. Dengue virus, Zika virus and hepatitis C virus belong to the most prominent human pathogenic Flaviviridae With a genome of roughly ten kilobases encoding only ten viral proteins, Flaviviridae display intricate mechanisms to engage the host cell machinery for their purpose. In this review, we will highlight how dengue virus, hepatitis C virus, Japanese encephalitis virus, tick-borne encephalitis virus, West Nile virus, yellow fever virus, and Zika virus proteins engage host proteins and how this knowledge helps elucidate Flaviviridae infection. We will specifically address the protein composition of the virus particle as well as the protein interactions during virus entry, replication, particle assembly, and release from the host cell. Finally, we will give a perspective on future challenges in Flaviviridae interaction proteomics and why we believe these challenges should be met. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Viral encephalitis after allogeneic stem cell transplantation: a rare complication with distinct characteristics of different causative agents

PubMed Central

Schmidt-Hieber, Martin; Schwender, Julie; Heinz, Werner J.; Zabelina, Tatjana; Kühl, Jörn S.; Mousset, Sabine; Schüttrumpf, Silke; Junghanss, Christian; Silling, Gerda; Basara, Nadezda; Neuburger, Stefan; Thiel, Eckhard; Blau, Igor W.

2011-01-01

Background Limited data are available on characteristics of viral encephalitis in patients after allogeneic stem cell transplantation. Design and Methods We analyzed 2,628 patients after allogeneic stem cell transplantation to identify risk factors and characteristics of viral encephalitis. Results Viral encephalitis occurred in 32 patients (1.2%, 95% confidence interval 0.8%–1.6%) and was associated with the use of OKT-3 or alemtuzumab for T-cell depletion (P<0.001) and an increased mortality (P=0.011) in comparison to patients without viral encephalitis. Detected viruses included human herpesvirus-6 (28%), Epstein-Barr virus (19%), herpes simplex virus (13%), JC virus (9%), varicella zoster virus (6%), cytomegalovirus (6%) and adenovirus (3%). More than one virus was identified in 16% of the patients. The median onset time was 106 days after allogeneic stem cell transplantation for the total group of 32 patients, but onset times were shortest in those with human herpesvirus-6 encephalitis and longest in those with JC virus-associated progressive multifocal leukoencephalopathy. The probability of a sustained response to treatment was 63% (95% confidence interval 44%–82%) with a median survival of 94 (95% confidence interval 36–152) days after onset, but significant variation was found when considering different causative viruses. Patients with herpes simplex virus encephalitis had the most favorable outcome with no encephalitis-related deaths. Conclusions The use of OKT-3 or alemtuzumab for in vivo T-cell depletion is associated with an increased risk of viral encephalitis after allogeneic stem cell transplantation. Different viruses are frequently associated with distinct characteristics such as onset time, response to treatment and outcome. PMID:20851868

Outbreak of Powassan encephalitis--Maine and Vermont, 1999-2001.

PubMed

2001-09-07

Powassan (POW) virus, a North American tickborne flavivirus related to the Eastern Hemisphere's tickborne encephalitis viruses, was first isolated from a patient with encephalitis in 1958. During 1958-1998, 27 human POW encephalitis cases were reported from Canada and the northeastern United States. During September 1999-July 2001, four Maine and Vermont residents with encephalitis were found to be infected with POW virus. These persons were tested for other arbovirus infections found in the northeast after testing for West Nile virus (WNV) infection was negative. This report describes these four cases, summarizes the results of ecologic investigations, and discusses a potential association between ticks that infest medium-sized mammals and the risk for human exposure to POW virus. The findings underscore the need for personal protective measures to prevent tick bites and continued encephalitis surveillance.

A BSL-4 high-throughput screen identifies sulfonamide inhibitors of Nipah virus.

PubMed

Tigabu, Bersabeh; Rasmussen, Lynn; White, E Lucile; Tower, Nichole; Saeed, Mohammad; Bukreyev, Alexander; Rockx, Barry; LeDuc, James W; Noah, James W

2014-04-01

Nipah virus is a biosafety level 4 (BSL-4) pathogen that causes severe respiratory illness and encephalitis in humans. To identify novel small molecules that target Nipah virus replication as potential therapeutics, Southern Research Institute and Galveston National Laboratory jointly developed an automated high-throughput screening platform that is capable of testing 10,000 compounds per day within BSL-4 biocontainment. Using this platform, we screened a 10,080-compound library using a cell-based, high-throughput screen for compounds that inhibited the virus-induced cytopathic effect. From this pilot effort, 23 compounds were identified with EC50 values ranging from 3.9 to 20.0 μM and selectivities >10. Three sulfonamide compounds with EC50 values <12 μM were further characterized for their point of intervention in the viral replication cycle and for broad antiviral efficacy. Development of HTS capability under BSL-4 containment changes the paradigm for drug discovery for highly pathogenic agents because this platform can be readily modified to identify prophylactic and postexposure therapeutic candidates against other BSL-4 pathogens, particularly Ebola, Marburg, and Lassa viruses.

A BSL-4 High-Throughput Screen Identifies Sulfonamide Inhibitors of Nipah Virus

PubMed Central

Tigabu, Bersabeh; Rasmussen, Lynn; White, E. Lucile; Tower, Nichole; Saeed, Mohammad; Bukreyev, Alexander; Rockx, Barry; LeDuc, James W.

2014-01-01

Abstract Nipah virus is a biosafety level 4 (BSL-4) pathogen that causes severe respiratory illness and encephalitis in humans. To identify novel small molecules that target Nipah virus replication as potential therapeutics, Southern Research Institute and Galveston National Laboratory jointly developed an automated high-throughput screening platform that is capable of testing 10,000 compounds per day within BSL-4 biocontainment. Using this platform, we screened a 10,080-compound library using a cell-based, high-throughput screen for compounds that inhibited the virus-induced cytopathic effect. From this pilot effort, 23 compounds were identified with EC50 values ranging from 3.9 to 20.0 μM and selectivities >10. Three sulfonamide compounds with EC50 values <12 μM were further characterized for their point of intervention in the viral replication cycle and for broad antiviral efficacy. Development of HTS capability under BSL-4 containment changes the paradigm for drug discovery for highly pathogenic agents because this platform can be readily modified to identify prophylactic and postexposure therapeutic candidates against other BSL-4 pathogens, particularly Ebola, Marburg, and Lassa viruses. PMID:24735442

The neurovirulence and neuroinvasiveness of chimeric tick-borne encephalitis/dengue virus can be attenuated by introducing defined mutations into the envelope and NS5 protein genes and the 3' non-coding region of the genome

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

Engel, Amber R., E-mail: engelam@mail.nih.go; Rumyantsev, Alexander A., E-mail: alexander.rumyantsev@sanofipasteur.co; Maximova, Olga A., E-mail: maximovao@mail.nih.go

Tick-borne encephalitis (TBE) is a severe disease affecting thousands of people throughout Eurasia. Despite the use of formalin-inactivated vaccines in endemic areas, an increasing incidence of TBE emphasizes the need for an alternative vaccine that will induce a more durable immunity against TBE virus (TBEV). The chimeric attenuated virus vaccine candidate containing the structural protein genes of TBEV on a dengue virus genetic background (TBEV/DEN4) retains a high level of neurovirulence in both mice and monkeys. Therefore, attenuating mutations were introduced into the envelope (E{sub 315}) and NS5 (NS5{sub 654,655}) proteins, and into the 3' non-coding region ({Delta}30) of TBEV/DEN4.more » The variant that contained all three mutations (v{Delta}30/E{sub 315}/NS5{sub 654,655}) was significantly attenuated for neuroinvasiveness and neurovirulence and displayed a reduced level of replication and virus-induced histopathology in the brains of mice. The high level of safety in the central nervous system indicates that v{Delta}30/E{sub 315}/NS5{sub 654,655} should be further evaluated as a TBEV vaccine.« less

[Post-herpes simplex encephalitis chorea: Viral replication or immunological mechanism?].

PubMed

Benrhouma, H; Nasri, A; Kraoua, I; Klaa, H; Turki, I; Gouider-Khouja, N

2015-09-01

Herpes simplex encephalitis is a severe neurological condition, whose outcome is improved if treated early with acyclovir. Post-herpes simplex encephalitis with acute chorea has rarely been reported. We report on two observations of children presenting with post-herpes simplex encephalitis with acute chorea, related to two different pathophysiological mechanisms. The first one is an 11-month-old girl developing relapsing herpes simplex encephalitis with chorea due to resumption of viral replication. The second one is a 2-year-old boy with relapsing post-herpes simplex encephalitis acute chorea caused by an immunoinflammatory mechanism. We discuss the different neurological presentations of herpetic relapses, notably those presenting with movement disorders, as well as their clinical, paraclinical, physiopathological, and therapeutic aspects. Post-herpes simplex encephalitis with acute chorea may involve two mechanisms: resumption of viral replication or an immunoinflammatory mechanism. Treatment of post-herpes simplex encephalitis with acute chorea depends on the underlying mechanism, while prevention is based on antiviral treatment of herpes simplex encephalitis with acyclovir at the dose of 20mg/kg/8h for 21 days. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

The Role of IKKβ in Venezuelan Equine Encephalitis Virus Infection

PubMed Central

Amaya, Moushimi; Voss, Kelsey; Sampey, Gavin; Senina, Svetlana; de la Fuente, Cynthia; Mueller, Claudius; Calvert, Valerie; Kehn-Hall, Kylene; Carpenter, Calvin; Kashanchi, Fatah; Bailey, Charles; Mogelsvang, Soren; Petricoin, Emanuel; Narayanan, Aarthi

2014-01-01

Venezuelan equine encephalitis virus (VEEV) belongs to the genus Alphavirus, family Togaviridae. VEEV infection is characterized by extensive inflammation and studies from other laboratories implicated an involvement of the NF-κB cascade in the in vivo pathology. Initial studies indicated that at early time points of VEEV infection, the NF-κB complex was activated in cells infected with the TC-83 strain of VEEV. One upstream kinase that contributes to the phosphorylation of p65 is the IKKβ component of the IKK complex. Our previous studies with Rift valley fever virus, which exhibited early activation of the NF-κB cascade in infected cells, had indicated that the IKKβ component underwent macromolecular reorganization to form a novel low molecular weight form unique to infected cells. This prompted us to investigate if the IKK complex undergoes a comparable macromolecular reorganization in VEEV infection. Size-fractionated VEEV infected cell extracts indicated a macromolecular reorganization of IKKβ in VEEV infected cells that resulted in formation of lower molecular weight complexes. Well-documented inhibitors of IKKβ function, BAY-11-7082, BAY-11-7085 and IKK2 compound IV, were employed to determine whether IKKβ function was required for the production of infectious progeny virus. A decrease in infectious viral particles and viral RNA copies was observed with inhibitor treatment in the attenuated and virulent strains of VEEV infection. In order to further validate the requirement of IKKβ for VEEV replication, we over-expressed IKKβ in cells and observed an increase in viral titers. In contrast, studies carried out using IKKβ−/− cells demonstrated a decrease in VEEV replication. In vivo studies demonstrated that inhibitor treatment of TC-83 infected mice increased their survival. Finally, proteomics studies have revealed that IKKβ may interact with the viral protein nsP3. In conclusion, our studies have revealed that the host IKKβ protein may be critically involved in VEEV replication. PMID:24586253

Altered development of the brain after focal herpesvirus infection of the central nervous system.

PubMed

Koontz, Thad; Bralic, Marina; Tomac, Jelena; Pernjak-Pugel, Ester; Bantug, Glen; Jonjic, Stipan; Britt, William J

2008-02-18

Human cytomegalovirus infection of the developing central nervous system (CNS) is a major cause of neurological damage in newborn infants and children. To investigate the pathogenesis of this human infection, we developed a mouse model of infection in the developing CNS. Intraperitoneal inoculation of newborn animals with murine cytomegalovirus resulted in virus replication in the liver followed by virus spread to the brain. Virus infection of the CNS was associated with the induction of inflammatory responses, including the induction of a large number of interferon-stimulated genes and histological evidence of focal encephalitis with recruitment of mononuclear cells to foci containing virus-infected cells. The morphogenesis of the cerebellum was delayed in infected animals. The defects in cerebellar development in infected animals were generalized and, although correlated temporally with virus replication and CNS inflammation, spatially unrelated to foci of virus-infected cells. Specific defects included decreased granular neuron proliferation and migration, expression of differentiation markers, and activation of neurotrophin receptors. These findings suggested that in the developing CNS, focal virus infection and induction of inflammatory responses in resident and infiltrating mononuclear cells resulted in delayed cerebellar morphogenesis.

Altered development of the brain after focal herpesvirus infection of the central nervous system

PubMed Central

Koontz, Thad; Bralic, Marina; Tomac, Jelena; Pernjak-Pugel, Ester; Bantug, Glen; Jonjic, Stipan; Britt, William J.

2008-01-01

Human cytomegalovirus infection of the developing central nervous system (CNS) is a major cause of neurological damage in newborn infants and children. To investigate the pathogenesis of this human infection, we developed a mouse model of infection in the developing CNS. Intraperitoneal inoculation of newborn animals with murine cytomegalovirus resulted in virus replication in the liver followed by virus spread to the brain. Virus infection of the CNS was associated with the induction of inflammatory responses, including the induction of a large number of interferon-stimulated genes and histological evidence of focal encephalitis with recruitment of mononuclear cells to foci containing virus-infected cells. The morphogenesis of the cerebellum was delayed in infected animals. The defects in cerebellar development in infected animals were generalized and, although correlated temporally with virus replication and CNS inflammation, spatially unrelated to foci of virus-infected cells. Specific defects included decreased granular neuron proliferation and migration, expression of differentiation markers, and activation of neurotrophin receptors. These findings suggested that in the developing CNS, focal virus infection and induction of inflammatory responses in resident and infiltrating mononuclear cells resulted in delayed cerebellar morphogenesis. PMID:18268036

Increased Relative Risk of Tick-Borne Encephalitis in Warmer Weather.

PubMed

Daniel, Milan; Danielová, Vlasta; Fialová, Alena; Malý, Marek; Kříž, Bohumír; Nuttall, Patricia A

2018-01-01

Tick-borne encephalitis (TBE) is a serious acute neuroinfection of humans caused by a tick-borne flavivirus. The disease is typically seasonal, linked to the host-seeking activity of Ixodes ricinus (predominantly nymphs), the principal European tick vector species. To address the need for accurate risk predictions of contracting TBE, data on 4,044 TBE cases reported in the Czech Republic during 2001-2006 were compared with questing activity of I. ricinus nymphs monitored weekly at a defined location for the same 6-year period. A time shift of 21 days between infected tick bite and recorded disease onset provided the optimal model for comparing the number of cases of TBE with numbers of questing nymphs. Mean annual distribution of TBE cases and tick counts showed a similar bimodal distribution. Significantly, the ratio of TBE cases to questing nymphs was highest in the summer-autumn period even though the number of questing nymphs peaked in the spring-summer period. However, this pattern changed during a period of extreme meteorological events of flooding and abnormally high temperatures, indicating that changes in climate affect the incidence of TBE. Previous studies failed to link human behavior with changes in incidence of TBE but showed extrinsic temperature impacts arbovirus replication. Hence, we hypothesize the apparent discrepancy between peak nymphal tick activity and greatest risk of contracting TBE is due to the effect of temperature on virus replication in the tick vector. Relative proportions of questing nymphs and the numbers of weeks in which they were found were greater in summer-autumn compared with spring-summer at near-ground temperatures >5°C and at standard day and weekly average temperatures of >15°C. Thus, during the summer-autumn period, the virus dose in infected tick bites is likely greater owing to increased virus replication at higher microclimatic temperatures, consequently increasing the relative risk of contracting TBE per summer-autumn tick bite. The data support the use of weather-based forecasts of tick attack risk (based on daytime ambient temperature) supplemented with weekly average temperature (as a proxy for virus replication) to provide much-needed real-time forecasts of TBE risk.

Adaptive evolution of simian immunodeficiency viruses isolated from two conventional progressor macaques with neuroaids

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

Foley, Brian T; Korber, Bette T

2008-01-01

Simian immunodeficiency virus infection of macaques may result in neuroAIDS, a feature more commonly observed in macaques with rapid progressive disease than in those with conventional disease. This is the first report of two conventional progressors (H631 and H636) with encephalitis in rhesus macaques inoculated with a derivative of SIVsmES43-3. Phylogenetic analyses of viruses isolated from the cerebral spinal fluid (CSF) and plasma from both animals demonstrated tissue compartmentalization. Additionally, virus from the central nervous system (CNS) was able to infect primary macaque monocyte-derived macrophages more efficiently than virus from plasma. Conversely, virus isolated from plasma was able to replicatemore » better in peripheral blood mononuclear cells than virus from CNS. We speculate that these viruses were under different selective pressures in their separate compartments. Furthermore, these viruses appear to have undergone adaptive evolution to preferentially replicate in their respective cell targets. Analysis of the number of potential N-linked glycosylation sites (PNGS) in gp160 showed that there was a statistically significant loss of PNGS in viruses isolated from CNS in both macaques compared to SIVsmE543-3. Moreover, virus isolated from the brain in H631, had statistically significant loss of PNGS compared to virus isolated from CSF and plasma of the same animal. It is possible that the brain isolate may have adapted to decrease the number of PNGS given that humoral immune selection pressure is less likely to be encountered in the brain. These viruses provide a relevant model to study the adaptations required for SIV to induce encephalitis.« less

Selective Inhibitor of Nuclear Export (SINE) Compounds Alter New World Alphavirus Capsid Localization and Reduce Viral Replication in Mammalian Cells.

PubMed

Lundberg, Lindsay; Pinkham, Chelsea; de la Fuente, Cynthia; Brahms, Ashwini; Shafagati, Nazly; Wagstaff, Kylie M; Jans, David A; Tamir, Sharon; Kehn-Hall, Kylene

2016-11-01

The capsid structural protein of the New World alphavirus, Venezuelan equine encephalitis virus (VEEV), interacts with the host nuclear transport proteins importin α/β1 and CRM1. Novel selective inhibitor of nuclear export (SINE) compounds, KPT-185, KPT-335 (verdinexor), and KPT-350, target the host's primary nuclear export protein, CRM1, in a manner similar to the archetypical inhibitor Leptomycin B. One major limitation of Leptomycin B is its irreversible binding to CRM1; which SINE compounds alleviate because they are slowly reversible. Chemically inhibiting CRM1 with these compounds enhanced capsid localization to the nucleus compared to the inactive compound KPT-301, as indicated by immunofluorescent confocal microscopy. Differences in extracellular versus intracellular viral RNA, as well as decreased capsid in cell free supernatants, indicated the inhibitors affected viral assembly, which led to a decrease in viral titers. The decrease in viral replication was confirmed using a luciferase-tagged virus and through plaque assays. SINE compounds had no effect on VEEV TC83_Cm, which encodes a mutated form of capsid that is unable to enter the nucleus. Serially passaging VEEV in the presence of KPT-185 resulted in mutations within the nuclear localization and nuclear export signals of capsid. Finally, SINE compound treatment also reduced the viral titers of the related eastern and western equine encephalitis viruses, suggesting that CRM1 maintains a common interaction with capsid proteins across the New World alphavirus genus.

Properties of the tick-borne encephalitis virus population during persistent infection of ixodid ticks and tick cell lines.

PubMed

Belova, Oxana A; Litov, Alexander G; Kholodilov, Ivan S; Kozlovskaya, Liubov I; Bell-Sakyi, Lesley; Romanova, Lidiya Iu; Karganova, Galina G

2017-10-01

Tick-borne encephalitis virus (TBEV) is the causative agent of tick-borne encephalitis (TBE), a vector-borne zoonotic neuroinfection. For successful circulation in natural foci the virus has to survive in the vector for a long period of time. Information about the effect of long-term infection of ticks on properties of the viral population is of great importance. In recent years, changes in the eco-epidemiology of TBEV due to changes in distribution of ixodid ticks have been observed. These changes in TBEV-endemic areas could result in a shift of the main tick vector species, which in turn may lead to changes in properties of the virus. In the present study we evaluated the selective pressure on the TBEV population during persistent infection of various species of ticks and tick cell lines. TBEV effectively replicated and formed persistent infection in ticks and tick cell lines of the vector species (Ixodes spp.), potential vectors (Dermacentor spp.) and non-vector ticks (Hyalomma spp.). During TBEV persistence in Ixodes and Dermacentor ticks, properties of the viral population remained virtually unchanged. In contrast, persistent TBEV infection of tick cell lines from both vector and non-vector ticks favoured selection of viral variants with low neuroinvasiveness for laboratory mice and substitutions in the E protein that increased local positive charge of the virion. Thus, selective pressure on viral population may differ in ticks and tick cell lines during persistent infection. Nevertheless, virus variants with properties of the original strain adapted to mouse CNS were not eliminated from the viral population during long-term persistence of TBEV in ticks and tick cell lines. Copyright © 2017 Elsevier GmbH. All rights reserved.

Annual Progress Report--Fiscal Year 1979

DTIC Science & Technology

1979-10-01

fever virus Ebola fever virus Korean hemorrhagic fever virus Rift Valley fever virus Bolivian hemorrhagic fever virus...Machupo) Argentinian hemorrhagic fever virus (Junin) Dengue fever virus Congo/Crimean hemorrhagic fever virus Sand fly fever virus Eastern encephalitis...virus Western encephalitis virus Venezuelan fever virus Japanese B fever virus Chikungunya virus Tacaribe virus Pichinde virus Yellow fever

Eastern equine encephalomyelitis

USGS Publications Warehouse

Hansen, W.; Docherty, D.E.

1999-01-01

Eastern equine encephalitis (EEE) is caused by infection with an RNA virus classified in the family Togaviridae. The virus is also referred to as an “arbovirus” because virus replication takes place within mosquitoes that then transmit the disease agent to vertebrate hosts such as birds and mammals, including humans. The term arbovirus is shortened nomenclature for arthropod (insect) borne (transmitted) viruses. Culiseta melanura is the most important mosquito vector; it silently (no disease) transmits and maintains the virus among birds. However, several other mosquito species can transmit this virus, including the introduced Asian tiger mosquito. New hosts become infected when they enter this endemic natural cycle and are fed upon by an infected mosquito. Therefore, the presence of mosquito habitat, the feeding habits of different mosquito species, and the activity patterns of vertebrate hosts are among the important factors for disease transmission.

Japanese encephalitis virus replication is negatively regulated by autophagy and occurs on LC3-I- and EDEM1-containing membranes.

PubMed

Sharma, Manish; Bhattacharyya, Sankar; Nain, Minu; Kaur, Manpreet; Sood, Vikas; Gupta, Vishal; Khasa, Renu; Abdin, Malik Z; Vrati, Sudhanshu; Kalia, Manjula

2014-09-01

Autophagy is a lysosomal degradative pathway that has diverse physiological functions and plays crucial roles in several viral infections. Here we examine the role of autophagy in the life cycle of JEV, a neurotropic flavivirus. JEV infection leads to induction of autophagy in several cell types. JEV replication was significantly enhanced in neuronal cells where autophagy was rendered dysfunctional by ATG7 depletion, and in Atg5-deficient mouse embryonic fibroblasts (MEFs), resulting in higher viral titers. Autophagy was functional during early stages of infection however it becomes dysfunctional as infection progressed resulting in accumulation of misfolded proteins. Autophagy-deficient cells were highly susceptible to virus-induced cell death. We also observed JEV replication complexes that are marked by nonstructural protein 1 (NS1) and dsRNA colocalized with endogenous LC3 but not with GFP-LC3. Colocalization of NS1 and LC3 was also observed in Atg5 deficient MEFs, which contain only the nonlipidated form of LC3. Viral replication complexes furthermore show association with a marker of the ER-associated degradation (ERAD) pathway, EDEM1 (ER degradation enhancer, mannosidase α-like 1). Our data suggest that virus replication occurs on ERAD-derived EDEM1 and LC3-I-positive structures referred to as EDEMosomes. While silencing of ERAD regulators EDEM1 and SEL1L suppressed JEV replication, LC3 depletion exerted a profound inhibition with significantly reduced RNA levels and virus titers. Our study suggests that while autophagy is primarily antiviral for JEV and might have implications for disease progression and pathogenesis of JEV, nonlipidated LC3 plays an important autophagy independent function in the virus life cycle.

Japanese Encephalitis Virus in Meningitis Patients, Japan

PubMed Central

Ito, Mikako; Takao, Shinichi; Shimazu, Yukie; Fukuda, Shinji; Miyazaki, Kazuo; Kurane, Ichiro; Takasaki, Tomohiko

2005-01-01

Cerebrospinal fluid specimens from 57 patients diagnosed with meningitis were tested for Japanese encephalitis virus. Total RNA was extracted from the specimens and amplified. Two products had highest homology with Nakayama strain and 2 with Ishikawa strain. Results suggest that Japanese encephalitis virus causes some aseptic meningitis in Japan. PMID:15757569

Characterization of Reemerging Chikungunya Virus

PubMed Central

Sourisseau, Marion; Schilte, Clémentine; Casartelli, Nicoletta; Trouillet, Céline; Guivel-Benhassine, Florence; Rudnicka, Dominika; Sol-Foulon, Nathalie; Roux, Karin Le; Prevost, Marie-Christine; Fsihi, Hafida; Frenkiel, Marie-Pascale; Blanchet, Fabien; Afonso, Philippe V; Ceccaldi, Pierre-Emmanuel; Ozden, Simona; Gessain, Antoine; Schuffenecker, Isabelle; Verhasselt, Bruno; Zamborlini, Alessia; Saïb, Ali; Rey, Felix A; Arenzana-Seisdedos, Fernando; Desprès, Philippe; Michault, Alain; Albert, Matthew L; Schwartz, Olivier

2007-01-01

An unprecedented epidemic of chikungunya virus (CHIKV) infection recently started in countries of the Indian Ocean area, causing an acute and painful syndrome with strong fever, asthenia, skin rash, polyarthritis, and lethal cases of encephalitis. The basis for chikungunya disease and the tropism of CHIKV remain unknown. Here, we describe the replication characteristics of recent clinical CHIKV strains. Human epithelial and endothelial cells, primary fibroblasts and, to a lesser extent, monocyte-derived macrophages, were susceptible to infection and allowed viral production. In contrast, CHIKV did not replicate in lymphoid and monocytoid cell lines, primary lymphocytes and monocytes, or monocyte-derived dendritic cells. CHIKV replication was cytopathic and associated with an induction of apoptosis in infected cells. Chloroquine, bafilomycin-A1, and short hairpin RNAs against dynamin-2 inhibited viral production, indicating that viral entry occurs through pH-dependent endocytosis. CHIKV was highly sensitive to the antiviral activity of type I and II interferons. These results provide a general insight into the interaction between CHIKV and its mammalian host. PMID:17604450

Zika Virus Antagonizes Type I Interferon Responses during Infection of Human Dendritic Cells

PubMed Central

Maddur, Mohan S.; O’Neal, Justin T.; Fedorova, Nadia B.; Puri, Vinita; Pulendran, Bali; Suthar, Mehul S.

2017-01-01

Zika virus (ZIKV) is an emerging mosquito-borne flavivirus that is causally linked to severe neonatal birth defects, including microcephaly, and is associated with Guillain-Barre syndrome in adults. Dendritic cells (DCs) are an important cell type during infection by multiple mosquito-borne flaviviruses, including dengue virus, West Nile virus, Japanese encephalitis virus, and yellow fever virus. Despite this, the interplay between ZIKV and DCs remains poorly defined. Here, we found human DCs supported productive infection by a contemporary Puerto Rican isolate with considerable variability in viral replication, but not viral binding, between DCs from different donors. Historic isolates from Africa and Asia also infected DCs with distinct viral replication kinetics between strains. African lineage viruses displayed more rapid replication kinetics and infection magnitude as compared to Asian lineage viruses, and uniquely induced cell death. Infection of DCs with both contemporary and historic ZIKV isolates led to minimal up-regulation of T cell co-stimulatory and MHC molecules, along with limited secretion of inflammatory cytokines. Inhibition of type I interferon (IFN) protein translation was observed during ZIKV infection, despite strong induction at the RNA transcript level and up-regulation of other host antiviral proteins. Treatment of human DCs with RIG-I agonist potently restricted ZIKV replication, while type I IFN had only modest effects. Mechanistically, we found all strains of ZIKV antagonized type I IFN-mediated phosphorylation of STAT1 and STAT2. Combined, our findings show that ZIKV subverts DC immunogenicity during infection, in part through evasion of type I IFN responses, but that the RLR signaling pathway is still capable of inducing an antiviral state, and therefore may serve as an antiviral therapeutic target. PMID:28152048

Regulation of Flavivirus RNA synthesis and replication

PubMed Central

Selisko, Barbara; Wang, Chunling; Harris, Eva; Canard, Bruno

2014-01-01

RNA synthesis and replication of the members of the Flavivirus genus (including dengue, West Nile and Japanese encephalitis viruses) is regulated by a wide variety of mechanisms and actors. These include the sequestration of the RNA-dependent RNA polymerase (RdRp) for functions other than RNA synthesis, regulatory interactions with other viral and host proteins within the replication complex (RC), and regulatory elements within the RNA genome itself. In this review, we discuss our current knowledge of the multiple levels at which Flavivirus RNA synthesis is controlled. We aim to bring together two active research fields: the structural and functional biology of individual proteins of the RC and the impressive wealth of knowledge acquired regarding the viral genomic RNA. PMID:25462437

Quantification of vector and host competence for Japanese encephalitis virus: a systematic review of the literature

USDA-ARS?s Scientific Manuscript database

Japanese encephalitis virus (JEV) is a virus of the Flavivirus genus that may result in encephalitis in human hosts. This vector-borne zoonosis occurs in Eastern and Southeastern Asia and an intentional or inadvertent introduction into the United States (US) will have major public health and economi...

West Nile Virus Encephalitis: The First Human Case Recorded in Brazil

PubMed Central

Vieira, Marcelo A. C. S.; Romano, Alessandro P. M.; Borba, Amaríles S.; Silva, Eliana V. P.; Chiang, Jannifer O.; Eulálio, Kelsen D.; Azevedo, Raimunda S. S.; Rodrigues, Sueli G.; Almeida-Neto, Walfrido S.; Vasconcelos, Pedro F. C.

2015-01-01

A Brazilian ranch worker with encephalitis and flaccid paralysis was evaluated in the regional Acute Encephalitis Syndromic Surveillance Program. This was the first Brazilian patient who met the Centers for Disease Control and Prevention (CDC) confirmation criteria for West Nile virus disease. Owing to the overlapping of neurological manifestations attributable to several viral infections of the central nervous system, this report exemplifies the importance of human acute encephalitis surveillance. The syndromic approach to human encephalitis cases may enable early detection of the introduction of unusual virus or endemic occurrence of potentially alarming diseases within a region. PMID:26055749

[The role of wild murine rodents in the selection of different strains of tick-borne encephalitis and Powassan viruses].

PubMed

Leonova, G N; Krugliak, S P; Lozovskaia, S A; Rybachuk, V N

1987-01-01

The study demonstrated the role of wild murine rodents in selection of different strains of tick-borne encephalitis and Powassan viruses, determined their ecological characteristics reflected in the epidemiological features of tick-borne encephalitis and Powassan encephalitis in southern Far East.

Powassan virus encephalitis, Minnesota, USA.

PubMed

Birge, Justin; Sonnesyn, Steven

2012-10-01

Powassan virus (POWV) is a rare tick-borne agent of encephalitis in North America. Historically, confirmed cases occurred mainly in the northeastern United States. Since 2008, confirmed cases in Minnesota and Wisconsin have increased. We report a fatal case of POWV encephalitis in Minnesota. POWV infection should be suspected in tick-exposed patients with viral encephalitis.

Powassan Virus Encephalitis, Minnesota, USA

PubMed Central

Sonnesyn, Steven

2012-01-01

Powassan virus (POWV) is a rare tick-borne agent of encephalitis in North America. Historically, confirmed cases occurred mainly in the northeastern United States. Since 2008, confirmed cases in Minnesota and Wisconsin have increased. We report a fatal case of POWV encephalitis in Minnesota. POWV infection should be suspected in tick-exposed patients with viral encephalitis. PMID:23017222

Structural Study of the C-Terminal Domain of Nonstructural Protein 1 from Japanese Encephalitis Virus.

PubMed

Poonsiri, Thanalai; Wright, Gareth S A; Diamond, Michael S; Turtle, Lance; Solomon, Tom; Antonyuk, Svetlana V

2018-04-01

Japanese encephalitis virus (JEV) is a mosquito-transmitted flavivirus that is closely related to other emerging viral pathogens, including dengue virus (DENV), West Nile virus (WNV), and Zika virus (ZIKV). JEV infection can result in meningitis and encephalitis, which in severe cases cause permanent brain damage and death. JEV occurs predominantly in rural areas throughout Southeast Asia, the Pacific Islands, and the Far East, causing around 68,000 cases of infection worldwide each year. In this report, we present a 2.1-Å-resolution crystal structure of the C-terminal β-ladder domain of JEV nonstructural protein 1 (NS1-C). The surface charge distribution of JEV NS1-C is similar to those of WNV and ZIKV but differs from that of DENV. Analysis of the JEV NS1-C structure, with in silico molecular dynamics simulation and experimental solution small-angle X-ray scattering, indicates extensive loop flexibility on the exterior of the protein. This, together with the surface charge distribution, indicates that flexibility influences the protein-protein interactions that govern pathogenicity. These factors also affect the interaction of NS1 with the 22NS1 monoclonal antibody, which is protective against West Nile virus infection. Liposome and heparin binding assays indicate that only the N-terminal region of NS1 mediates interaction with membranes and that sulfate binding sites common to NS1 structures are not glycosaminoglycan binding interfaces. This report highlights several differences between flavivirus NS1 proteins and contributes to our understanding of their structure-pathogenic function relationships. IMPORTANCE JEV is a major cause of viral encephalitis in Asia. Despite extensive vaccination, epidemics still occur. Nonstructural protein 1 (NS1) plays a role in viral replication, and, because it is secreted, it can exhibit a wide range of interactions with host proteins. NS1 sequence and protein folds are conserved within the Flavivirus genus, but variations in NS1 protein-protein interactions among viruses likely contribute to differences in pathogenesis. Here, we compared characteristics of the C-terminal β-ladder domain of NS1 between flaviviruses, including surface charge, loop flexibility, epitope cross-reactivity, membrane adherence, and glycosaminoglycan binding. These structural features are central to NS1 functionality and may provide insight into the development of diagnostic tests and therapeutics. Copyright © 2018 American Society for Microbiology.

N-Desmethylclozapine, Fluoxetine, and Salmeterol Inhibit Postentry Stages of the Dengue Virus Life Cycle.

PubMed

Medigeshi, Guruprasad R; Kumar, Rinki; Dhamija, Ekta; Agrawal, Tanvi; Kar, Meenakshi

2016-11-01

Around 10,000 people die each year due to severe dengue disease, and two-thirds of the world population lives in a region where dengue disease is endemic. There has been remarkable progress in dengue virus vaccine development; however, there are no licensed antivirals for dengue disease, and none appear to be in clinical trials. We took the approach of repositioning approved drugs for anti-dengue virus activity by screening a library of pharmacologically active compounds. We identified N-desmethylclozapine, fluoxetine hydrochloride, and salmeterol xinafoate as dengue virus inhibitors based on reductions in the numbers of infected cells and viral titers. Dengue virus RNA levels were diminished in inhibitor-treated cells, and this effect was specific to dengue virus, as other flaviviruses, such as Japanese encephalitis virus and West Nile virus, or other RNA viruses, such as respiratory syncytial virus and rotavirus, were not affected by these inhibitors. All three inhibitors specifically inhibited dengue virus replication with 50% inhibitory concentrations (IC 50 s) in the high-nanomolar range. Estimation of negative-strand RNA intermediates and time-of-addition experiments indicated that inhibition was occurring at a postentry stage, most probably at the initiation of viral RNA replication. Finally, we show that inhibition is most likely due to the modulation of the endolysosomal pathway and induction of autophagy. Copyright © 2016 Medigeshi et al.

Enhancing the antiviral potency of ER α-glucosidase inhibitor IHVR-19029 against hemorrhagic fever viruses in vitro and in vivo.

PubMed

Ma, Julia; Zhang, Xuexiang; Soloveva, Veronica; Warren, Travis; Guo, Fang; Wu, Shuo; Lu, Huagang; Guo, Jia; Su, Qing; Shen, Helen; Solon, Eric; Comunale, Mary Ann; Mehta, Anand; Guo, Ju-Tao; Bavari, Sina; Du, Yanming; Block, Timothy M; Chang, Jinhong

2018-02-01

Targeting host functions essential for viral replication has been considered as a broad spectrum and resistance-refractory antiviral approach. However, only a few host functions have, thus far, been validated as broad-spectrum antiviral targets in vivo. ER α-glucosidases I and II have been demonstrated to be essential for the morphogenesis of many enveloped viruses, including members from four families of viruses causing hemorrhagic fever. In vivo antiviral efficacy of various iminosugar-based ER α-glucosidase inhibitors has been reported in animals infected with Dengue, Japanese encephalitis, Ebola, Marburg and influenza viruses. Herein, we established Huh7.5-derived cell lines with ER α-glucosidase I or II knockout using CRISPR/Cas9 and demonstrated that the replication of Dengue, Yellow fever and Zika viruses was reduced by only 1-2 logs in the knockout cell lines. The results clearly indicate that only a partial suppression of viral replication can possibly be achieved with a complete inhibition of ER-α-glucosidases I or II by their inhibitors. We therefore explore to improve the antiviral efficacy of a lead iminosugar IHVR-19029 through combination with another broad-spectrum antiviral agent, favipiravir (T-705). Indeed, combination of IHVR-19029 and T-705 synergistically inhibited the replication of Yellow fever and Ebola viruses in cultured cells. Moreover, in a mouse model of Ebola virus infection, combination of sub-optimal doses of IHVR-19029 and T-705 significantly increased the survival rate of infected animals. We have thus proved the concept of combinational therapeutic strategy for the treatment of viral hemorrhagic fevers with broad spectrum host- and viral- targeting antiviral agents. Copyright © 2017 Elsevier B.V. All rights reserved.

Fatal Tick-Borne Encephalitis Virus Infections Caused by Siberian and European Subtypes, Finland, 2015.

PubMed

Kuivanen, Suvi; Smura, Teemu; Rantanen, Kirsi; Kämppi, Leena; Kantonen, Jonas; Kero, Mia; Jääskeläinen, Anu; Jääskeläinen, Anne J; Sane, Jussi; Myllykangas, Liisa; Paetau, Anders; Vapalahti, Olli

2018-05-01

In most locations except for Russia, tick-borne encephalitis is mainly caused by the European virus subtype. In 2015, fatal infections caused by European and Siberian tick-borne encephalitis virus subtypes in the same Ixodes ricinus tick focus in Finland raised concern over further spread of the Siberian subtype among widespread tick species.

Quantification of vector and host competence and abundance for Japanese Encephalitis Virus: a systematic review of the literature.

USDA-ARS?s Scientific Manuscript database

Japanese encephalitis (JE) is a vector-borne disease caused by the Japanese encephalitis virus (JEV) that affects humans in Eastern and Southeastern Asia. Although it could be prevented by a vaccine, JE has no treatment and the inadvertent introduction of the virus into JEV-free countries, such as t...

A systematic review of the literature to identify and quantify host and vector competence and abundance of Japanese Encephalitis Virus

USDA-ARS?s Scientific Manuscript database

Japanese Encephalitis virus (JEV) is a mosquito-borne arbovirus that causes endemic and epidemic encephalitis in Eastern and Southeastern Asia. Swine and wading birds serve as reservoirs for the virus, which can be transmitted to humans via mosquitos. Currently, there is no specific treatment availa...

Fatal Infection with Murray Valley Encephalitis Virus Imported from Australia to Canada, 2011.

PubMed

Niven, Daniel J; Afra, Kevin; Iftinca, Mircea; Tellier, Raymond; Fonseca, Kevin; Kramer, Andreas; Safronetz, David; Holloway, Kimberly; Drebot, Michael; Johnson, Andrew S

2017-02-01

Murray Valley encephalitis virus (MVEV), a flavivirus belonging to the Japanese encephalitis serogroup, can cause severe clinical manifestations in humans. We report a fatal case of MVEV infection in a young woman who returned from Australia to Canada. The differential diagnosis for travel-associated encephalitis should include MVEV, particularly during outbreak years.

ST. LOUIS ENCEPHALITIS

PubMed Central

Smith, Margaret G.; Blattner, Russell J.; Heys, Florence M.

1947-01-01

Transmission of the virus of St. Louis encephalitis to normal chickens by the bite of infected mites (Dermanyssus gallinae) has been demonstrated. Both experimentally infected and naturally infected mites were shown to be capable of transferring the virus of St. Louis encephalitis to chickens by bite. Virus is present in the blood of such chickens in small amounts, so that demonstration of viremia was possible only by utilizing chorioallantoic passage in hens' eggs. However, there is sufficient virus present in the blood for uninfected chicken mites to acquire the virus by feeding on chickens in which viremia has resulted from previous bite of infected mites. Thus it has been shown that the arachnid vector Dermanyssus gallinae is capable of transmitting the virus of St. Louis encephalitis to normal chickens by bite and that such chickens can serve as a source of virus for uninfected mites. PMID:19871673

Herpes simplex encephalitis with thalamic, brainstem and cerebellar involvement.

PubMed

Garg, Meenal; Kulkarni, Shilpa; Udwadia Hegde, Anaita

2018-04-01

Herpes simplex virus encephalitis is a common and treatable cause of acute encephalitis in all age groups. Certain radiological features such as temporal parenchymal involvement facilitate the diagnosis. The use of herpes simplex virus polymerase chain reaction has expanded the clinical and imaging spectrum. We report the case of a young patient who presented with a movement disorder and predominant involvement of thalami, brainstem and cerebellum on magnetic resonance imaging, and was diagnosed with herpes simplex virus encephalitis. Differentiation from Japanese encephalitis may be difficult in these patients, especially in endemic areas, and may necessitate the use of relevant investigations in all patients.

Single-cycle replicable Rift Valley fever virus mutants as safe vaccine candidates

PubMed Central

Terasaki, Kaori; Tercero, Breanna R.; Makino, Shinji

2015-01-01

Rift Valley fever virus (RVFV) is an arbovirus circulating between ruminants and mosquitoes to maintain its enzootic cycle. Humans are infected with RVFV through mosquito bites or direct contact with materials of infected animals. The virus causes Rift Valley fever, which was first recognized in the Great Rift Valley of Kenya in 1931. RVFV is characterized by a febrile illness resulting in a high rate of abortions in ruminants and an acute febrile illness, followed by fatal hemorrhagic fever and encephalitis in humans. Initially, the virus was restricted to the eastern region of Africa, but the disease has now spread to southern and western Africa, as well as outside of the African continent, e.g., Madagascar, Saudi Arabia and Yemen. There is a serious concern that the virus may spread to other areas, such as North America and Europe. As vaccination is an effective tool to control RVFV epidemics, formalin-inactivated vaccines and live-attenuated RVFV vaccines have been used in endemic areas. The formalin-inactivated vaccines require boosters for effective protection, whereas the live-attenuated vaccines enable the induction of protective immunity by a single vaccination. However, the use of live-attenuated RVFV vaccines for large human populations having a varied health status is of concern, because of these vaccines’ residual neuro-invasiveness and neurovirulence. Recently, novel vaccine candidates have been developed using replication-defective RVFV that can undergo only a single round of replication in infected cells. The single-cycle replicable RVFV does not cause systemic infection in immunized hosts, but enables the conferring of protective immunity. This review summarizes the properties of various RVFV vaccines and recent progress on the development of the single-cycle replicable RVFV vaccines. PMID:26022573

Single-cycle replicable Rift Valley fever virus mutants as safe vaccine candidates.

PubMed

Terasaki, Kaori; Tercero, Breanna R; Makino, Shinji

2016-05-02

Rift Valley fever virus (RVFV) is an arbovirus circulating between ruminants and mosquitoes to maintain its enzootic cycle. Humans are infected with RVFV through mosquito bites or direct contact with materials of infected animals. The virus causes Rift Valley fever (RVF), which was first recognized in the Great Rift Valley of Kenya in 1931. RVF is characterized by a febrile illness resulting in a high rate of abortions in ruminants and an acute febrile illness, followed by fatal hemorrhagic fever and encephalitis in humans. Initially, the virus was restricted to the eastern region of Africa, but the disease has now spread to southern and western Africa, as well as outside of the African continent, e.g., Madagascar, Saudi Arabia and Yemen. There is a serious concern that the virus may spread to other areas, such as North America and Europe. As vaccination is an effective tool to control RVFV epidemics, formalin-inactivated vaccines and live-attenuated RVFV vaccines have been used in endemic areas. The formalin-inactivated vaccines require boosters for effective protection, whereas the live-attenuated vaccines enable the induction of protective immunity by a single vaccination. However, the use of live-attenuated RVFV vaccines for large human populations having a varied health status is of concern, because of these vaccines' residual neuro-invasiveness and neurovirulence. Recently, novel vaccine candidates have been developed using replication-defective RVFV that can undergo only a single round of replication in infected cells. The single-cycle replicable RVFV does not cause systemic infection in immunized hosts, but enables the conferring of protective immunity. This review summarizes the properties of various RVFV vaccines and recent progress on the development of the single-cycle replicable RVFV vaccines. Copyright © 2015 Elsevier B.V. All rights reserved.

World Reference Center for Arboviruses.

DTIC Science & Technology

1983-01-01

fever virus for antibody detection Antigen- detection ELISA was applied to dengue, and in another study o eastern encephalitis and Highland J viruses for...relatedness of RNA viruses ............................................. 60 Detection of eastern equine encephalitis virus and Highland J virus antigens...narrow. This suggests that Palyam group viruses are genetically quite stable. Virus identification. New viruses were identified in the Kemerovo group

Neuro-Immune Mechanisms in Response to Venezuelan Equine Encephalitis Virus Infection

DTIC Science & Technology

2000-01-01

iii ABSTRACT NEURO-IMMUNE MECHANISMS IN RESPONSE TO VENEZUELAN EQUINE ENCEPHALITIS VIRUS INFECTION Major Bruce A. Schoneboom directed by Franziska B...Grieder, DVM, Ph.D., Assistant Professor of Microbiology and Immunology, Molecular and Cellular Biology, and Neuroscience Venezuelan equine ...3. DATES COVERED - 4. TITLE AND SUBTITLE NEURO-IMMUNE MECHANISMS IN RESPONSE TO VENEZUELAN EQUINE ENCEPHALITIS VIRUS INFECTION 5a. CONTRACT

MicroRNA reduction of neuronal West Nile virus replication attenuates and affords a protective immune response in mice

PubMed Central

Brostoff, Terza; Pesavento, Patricia A.; Barker, Christopher M.; Kenney, Joan L.; Dietrich, Elizabeth A.; Duggal, Nisha K.; Bosco-Lauth, Angela M.; Brault, Aaron C.

2017-01-01

West Nile virus (WNV) is an important agent of human encephalitis that has quickly become endemic across much of the United States since its identification in North America in 1999. While the majority (~75%) of infections are subclinical, neurologic disease can occur in a subset of cases, with outcomes including permanent neurologic damage and death. Currently, there are no WNV vaccines approved for use in humans. This study introduces a novel vaccine platform for WNV to reduce viral replication in the central nervous system while maintaining peripheral replication to elicit strong neutralizing antibody titers. Vaccine candidates were engineered to incorporate microRNA (miRNA) target sequences for a cognate miRNA expressed only in neurons, allowing the host miRNAs to target viral transcription through endogenous RNA silencing. To maintain stability, these targets were incorporated in multiple locations within the 3′-untranslated region, flanking sequences essential for viral replication without affecting the viral open reading frame. All candidates replicated comparably to wild type WNV in vitro within cells that did not express the cognate miRNA. Insertional control viruses were also capable of neuroinvasion and neurovirulence in vivo in CD-1 mice. Vaccine viruses were safe at all doses tested and did not demonstrate mutations associated with a reversion to virulence when serially passaged in mice. All vaccine constructs were protective from lethal challenge in mice, producing 93–100% protection at the highest dose tested. Overall, this is a safe and effective attenuation strategy with broad potential application for vaccine development. PMID:27637937

MicroRNA reduction of neuronal West Nile virus replication attenuates and affords a protective immune response in mice.

PubMed

Brostoff, Terza; Pesavento, Patricia A; Barker, Christopher M; Kenney, Joan L; Dietrich, Elizabeth A; Duggal, Nisha K; Bosco-Lauth, Angela M; Brault, Aaron C

2016-10-17

West Nile virus (WNV) is an important agent of human encephalitis that has quickly become endemic across much of the United States since its identification in North America in 1999. While the majority (∼75%) of infections are subclinical, neurologic disease can occur in a subset of cases, with outcomes including permanent neurologic damage and death. Currently, there are no WNV vaccines approved for use in humans. This study introduces a novel vaccine platform for WNV to reduce viral replication in the central nervous system while maintaining peripheral replication to elicit strong neutralizing antibody titers. Vaccine candidates were engineered to incorporate microRNA (miRNA) target sequences for a cognate miRNA expressed only in neurons, allowing the host miRNAs to target viral transcription through endogenous RNA silencing. To maintain stability, these targets were incorporated in multiple locations within the 3'-untranslated region, flanking sequences essential for viral replication without affecting the viral open reading frame. All candidates replicated comparably to wild type WNV in vitro within cells that did not express the cognate miRNA. Insertional control viruses were also capable of neuroinvasion and neurovirulence in vivo in CD-1 mice. Vaccine viruses were safe at all doses tested and did not demonstrate mutations associated with a reversion to virulence when serially passaged in mice. All vaccine constructs were protective from lethal challenge in mice, producing 93-100% protection at the highest dose tested. Overall, this is a safe and effective attenuation strategy with broad potential application for vaccine development. Published by Elsevier Ltd.

Development of a Genetically Engineered Venezuelan Equine Encephalitis Virus Vaccine

DTIC Science & Technology

1988-12-20

immunization, the horses will be returned to the large animal biocontainment facility to be challenged with equine virulent VEE virus. The animals will be...AD £IT FiLE C p DEVELOPMENT OF A GENETICALLY ENGINEERED VENEZUELAN EQUINE ENCEPHALITIS VIRUS VACCINE ANNUAL REPORT to DENNIS W. TRENT 0DECEMBER 20...Engineered Venezuelan Equine Encephalitis Virus Vaccine 12. PERSONAL AUTHOR(S) Dennis W. Trent 13a. TYPE OF REPORT 13b. TIME COVERED 14. DATE OF REPORT

Zoonotic encephalitides caused by arboviruses: transmission and epidemiology of alphaviruses and flaviviruses

PubMed Central

Balasuriya, Udeni B. R.; Lee, Chong-kyo

2014-01-01

In this review, we mainly focus on zoonotic encephalitides caused by arthropod-borne viruses (arboviruses) of the families Flaviviridae (genus Flavivirus) and Togaviridae (genus Alphavirus) that are important in both humans and domestic animals. Specifically, we will focus on alphaviruses (Eastern equine encephalitis virus, Western equine encephalitis virus, Venezuelan equine encephalitis virus) and flaviviruses (Japanese encephalitis virus and West Nile virus). Most of these viruses were originally found in tropical regions such as Africa and South America or in some regions in Asia. However, they have dispersed widely and currently cause diseases around the world. Global warming, increasing urbanization and population size in tropical regions, faster transportation and rapid spread of arthropod vectors contribute in continuous spreading of arboviruses into new geographic areas causing reemerging or resurging diseases. Most of the reemerging arboviruses also have emerged as zoonotic disease agents and created major public health issues and disease epidemics. PMID:24427764

Zoonotic encephalitides caused by arboviruses: transmission and epidemiology of alphaviruses and flaviviruses.

PubMed

Go, Yun Young; Balasuriya, Udeni B R; Lee, Chong-Kyo

2014-01-01

In this review, we mainly focus on zoonotic encephalitides caused by arthropod-borne viruses (arboviruses) of the families Flaviviridae (genus Flavivirus) and Togaviridae (genus Alphavirus) that are important in both humans and domestic animals. Specifically, we will focus on alphaviruses (Eastern equine encephalitis virus, Western equine encephalitis virus, Venezuelan equine encephalitis virus) and flaviviruses (Japanese encephalitis virus and West Nile virus). Most of these viruses were originally found in tropical regions such as Africa and South America or in some regions in Asia. However, they have dispersed widely and currently cause diseases around the world. Global warming, increasing urbanization and population size in tropical regions, faster transportation and rapid spread of arthropod vectors contribute in continuous spreading of arboviruses into new geographic areas causing reemerging or resurging diseases. Most of the reemerging arboviruses also have emerged as zoonotic disease agents and created major public health issues and disease epidemics.

Subclinical infection without encephalitis in mice following intranasal exposure to Nipah virus-Malaysia and Nipah virus-Bangladesh.

PubMed

Dups, Johanna; Middleton, Deborah; Long, Fenella; Arkinstall, Rachel; Marsh, Glenn A; Wang, Lin-Fa

2014-06-02

Nipah virus and Hendra virus are closely related and following natural or experimental exposure induce similar clinical disease. In humans, encephalitis is the most serious outcome of infection and, hitherto, research into the pathogenesis of henipavirus encephalitis has been limited by the lack of a suitable model. Recently we reported a wild-type mouse model of Hendra virus (HeV) encephalitis that should facilitate detailed investigations of its neuropathogenesis, including mechanisms of disease recrudescence. In this study we investigated the possibility of developing a similar model of Nipah virus encephalitis. Aged and young adult wild type mice did not develop clinical disease including encephalitis following intranasal exposure to either the Malaysia (NiV-MY) or Bangladesh (NiV-BD) strains of Nipah virus. However viral RNA was detected in lung tissue of mice at euthanasia (21 days following exposure) accompanied by a non-neutralizing antibody response. In a subsequent time course trial this viral RNA was shown to be reflective of an earlier self-limiting and subclinical lower respiratory tract infection through successful virus re-isolation and antigen detection in lung. There was no evidence for viremia or infection of other organs, including brain. Mice develop a subclinical self-limiting lower respiratory tract infection but not encephalitis following intranasal exposure to NiV-BD or NiV-MY. These results contrast with those reported for HeV under similar exposure conditions in mice, demonstrating a significant biological difference in host clinical response to exposure with these viruses. This finding provides a new platform from which to explore the viral and/or host factors that determine the neuroinvasive ability of henipaviruses.

Experimental Transmission of Karshi and Langat (Tick-Borne Encephalitis Virus Complex) Viruses by Ornithodoros Ticks (Acari: Argasidae)

DTIC Science & Technology

2004-01-01

mosquitoes and Ornithodoros ticks were evaluated for their potential to transmit Karshi and Langat (tick-borne encephalitis virus complex) viruses in the...orally exposed to Langat virus, were able to transmit this virus after more than 3 years, the longest interval tested. Therefore, Ornithodoros spp

Emerging Causes of Arbovirus Encephalitis in North America: Powassan, Chikungunya, and Zika Viruses.

PubMed

Doughty, Christopher T; Yawetz, Sigal; Lyons, Jennifer

2017-02-01

Arboviruses are arthropod-borne viruses transmitted by the bite of mosquitoes, ticks, or other arthropods. Arboviruses are a common and an increasing cause of human illness in North America. Powassan virus, Chikungunya virus, and Zika virus are arboviruses that have all recently emerged as increasing causes of neurologic illness. Powassan virus almost exclusively causes encephalitis, but cases are rare, sporadic, and restricted to portions of North America and Russia. Chikungunya virus has spread widely across the world, causing millions of infections. Encephalitis is a rare manifestation of illness but is more common and severe in neonates and older adults. Zika virus has recently spread through much of the Americas and has been associated mostly with microcephaly and other congenital neurologic complications. Encephalitis occurring in infected adults has also been recently reported. This review will discuss the neuropathogenesis of these viruses, their transmission and geographic distribution, the spectrum of their neurologic manifestations, and the appropriate method of diagnosis.

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

Outcome of Encephalitis in Pediatric Intensive Care Unit.

PubMed

Hon, Kam-Lun Ellis; Tsang, Yin Ching K; Chan, Lawrence C N; Tsang, Hing Wing; Wong, Kit Ying Kitty; Wu, Yuet Hong Gordon; Chan, Paul K S; Cheung, Kam Lau; Ng, Eric Y K; Totapally, Balagangadhar R

2016-10-01

To review pathogens, morbidity and mortality in pediatric intensive care unit (PICU) patients with viral and infectious encephalitis. Retrospective chart review of all patients with encephalitis admitted to the PICU between 2002 and 2014 was done. Encephalitis (n = 46) accounted for 2.7 % of PICU admissions, but 11.8 % PICU mortality over a 12-y period. A microorganism (primarily virus) was identified in 59 % of encephalitis patients in the PICU. Enteroviruses and herpes viruses were isolated from the cerebrospinal fluid (CSF). Respiratory viruses [such as respiratory syncytial virus (RSV) and influenza viruses] and enteric viruses (such as rotavirus and norovirus) were obtained in the nasopharyngeal aspirate and stool respectively, but undetectable from the CSF. More than one-fourth patients with encephalitis died in the PICU. Boys accounted for 85 % of nonsurvivors and 52 % survivors (p = 0.038). Mechanical ventilation, inotrope, intravenous immunoglobulin (IVIG) and corticosteroid usage were significantly higher among non-survivors (p 0.001-0.044). Binomial logistic regression showed that patients who received corticosteroid had a lower chance of survival than those who did not after adjusting for gender, IVIG and mechanical ventilation (adjusted odd ratio = 0.071, 95 % CI 0.006-0.881; p 0.039). Eighteen (55 %) of the survivors had moderate-to-severe neurodevelopmental impairments. Encephalitis is associated with significant mortality despite intensive care. Over 25 % case died and 55 % of survivors had moderate-to-severe neurodevelopmental impairments. There appeared to be no emerging outbreaks of encephalitis during the 15-y study period.

Flaviviral NS4b, chameleon and jack-in-the-box roles in viral replication and pathogenesis, and a molecular target for antiviral intervention.

PubMed

Zmurko, Joanna; Neyts, Johan; Dallmeier, Kai

2015-07-01

Dengue virus and other flaviviruses such as the yellow fever, West Nile, and Japanese encephalitis viruses are emerging vector-borne human pathogens that affect annually more than 100 million individuals and that may cause debilitating and potentially fatal hemorrhagic and encephalitic diseases. Currently, there are no specific antiviral drugs for the treatment of flavivirus-associated disease. A better understanding of the flavivirus-host interactions during the different events of the flaviviral life cycle may be essential when developing novel antiviral strategies. The flaviviral non-structural protein 4b (NS4b) appears to play an important role in flaviviral replication by facilitating the formation of the viral replication complexes and in counteracting innate immune responses such as the following: (i) type I IFN signaling; (ii) RNA interference; (iii) formation of stress granules; and (iv) the unfolded protein response. Intriguingly, NS4b has recently been shown to constitute an excellent target for the selective inhibition of flavivirus replication. We here review the current knowledge on NS4b. © 2015 The Authors. Reviews in Medical Virology published by John Wiley & Sons Ltd.

Flaviviral NS4b, chameleon and jack‐in‐the‐box roles in viral replication and pathogenesis, and a molecular target for antiviral intervention

PubMed Central

Zmurko, Joanna; Dallmeier, Kai

2015-01-01

Summary Dengue virus and other flaviviruses such as the yellow fever, West Nile, and Japanese encephalitis viruses are emerging vector‐borne human pathogens that affect annually more than 100 million individuals and that may cause debilitating and potentially fatal hemorrhagic and encephalitic diseases. Currently, there are no specific antiviral drugs for the treatment of flavivirus‐associated disease. A better understanding of the flavivirus–host interactions during the different events of the flaviviral life cycle may be essential when developing novel antiviral strategies. The flaviviral non‐structural protein 4b (NS4b) appears to play an important role in flaviviral replication by facilitating the formation of the viral replication complexes and in counteracting innate immune responses such as the following: (i) type I IFN signaling; (ii) RNA interference; (iii) formation of stress granules; and (iv) the unfolded protein response. Intriguingly, NS4b has recently been shown to constitute an excellent target for the selective inhibition of flavivirus replication. We here review the current knowledge on NS4b. © 2015 The Authors. Reviews in Medical Virology published by John Wiley & Sons Ltd. PMID:25828437

Seroprevalence of selected disease agents from free-ranging black bears in Florida.

PubMed

Dunbar, M R; Cunningham, M W; Roof, J C

1998-07-01

Sera obtained from 66 free-ranging Florida black bears (Ursus americanus floridanus) from three geographic areas of Florida (USA) between November 1993 and August 1995 were tested for antibodies to 13 disease agents. Antibody prevalences were 3 positive of 37 tested (8%) Coxiella burnetti, 37 of 66 (56%) Toxoplasma gondii, 3 of 61 (5%) bluetongue virus/epizootic hemorrhagic disease virus (BTV/EHDV), 4 of 66 (6%) canine adenovirus-type 1, 5 of 66 (8%) canine distemper virus (CDV), 10 of 62 (16%) canine parvovirus (CPV), 7 of 66 (11%) eastern equine encephalitis virus, 4 of 66 (6%) western equine encephalitis virus, 2 of 66 (3%) Venezuelan equine encephalitis virus, and 11 of 66 (17%) St. Louis encephalitis virus. No samples had serologic evidence of exposure to Brucella spp. (n = 37), Francisella tularensis (n = 40), or pseudorabies virus (n = 37). This is the first known published report of antibodies to BTV/EHDV, CDV, and CPV in black bears.

[Experimental monkey encephalitis caused by Powassan virus].

PubMed

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

1981-01-01

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

Diagnosis and genetic analysis of Japanese encephalitis virus infected in horses.

PubMed

Lian, W C; Liau, M Y; Mao, C L

2002-10-01

Nervous disorders were found in two horses and verified as aseptic encephalitis by necropsy in the summer of 2000. To investigate agents that affected the horses, diagnostic procedures involving virus isolation, neutralization test and reverse transcription-polymerase chain reaction (RT-PCR) were performed. We intracranially inoculated litters of suckling mice with tissues suspected of containing aseptic encephalitis, including cerebrum, cerebellum, brain stem, thalamus, and cerebrospinal fluids; the mice were then observed for 14 days. Neutralizing antibodies against Japanese encephalitis (JE) viruses were present in the cerebrospinal fluid of the horses in titers of 10. Sequences of 500 nucleotides of the premembrane gene of JE virus, synthesized by RT-PCR, from both the cerebrum and cerebellum were determined. The phylogenetic analysis based on sequences of the premembrane gene revealed a relationship with the JE virus. The divergences at the nucleotide level of 1.2-5.7% and at the amino acid level of 0-4.3% were conserved with other JE strains. The results demonstrated that the pathogens causing equine encephalitis were JE viruses. The strains were closely related to Taiwanese isolates.

Biochemistry and Molecular Biology of Flaviviruses.

PubMed

Barrows, Nicholas J; Campos, Rafael K; Liao, Kuo-Chieh; Prasanth, K Reddisiva; Soto-Acosta, Ruben; Yeh, Shih-Chia; Schott-Lerner, Geraldine; Pompon, Julien; Sessions, October M; Bradrick, Shelton S; Garcia-Blanco, Mariano A

2018-04-25

Flaviviruses, such as dengue, Japanese encephalitis, tick-borne encephalitis, West Nile, yellow fever, and Zika viruses, are critically important human pathogens that sicken a staggeringly high number of humans every year. Most of these pathogens are transmitted by mosquitos, and not surprisingly, as the earth warms and human populations grow and move, their geographic reach is increasing. Flaviviruses are simple RNA-protein machines that carry out protein synthesis, genome replication, and virion packaging in close association with cellular lipid membranes. In this review, we examine the molecular biology of flaviviruses touching on the structure and function of viral components and how these interact with host factors. The latter are functionally divided into pro-viral and antiviral factors, both of which, not surprisingly, include many RNA binding proteins. In the interface between the virus and the hosts we highlight the role of a noncoding RNA produced by flaviviruses to impair antiviral host immune responses. Throughout the review, we highlight areas of intense investigation, or a need for it, and potential targets and tools to consider in the important battle against pathogenic flaviviruses.

Pathogenesis of Aerosolized Eastern Equine Encephalitis Virus Infection in Guinea Pigs

DTIC Science & Technology

2009-01-01

BioMed CentralVirology Journal ss Approved for public release. Distribution is unlimitedOpen AcceResearch Pathogenesis of aerosolized Eastern Equine ...NJ1959 or ArgM) of eastern equine encephalitis virus (EEEV) at two exclusive particle size distributions. Mice were more susceptible to either strain...fatal human infection and thus should serve as a suitable animal model for aerosol exposure to EEEV. Introduction Eastern equine encephalitis (EEE) virus

Fatal Case of Deer Tick Virus Encephalitis

PubMed Central

Tavakoli, Norma P.; Wang, Heng; Dupuis, Michelle; Hull, Rene; Ebel, Gregory D.; Gilmore, Emily J.; Faust, Phyllis L.

2010-01-01

SUMMARY Deer tick virus is related to Powassan virus, a tickborne encephalitis virus. A 62-year-old man presented with a meningoencephalitis syndrome and eventually died. Analyses of tissue samples obtained during surgery and at autopsy revealed a widespread necrotizing meningoencephalitis. Nucleic acid was extracted from formalin-fixed tissue, and the presence of deer tick virus was verified on a flavivirus-specific polymerase-chain-reaction (PCR) assay, followed by sequence confirmation. Immunohistochemical analysis with antisera specific for deer tick virus identified numerous immunoreactive neurons, with prominent involvement of large neurons in the brain stem, cerebellum, basal ganglia, thalamus, and spinal cord. This case demonstrates that deer tick virus can be a cause of fatal encephalitis. PMID:19439744

Fatal case of deer tick virus encephalitis.

PubMed

Tavakoli, Norma P; Wang, Heng; Dupuis, Michelle; Hull, Rene; Ebel, Gregory D; Gilmore, Emily J; Faust, Phyllis L

2009-05-14

Deer tick virus is related to Powassan virus, a tickborne encephalitis virus. A 62-year-old man presented with a meningoencephalitis syndrome and eventually died. Analyses of tissue samples obtained during surgery and at autopsy revealed a widespread necrotizing meningoencephalitis. Nucleic acid was extracted from formalin-fixed tissue, and the presence of deer tick virus was verified on a flavivirus-specific polymerase-chain-reaction (PCR) assay, followed by sequence confirmation. Immunohistochemical analysis with antisera specific for deer tick virus identified numerous immunoreactive neurons, with prominent involvement of large neurons in the brain stem, cerebellum, basal ganglia, thalamus, and spinal cord. This case demonstrates that deer tick virus can be a cause of fatal encephalitis. 2009 Massachusetts Medical Society

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

PubMed Central

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

2008-01-01

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

Nucleoside Inhibitors of Tick-Borne Encephalitis Virus

PubMed Central

Eyer, Luděk; Valdés, James J.; Gil, Victor A.; Nencka, Radim; Hřebabecký, Hubert; Šála, Michal; Salát, Jiří; Černý, Jiří; Palus, Martin; De Clercq, Erik

2015-01-01

Tick-borne encephalitis virus (TBEV) is a leading cause of human neuroinfections in Europe and Northeast Asia. There are no antiviral therapies for treating TBEV infection. A series of nucleoside analogues was tested for the ability to inhibit the replication of TBEV in porcine kidney cells and human neuroblastoma cells. The interactions of three nucleoside analogues with viral polymerase were simulated using advanced computational methods. The nucleoside analogues 7-deaza-2′-C-methyladenosine (7-deaza-2′-CMA), 2′-C-methyladenosine (2′-CMA), and 2′-C-methylcytidine (2′-CMC) inhibited TBEV replication. These compounds showed dose-dependent inhibition of TBEV-induced cytopathic effects, TBEV replication (50% effective concentrations [EC50]of 5.1 ± 0.4 μM for 7-deaza-2′-CMA, 7.1 ± 1.2 μM for 2′-CMA, and 14.2 ± 1.9 μM for 2′-CMC) and viral antigen production. Notably, 2′-CMC was relatively cytotoxic to porcine kidney cells (50% cytotoxic concentration [CC50] of ∼50 μM). The anti-TBEV effect of 2′-CMA in cell culture diminished gradually after day 3 posttreatment. 7-Deaza-2′-CMA showed no detectable cellular toxicity (CC50 > 50 μM), and the antiviral effect in culture was stable for >6 days posttreatment. Computational molecular analyses revealed that compared to the other two compounds, 7-deaza-2′-CMA formed a large cluster near the active site of the TBEV polymerase. High antiviral activity and low cytotoxicity suggest that 7-deaza-2′-CMA is a promising candidate for further investigation as a potential therapeutic agent in treating TBEV infection. PMID:26124166

A case of urinary retention in the early stages of herpes simplex virus type-1 encephalitis.

PubMed

Fukuoka, Takuya; Nakazato, Yoshihiko; Miyake, Akifumi; Tamura, Naotoshi; Araki, Nobuo; Yamamoto, Toshimasa

2017-06-01

A 70-year-old man developed urinary retention in the early stages of herpes simplex virus (HSV) type-1 encephalitis. A nerve conduction study suggested latent myeloradiculitis. This is the first report of human herpes simplex virus-1 encephalitis followed by urinary retention at early stage from the onset like the Elsberg syndrome. Although relatively few similar cases have been reported, we consider that urinary retention is common in HSV-1 encephalitis, in which disturbances of consciousness usually require bladder catheterization from the onset. We further emphasize that urinary retention may occasionally occur in early stages of HSV-1 encephalitis, with a significant possibility of recovery. Copyright © 2017. Published by Elsevier B.V.

Cholesterol effectively blocks entry of flavivirus.

PubMed

Lee, Chyan-Jang; Lin, Hui-Ru; Liao, Ching-Len; Lin, Yi-Ling

2008-07-01

Japanese encephalitis virus (JEV) and dengue virus serotype 2 (DEN-2) are enveloped flaviviruses that enter cells through receptor-mediated endocytosis and low pH-triggered membrane fusion and then replicate in intracellular membrane structures. Lipid rafts, cholesterol-enriched lipid-ordered membrane domains, are platforms for a variety of cellular functions. In this study, we found that disruption of lipid raft formation by cholesterol depletion with methyl-beta-cyclodextrin or cholesterol chelation with filipin III reduces JEV and DEN-2 infection, mainly at the intracellular replication steps and, to a lesser extent, at viral entry. Using a membrane flotation assay, we found that several flaviviral nonstructural proteins are associated with detergent-resistant membrane structures, indicating that the replication complex of JEV and DEN-2 localizes to the membranes that possess the lipid raft property. Interestingly, we also found that addition of cholesterol readily blocks flaviviral infection, a result that contrasts with previous reports of other viruses, such as Sindbis virus, whose infectivity is enhanced by cholesterol. Cholesterol mainly affected the early step of the flavivirus life cycle, because the presence of cholesterol during viral adsorption greatly blocked JEV and DEN-2 infectivity. Flavirial entry, probably at fusion and RNA uncoating steps, was hindered by cholesterol. Our results thus suggest a stringent requirement for membrane components, especially with respect to the amount of cholesterol, in various steps of the flavivirus life cycle.

Rift valley Fever virus encephalitis is associated with an ineffective systemic immune response and activated T cell infiltration into the CNS in an immunocompetent mouse model.

PubMed

Dodd, Kimberly A; McElroy, Anita K; Jones, Tara L; Zaki, Sherif R; Nichol, Stuart T; Spiropoulou, Christina F

2014-06-01

Rift Valley fever virus (RVFV) causes outbreaks of severe disease in livestock and humans throughout Africa and the Arabian Peninsula. In people, RVFV generally causes a self-limiting febrile illness but in a subset of individuals, it progresses to more serious disease. One manifestation is a delayed-onset encephalitis that can be fatal or leave the afflicted with long-term neurologic sequelae. In order to design targeted interventions, the basic pathogenesis of RVFV encephalitis must be better understood. To characterize the host immune responses and viral kinetics associated with fatal and nonfatal infections, mice were infected with an attenuated RVFV lacking NSs (ΔNSs) that causes lethal disease only when administered intranasally (IN). Following IN infection, C57BL/6 mice developed severe neurologic disease and succumbed 7-9 days post-infection. In contrast, inoculation of ΔNSs virus subcutaneously in the footpad (FP) resulted in a subclinical infection characterized by a robust immune response with rapid antibody production and strong T cell responses. IN-inoculated mice had delayed antibody responses and failed to clear virus from the periphery. Severe neurological signs and obtundation characterized end stage-disease in IN-inoculated mice, and within the CNS, the development of peak virus RNA loads coincided with strong proinflammatory responses and infiltration of activated T cells. Interestingly, depletion of T cells did not significantly alter survival, suggesting that neurologic disease is not a by-product of an aberrant immune response. Comparison of fatal (IN-inoculated) and nonfatal (FP-inoculated) ΔNSs RVFV infections in the mouse model highlighted the role of the host immune response in controlling viral replication and therefore determining clinical outcome. There was no evidence to suggest that neurologic disease is immune-mediated in RVFV infection. These results provide important insights for the future design of vaccines and therapeutic options.

Acute encephalitis in the immunocompromised individual.

PubMed

Saylor, Deanna; Thakur, Kiran; Venkatesan, Arun

2015-08-01

This article describes recent advances in the diagnosis and management of encephalitis in immunocompromised individuals. Herpes simplex virus (HSV) and varicella zoster virus (VZV) are common causes of encephalitis in immunocompromised individuals, although clinical manifestations may be atypical, and thus challenging to recognize. Recently, an increased incidence of HSV and VZV central nervous system infections has been reported in association with novel immunosuppressive and immunomodulatory treatments. The free-living ameba Balamuthia mandrillaris causes granulomatous encephalitis predominantly in immunocompromised individuals and is associated with nearly uniform fatality. In the setting of organ transplantation, the recipient's immunocompromised state along with the potential for donor-transmitted infections can result in a unique epidemiology of encephalitis, including infection by human herpes virus-6 and BK virus. Recent studies utilizing next-generation sequencing techniques have identified several pathogens, including Leptospira santarosai and a neurotropic astrovirus, as causes of encephalitis in immunocompromised individuals. Diagnosis and management of encephalitis is challenging in immunocompromised individuals, in part because of atypical clinical presentations and the presence of uncommon or novel infectious agents. Unbiased techniques for pathogen discovery are likely to play an increasing role in the diagnosis of central nervous system infections in immunocompromised individuals.

World Reference Center for Arboviruses.

DTIC Science & Technology

1997-07-01

reagent bank, to identify emerging viruses by antigenic and genetic methods, and (d) ordering and cataloguing the virus collection into a computer...encephalitis viruses in mosquitoes collected in Rhode Island and Connecticut. Eastern equine encephalitis (EKE) virus was isolated from 93 of 1800...Results of ri state mosquito- virus isolation studies Viruses identified Date of first isolation Number of isolations Date of last isolation Other

Export Controls: Controls Over the Export Licensing Process for Chemical and Biological Items

DTIC Science & Technology

2005-03-30

Akabane virus Bovine spongiform encephalopathy agent Camel pox virus Central European tick-borne encephalitis Cercopithecine herpesvirus 1...Herpes B virus) Coccidioides immitis Coccidioides posadasii Cowdria ruminantium (Heartwater) Far Eastern tick-borne encephalitis Liberobacter

A Molecularly Cloned, Live-Attenuated Japanese Encephalitis Vaccine SA14-14-2 Virus: A Conserved Single Amino Acid in the ij Hairpin of the Viral E Glycoprotein Determines Neurovirulence in Mice

PubMed Central

Kim, Jin-Kyoung; Yun, Gil-Nam; Lee, Eun-Young; Li, Long; Kuhn, Richard J.; Rossmann, Michael G.; Morrey, John D.; Lee, Young-Min

2014-01-01

Japanese encephalitis virus (JEV), a mosquito-borne flavivirus that causes fatal neurological disease in humans, is one of the most important emerging pathogens of public health significance. JEV represents the JE serogroup, which also includes West Nile, Murray Valley encephalitis, and St. Louis encephalitis viruses. Within this serogroup, JEV is a vaccine-preventable pathogen, but the molecular basis of its neurovirulence remains unknown. Here, we constructed an infectious cDNA of the most widely used live-attenuated JE vaccine, SA14-14-2, and rescued from the cDNA a molecularly cloned virus, SA14-14-2MCV, which displayed in vitro growth properties and in vivo attenuation phenotypes identical to those of its parent, SA14-14-2. To elucidate the molecular mechanism of neurovirulence, we selected three independent, highly neurovirulent variants (LD50, <1.5 PFU) from SA14-14-2MCV (LD50, >1.5×105 PFU) by serial intracerebral passage in mice. Complete genome sequence comparison revealed a total of eight point mutations, with a common single G1708→A substitution replacing a Gly with Glu at position 244 of the viral E glycoprotein. Using our infectious SA14-14-2 cDNA technology, we showed that this single Gly-to-Glu change at E-244 is sufficient to confer lethal neurovirulence in mice, including rapid development of viral spread and tissue inflammation in the central nervous system. Comprehensive site-directed mutagenesis of E-244, coupled with homology-based structure modeling, demonstrated a novel essential regulatory role in JEV neurovirulence for E-244, within the ij hairpin of the E dimerization domain. In both mouse and human neuronal cells, we further showed that the E-244 mutation altered JEV infectivity in vitro, in direct correlation with the level of neurovirulence in vivo, but had no significant impact on viral RNA replication. Our results provide a crucial step toward developing novel therapeutic and preventive strategies against JEV and possibly other encephalitic flaviviruses. PMID:25077483

Rabies direct fluorescent antibody test does not inactivate rabies or eastern equine encephalitis viruses.

PubMed

Jarvis, Jodie A; Franke, Mary A; Davis, April D

2016-08-01

An examination using the routine rabies direct fluorescent antibody test was performed on rabies or Eastern equine encephalitis positive mammalian brain tissue to assess inactivation of the virus. Neither virus was inactivated with acetone fixation nor the routine test, thus laboratory employees should treat all samples as rabies and when appropriate Eastern equine encephalitis positive throughout the whole procedure. Copyright © 2016 Elsevier B.V. All rights reserved.

Coltiviruses and Seadornaviruses in North America, Europe, and Asia

PubMed Central

Jaafar, Fauziah Mohd; de Micco, Philippe; de Lamballerie, Xavier

2005-01-01

Coltiviruses are tickborne viruses of the genus Coltivirus. The type species, Colorado tick fever virus (from North America), has been isolated from patients with flulike syndromes, meningitis, encephalitis, and other severe complications. Another coltivirus, Eyach virus, has been isolated from ticks in France and Germany and incriminated in febrile illnesses and neurologic syndromes. Seadornaviruses are endemic in Southeast Asia, particularly Indonesia and China. The prototype virus of the genus, Banna virus (BAV), has been isolated from many mosquito species, humans with encephalitis, pigs, and cattle. Two other seadornaviruses, Kadipiro and Liao Ning, were isolated only from mosquitoes. The epidemiology of seadornaviruses remains poorly documented. Evidence suggests that BAV is responsible for encephalitis in humans. Infection with BAV may be underreported because it circulates in regions with a high incidence of Japanese encephalitis and could be misdiagnosed as this disease. PMID:16318717

Antibodies to H5 subtype avian influenza virus and Japanese encephalitis virus in northern pintails (Anas acuta) sampled in Japan

USDA-ARS?s Scientific Manuscript database

Blood samples from 105 northern pintails (Anas acuta) captured on Hokkaido, Japan were tested for antibodies to avian influenza virus (AIV), Japanese encephalitis virus (JEV) and West Nile virus (WNV) to assess possible involvement of this species in the transmission and spread of economically impor...

Molecular characterization of two Rocio flavivirus strains isolated during the encephalitis epidemic in São Paulo State, Brazil and the development of a one-step RT-PCR assay for diagnosis.

PubMed

Coimbra, Terezinha Lisieux Moraes; Santos, Raimundo N; Petrella, Selma; Nagasse-Sugahara, Teresa Keico; Castrignano, Silvana Beres; Santos, Cecília L Simões

2008-01-01

Rocio virus (ROCV) was responsible for an explosive encephalitis epidemic in the 1970s affecting about 1,000 residents of 20 coastland counties in São Paulo State, Brazil. ROCV was first isolated in 1975 from the cerebellum of a fatal human case of encephalitis. Clinical manifestations of the illness are similar to those described for St. Louis encephalitis. ROCV shows intense antigenic cross-reactivity with Japanese encephalitis complex (JEC) viruses, particularly with Ilheus (ILHV), St. Louis encephalitis, Murray Valley and West Nile viruses. In this study, we report a specific RT-PCR assay for ROCV diagnosis and the molecular characterization of the SPAn37630 and SPH37623 strains. Partial nucleotide sequences of NS5 and E genes determined from both strains were used in phylogenetic analysis. The results indicated that these strains are closely related to JEC viruses, but forming a distinct subclade together with ILHV, in accordance with results recently reported by Medeiros et al. (2007).

Mucosal and systemic adjuvant activity of alphavirus replicon particles

NASA Astrophysics Data System (ADS)

Thompson, Joseph M.; Whitmore, Alan C.; Konopka, Jennifer L.; Collier, Martha L.; Richmond, Erin M. B.; Davis, Nancy L.; Staats, Herman F.; Johnston, Robert E.

2006-03-01

Vaccination represents the most effective control measure in the fight against infectious diseases. Local mucosal immune responses are critical for protection from, and resolution of, infection by numerous mucosal pathogens. Antigen processing across mucosal surfaces is the natural route by which mucosal immunity is generated, as peripheral antigen delivery typically fails to induce mucosal immune responses. However, we demonstrate in this article that mucosal immune responses are evident at multiple mucosal surfaces after parenteral delivery of Venezuelan equine encephalitis virus replicon particles (VRP). Moreover, coinoculation of null VRP (not expressing any transgene) with inactivated influenza virions, or ovalbumin, resulted in a significant increase in antigen-specific systemic IgG and fecal IgA antibodies, compared with antigen alone. Pretreatment of VRP with UV light largely abrogated this adjuvant effect. These results demonstrate that alphavirus replicon particles possess intrinsic systemic and mucosal adjuvant activity and suggest that VRP RNA replication is the trigger for this activity. We feel that these observations and the continued experimentation they stimulate will ultimately define the specific components of an alternative pathway for the induction of mucosal immunity, and if the activity is evident in humans, will enable new possibilities for safe and inexpensive subunit and inactivated vaccines. vaccine vector | Venezuelan equine encephalitis virus | viral immunology | RNA virus

Arboviruses pathogenic for domestic and wild animals.

PubMed

Hubálek, Zdenek; Rudolf, Ivo; Nowotny, Norbert

2014-01-01

The objective of this chapter is to provide an updated and concise systematic review on taxonomy, history, arthropod vectors, vertebrate hosts, animal disease, and geographic distribution of all arboviruses known to date to cause disease in homeotherm (endotherm) vertebrates, except those affecting exclusively man. Fifty arboviruses pathogenic for animals have been documented worldwide, belonging to seven families: Togaviridae (mosquito-borne Eastern, Western, and Venezuelan equine encephalilitis viruses; Sindbis, Middelburg, Getah, and Semliki Forest viruses), Flaviviridae (mosquito-borne yellow fever, Japanese encephalitis, Murray Valley encephalitis, West Nile, Usutu, Israel turkey meningoencephalitis, Tembusu and Wesselsbron viruses; tick-borne encephalitis, louping ill, Omsk hemorrhagic fever, Kyasanur Forest disease, and Tyuleniy viruses), Bunyaviridae (tick-borne Nairobi sheep disease, Soldado, and Bhanja viruses; mosquito-borne Rift Valley fever, La Crosse, Snowshoe hare, and Cache Valley viruses; biting midges-borne Main Drain, Akabane, Aino, Shuni, and Schmallenberg viruses), Reoviridae (biting midges-borne African horse sickness, Kasba, bluetongue, epizootic hemorrhagic disease of deer, Ibaraki, equine encephalosis, Peruvian horse sickness, and Yunnan viruses), Rhabdoviridae (sandfly/mosquito-borne bovine ephemeral fever, vesicular stomatitis-Indiana, vesicular stomatitis-New Jersey, vesicular stomatitis-Alagoas, and Coccal viruses), Orthomyxoviridae (tick-borne Thogoto virus), and Asfarviridae (tick-borne African swine fever virus). They are transmitted to animals by five groups of hematophagous arthropods of the subphyllum Chelicerata (order Acarina, families Ixodidae and Argasidae-ticks) or members of the class Insecta: mosquitoes (family Culicidae); biting midges (family Ceratopogonidae); sandflies (subfamily Phlebotominae); and cimicid bugs (family Cimicidae). Arboviral diseases in endotherm animals may therefore be classified as: tick-borne (louping ill and tick-borne encephalitis, Omsk hemorrhagic fever, Kyasanur Forest disease, Tyuleniy fever, Nairobi sheep disease, Soldado fever, Bhanja fever, Thogoto fever, African swine fever), mosquito-borne (Eastern, Western, and Venezuelan equine encephalomyelitides, Highlands J disease, Getah disease, Semliki Forest disease, yellow fever, Japanese encephalitis, Murray Valley encephalitis, West Nile encephalitis, Usutu disease, Israel turkey meningoencephalitis, Tembusu disease/duck egg-drop syndrome, Wesselsbron disease, La Crosse encephalitis, Snowshoe hare encephalitis, Cache Valley disease, Main Drain disease, Rift Valley fever, Peruvian horse sickness, Yunnan disease), sandfly-borne (vesicular stomatitis-Indiana, New Jersey, and Alagoas, Cocal disease), midge-borne (Akabane disease, Aino disease, Schmallenberg disease, Shuni disease, African horse sickness, Kasba disease, bluetongue, epizootic hemorrhagic disease of deer, Ibaraki disease, equine encephalosis, bovine ephemeral fever, Kotonkan disease), and cimicid-borne (Buggy Creek disease). Animals infected with these arboviruses regularly develop a febrile disease accompanied by various nonspecific symptoms; however, additional severe syndromes may occur: neurological diseases (meningitis, encephalitis, encephalomyelitis); hemorrhagic symptoms; abortions and congenital disorders; or vesicular stomatitis. Certain arboviral diseases cause significant economic losses in domestic animals-for example, Eastern, Western and Venezuelan equine encephalitides, West Nile encephalitis, Nairobi sheep disease, Rift Valley fever, Akabane fever, Schmallenberg disease (emerged recently in Europe), African horse sickness, bluetongue, vesicular stomatitis, and African swine fever; all of these (except for Akabane and Schmallenberg diseases) are notifiable to the World Organisation for Animal Health (OIE, 2012). © 2014 Elsevier Inc. All rights reserved.

Inadequately Treated Wastewater as a Source of Human Enteric Viruses in the Environment

PubMed Central

Okoh, Anthony I.; Sibanda, Thulani; Gusha, Siyabulela S.

2010-01-01

Human enteric viruses are causative agents in both developed and developing countries of many non-bacterial gastrointestinal tract infections, respiratory tract infections, conjunctivitis, hepatitis and other more serious infections with high morbidity and mortality in immunocompromised individuals such as meningitis, encephalitis and paralysis. Human enteric viruses infect and replicate in the gastrointestinal tract of their hosts and are released in large quantities in the stools of infected individuals. The discharge of inadequately treated sewage effluents is the most common source of enteric viral pathogens in aquatic environments. Due to the lack of correlation between the inactivation rates of bacterial indicators and viral pathogens, human adenoviruses have been proposed as a suitable index for the effective indication of viral contaminants in aquatic environments. This paper reviews the major genera of pathogenic human enteric viruses, their pathogenicity and epidemiology, as well as the role of wastewater effluents in their transmission. PMID:20644692

Mutation of domain III and domain VI in L gene conserved domain of Nipah virus

NASA Astrophysics Data System (ADS)

Jalani, Siti Aishah; Ibrahim, Nazlina

2016-11-01

Nipah virus (NiV) is the etiologic agent responsible for the respiratory illness and causes fatal encephalitis in human. NiV L protein subunit is thought to be responsible for the majority of enzymatic activities involved in viral transcription and replication. The L protein which is the viral RNA dependent RNA polymerase has high sequence homology among negative sense RNA viruses. In negative stranded RNA viruses, based on sequence alignment six conserved domain (domain I-IV) have been determined. Each domain is separated on variable regions that suggest the structure to consist concatenated functional domain. To directly address the roles of domains III and VI, site-directed mutations were constructed by the substitution of bases at sequences 2497, 2500, 5528 and 5532. Each mutated L gene can be used in future studies to test the ability for expression on in vitro translation.

PHOTOSENSITIZATION OF ARBOVIRUSES BY ACRIDINE DYES

DTIC Science & Technology

This paper describes the photodynamic action of proflavine and acridine orange on eastern equine encephalitis (EEE) and Venezuelan equine...encephalitis (VEE) viruses. The viruses were more sensitive to the photodynamic action of acridine orange than to that of proflavine . VEE virus was slightly more

Experimental encephalitis in monkeys caused by the Powassan virus.

PubMed

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

1985-01-01

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

Intrinsic Innate Immunity Fails To Control Herpes Simplex Virus and Vesicular Stomatitis Virus Replication in Sensory Neurons and Fibroblasts

PubMed Central

Rosato, Pamela C.

2014-01-01

ABSTRACT Herpes simplex virus 1 (HSV-1) establishes lifelong latent infections in the sensory neurons of the trigeminal ganglia (TG), wherein it retains the capacity to reactivate. The interferon (IFN)-driven antiviral response is critical for the control of HSV-1 acute replication. We therefore sought to further investigate this response in TG neurons cultured from adult mice deficient in a variety of IFN signaling components. Parallel experiments were also performed in fibroblasts isolated concurrently. We showed that HSV-1 replication was comparable in wild-type (WT) and IFN signaling-deficient neurons and fibroblasts. Unexpectedly, a similar pattern was observed for the IFN-sensitive vesicular stomatitis virus (VSV). Despite these findings, TG neurons responded to IFN-β pretreatment with STAT1 nuclear localization and restricted replication of both VSV and an HSV-1 strain deficient in γ34.5, while wild-type HSV-1 replication was unaffected. This was in contrast to fibroblasts in which all viruses were restricted by the addition of IFN-β. Taken together, these data show that adult TG neurons can mount an effective antiviral response only if provided with an exogenous source of IFN-β, and HSV-1 combats this response through γ34.5. These results further our understanding of the antiviral response of neurons and highlight the importance of paracrine IFN-β signaling in establishing an antiviral state. IMPORTANCE Herpes simplex virus 1 (HSV-1) is a ubiquitous virus that establishes a lifelong latent infection in neurons. Reactivation from latency can cause cold sores, blindness, and death from encephalitis. Humans with deficiencies in innate immunity have significant problems controlling HSV infections. In this study, we therefore sought to elucidate the role of neuronal innate immunity in the control of viral infection. Using neurons isolated from mice, we found that the intrinsic capacity of neurons to restrict virus replication was unaffected by the presence or absence of innate immunity. In contrast, neurons were able to mount a robust antiviral response when provided with beta interferon, a molecule that strongly stimulates innate immunity, and that HSV-1 can combat this response through the γ34.5 viral gene. Our results have important implications for understanding how the nervous system defends itself against virus infections. PMID:24942587

La Crosse virus (LACV) Gc fusion peptide mutants have impaired growth and fusion phenotypes, but remain neurotoxic

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

Soldan, Samantha S., E-mail: sssoldan@mail.med.upenn.ed; Hollidge, Bradley S.; Department of Neuroscience Graduate Group, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-4283

La Crosse virus is a leading cause of pediatric encephalitis in the Midwestern United States and an emerging pathogen in the American South. The LACV glycoprotein Gc plays a critical role in entry as the virus attachment protein. A 22 amino acid hydrophobic region within Gc (1066-1087) was recently identified as the LACV fusion peptide. To further define the role of Gc (1066-1087) in virus entry, fusion, and neuropathogenesis, a panel of recombinant LACV (rLACV) fusion peptide mutant viruses was generated. Replication of mutant rLACVs was significantly reduced. In addition, the fusion peptide mutants demonstrated decreased fusion phenotypes relative tomore » LACV-WT. Interestingly, these viruses maintained their ability to cause neuronal loss in culture, suggesting that the fusion peptide of LACV Gc is a determinant of properties associated with neuroinvasion (growth to high titer in muscle cells and a robust fusion phenotype), but not necessarily of neurovirulence.« less

Lentiviral infection of proliferating brain macrophages in HIV and simian immunodeficiency virus encephalitis despite sterile alpha motif and histidine-aspartate domain-containing protein 1 expression

PubMed Central

Lindgren, Allison A.; Filipowicz, Adam R.; Hattler, Julian B.; Kim, Soon Ok; Chung, Hye Kyung; Kuroda, Marcelo J.; Johnson, Edward M.; Kim, Woong-Ki

2018-01-01

Objective: HIV-1 infection of the brain and related cognitive impairment remain prevalent in HIV-1-infected individuals despite combination antiretroviral therapy. Sterile alpha motif and histidine-aspartate domain-containing protein 1 (SAMHD1) is a newly identified host restriction factor that blocks the replication of HIV-1 and other retroviruses in myeloid cells. Cell cycle-regulated phosphorylation at residue Thr592 and viral protein X (Vpx)-mediated degradation of SAMHD1 have been shown to bypass SAMHD1 restriction in vitro. Herein, we investigated expression and phosphorylation of SAMHD1 in vivo in relation to macrophage infection and proliferation during the neuropathogenesis of HIV-1 and simian immunodeficiency virus (SIV) encephalitis. Methods: Using brain and other tissues from uninfected and SIV-infected macaques with or without encephalitis, we performed immunohistochemistry, multilabel fluorescence microscopy and western blot to examine the expression, localization and phosphorylation of SAMHD1. Results: The number of SAMHD1+ nuclei increased in encephalitic brains despite the presence of Vpx. Many of these cells were perivascular macrophages, although subsets of SAMHD1+ microglia and endothelial cells were also observed. The SAMHD1+ macrophages were shown to be both infected and proliferating. Moreover, the presence of cycling SAMHD1+ brain macrophages was confirmed in the tissue of HIV-1-infected patients with encephalitis. Finally, western blot analysis of brain-protein extracts from SIV-infected macaques showed that SAMHD1 protein exists in the brain mainly as an inactive Thr592-phosphorylated form. Conclusion: The ability of SAMHD1 to act as a restriction factor for SIV/HIV in the brain is likely bypassed in proliferating brain macrophages through the phosphorylation-mediated inactivation, not Vpx-mediated degradation of SAMHD1. PMID:29698322

Characterization of tick-borne encephalitis virus from Latvia.

PubMed

Mavtchoutko, V; Vene, S; Haglund, M; Forsgren, M; Duks, A; Kalnina, V; Hörling, J; Lundkvist, A

2000-02-01

Viruses of the tick-borne encephalitis (TBE) antigenic complex, within the family Flaviviridae, cause a variety of diseases including uncomplicated febrile illness, encephalitis, meningo-encephalitis, hemorrhagic fever and chronic disease in humans, domesticated animals or wildlife species. TBE is a serious problem in Latvia with up to a 1,000 patients confirmed serologically annually 1994-1995. No previous data had been reported on the causative agent of TBE in Latvia. In the present study, a virus was isolated from serum of a patient with clinical symptoms of an acute TBE infection. Nucleotide sequence information obtained by direct reverse transcription-polymerase chain reaction (RT-PCR) and the serological characteristics of the isolated virus strain, designated TBE-Latvia-1-96, indicated a closer relationship to the Vasilchenko strain, isolated in Novosibirsk (Siberia, Russia), as compared to the western European or far eastern subtypes of TBE viruses. In a mouse neurovirulence assay, a significant difference in survival rates (days) was shown between Latvia-1-96 and the western European TBE virus subtype. Copyright 2000 Wiley-Liss, Inc.

Experimental Transmission of Eastern Equine Encephalitis Virus by Strains of Aedes albopictus and A. taeniorhynchus (Diptera: Culicidae)

DTIC Science & Technology

1994-01-01

AD-A281 335 0 Experimental Transmission of Eastern Equine Encephaliti Vi 4 by Strains of Aedes albopictus and A. taeniorhynch &1j (Diptera: Culicidae...co m •strains of Aedes albopictus (Skuse) was assessed for eastern equine encephalitis (EEE) virus isolated from Ae. albopictus collected in Polk...County, Florida. Both species became infected with and transmitted EEE virus by bite after feeding on 1-d-old chicks that had _been inoculated with EEE

Mixing of M Segment DNA Vaccines to Hantaan Virus and Puumala Virus Reduces Their Immunogenicity in Hamsters

DTIC Science & Technology

2008-01-01

vaccines for Rift Valley fever virus, tick- borne encephalitis virus, Hantaan virus, and Crimean Congo hemorrhagic fever virus. Vaccine 2006;24(May 22 (21)):4657–66. ...Valley fever virus, tick-borne encephalitis virus, TNV, and Crimean Congo hemorrhagic fever virus [19]. Thus, it s clearly possible to develop certain...online 25 April 2008 eywords: a b s t r a c t To determine if DNA vaccines for two hantaviruses causing hemorrhagic

Acute encephalitis, a poliomyelitis-like syndrome and neurological sequelae in a hamster model for flavivirus infections.

PubMed

Leyssen, Pieter; Croes, Romaric; Rau, Philipp; Heiland, Sabine; Verbeken, Erik; Sciot, Raphael; Paeshuyse, Jan; Charlier, Nathalie; De Clercq, Erik; Meyding-Lamadé, Uta; Neyts, Johan

2003-07-01

Infection of hamsters with the murine flavivirus Modoc results in (meningo)encephalitis, which is, during the acute phase, frequently associated with flaccid paralysis, as also observed in patients with West Nile virus encephalitis. Twenty percent of the hamsters that recover from the acute encephalitis develop life-long neurological sequelae, reminiscent of those observed, for example, in survivors of Japanese encephalitis. Magnetic resonance imaging and histology revealed severe lesions predominantly located in the olfactory-limbic system, both in hamsters with acute encephalitis as in survivors. Prominent pathology was also detected in the spinal cord of hamsters with paralysis. Modoc virus infections in hamsters provide a unique model for the study of encephalitis, a poliomyelitis-like syndrome and neurological sequelae following flavivirus infection.

Serological evidence of widespread exposure of Grenada fruit bats to chikungunya virus.

PubMed

Stone, D; Lyons, A C; Huang, Y-J S; Vanlandingham, D L; Higgs, S; Blitvich, B J; Adesiyun, A A; Santana, S E; Leiser-Miller, L; Cheetham, S

2018-03-25

Antibody detection against selected potentially zoonotic vector-borne alphaviruses and flaviviruses was conducted on sera from bats from all six parishes in Grenada, West Indies. Sera were tested for (i) antibodies to flaviviruses West Nile virus, St. Louis encephalitis virus, Ilhéus virus, Bussuquara virus (BSQV), Rio Bravo virus and all four serotypes of dengue virus (DENV) by plaque reduction neutralization test (PRNT); (ii) antibodies to alphaviruses western equine encephalitis virus, Venezuelan equine encephalitis virus and eastern equine encephalitis virus by epitope-blocking enzyme-linked immunosorbent assay (ELISA); and (iii) antibodies to the alphavirus chikungunya (CHIKV) by PRNT. Two species of fruit bats were sampled, Artibeus jamaicensis and Artibeus lituratus, all roosting in or within 1,000 m of human settlements. Fifteen (36%) of the 42 bats tested for neutralizing antibodies to CHIKV were positive. The CHIKV-seropositive bats lived in localities spanning five of the six parishes. All 43 bats tested for epitope-blocking ELISA antibody to the other alphaviruses were negative, except one positive for Venezuelan equine encephalitis virus. All 50 bats tested for neutralizing antibody to flaviviruses were negative, except one that had a BSQV PRNT 80 titre of 20. The CHIKV serology results indicate that bats living close to and within human settlements were exposed to CHIKV in multiple locations. Importantly, bats for this study were trapped a year after the introduction and peak of the human CHIKV epidemic in Grenada. Thus, our data indicate that bats were exposed to CHIKV possibly during a time of marked decline in human cases. © 2018 Blackwell Verlag GmbH.

Protective immunity to Japanese encephalitis virus associated with anti-NS1 antibodies in a mouse model.

PubMed

Li, Yize; Counor, Dorian; Lu, Peng; Duong, Veasna; Yu, Yongxin; Deubel, Vincent

2012-07-24

Japanese encephalitis virus (JEV) is a major mosquito-borne pathogen that causes viral encephalitis throughout Asia. Vaccination with an inactive JEV particle or attenuated virus is an efficient preventative measure for controlling infection. Flavivirus NS1 protein is a glycoprotein secreted during viral replication that plays multiple roles in the viral life cycle and pathogenesis. Utilizing JEV NS1 as an antigen in viral vectors induces a limited protective immune response against infection. Previous studies using E. coli-expressed JEV NS1 to immunize mice induced protection against lethal challenge; however, the protection mechanism through cellular and humoral immune responses was not described. JEV NS1 was expressed in and purified from Drosophila S2 cells in a native glycosylated multimeric form, which induced T-cell and antibody responses in immunized C3H/HeN mice. Mice vaccinated with 1 μg NS1 with or without water-in-oil adjuvant were partially protected against viral challenge and higher protection was observed in mice with higher antibody titers. IgG1 was preferentially elicited by an adjuvanted NS1 protein, whereas a larger load of IFN-γ was produced in splenocytes from mice immunized with aqueous NS1. Mice that passively received anti-NS1 mouse polyclonal immune sera were protected, and this phenomenon was dose-dependent, whereas protection was low or delayed after the passive transfer of anti-NS1 MAbs. The purified NS1 subunit induced protective immunity in relation with anti-NS1 IgG1 antibodies. NS1 protein efficiently stimulated Th1-cell proliferation and IFN-γ production. Protection against lethal challenge was elicited by passive transfer of anti-NS1 antisera, suggesting that anti-NS1 antibodies play a substantial role in anti-viral immunity.

Evaluation of a caprine arthritis-encephalitis virus/maedi-visna virus indirect enzyme-linked immunosorbent assay in the serological diagnosis of ovine progressive pneumonia virus in U.S. sheep

USDA-ARS?s Scientific Manuscript database

Serological diagnostic testing of sheep and goats using enzyme immunosorbent assays (ELISAs) is the most common method of determining small ruminant lentivirus (SRLV) infection. A caprine arthritis-encephalitis virus (CAEV)/maedi-visna virus (MVV) indirect (i) ELISA, which utilizes MVV EV1 capsid a...

Japanese encephalitis - the prospects for new treatments.

PubMed

Turtle, Lance; Solomon, Tom

2018-04-26

Japanese encephalitis is a mosquito-borne disease that occurs in Asia and is caused by Japanese encephalitis virus (JEV), a member of the genus Flavivirus. Although many flaviviruses can cause encephalitis, JEV causes particularly severe neurological manifestations. The virus causes loss of more disability-adjusted life years than any other arthropod-borne virus owing to the frequent neurological sequelae of the condition. Despite substantial advances in our understanding of Japanese encephalitis from in vitro studies and animal models, studies of pathogenesis and treatment in humans are lagging behind. Few mechanistic studies have been conducted in humans, and only four clinical trials of therapies for Japanese encephalitis have taken place in the past 10 years despite an estimated incidence of 69,000 cases per year. Previous trials for Japanese encephalitis might have been too small to detect important benefits of potential treatments. Many potential treatment targets exist for Japanese encephalitis, and pathogenesis and virological studies have uncovered mechanisms by which these drugs could work. In this Review, we summarize the epidemiology, clinical features, prevention and treatment of Japanese encephalitis and focus on potential new therapeutic strategies, based on repurposing existing compounds that are already suitable for human use and could be trialled without delay. We use our newly improved understanding of Japanese encephalitis pathogenesis to posit potential treatments and outline some of the many challenges that remain in tackling the disease in humans.

Herpes Simplex Encephalitis during Treatment with Tumor Necrosis Factor-α Inhibitors

PubMed Central

Bradford, Russell D.; Pettit, April C.; Wright, Patty W.; Mulligan, Mark J.; Moreland, Larry W.; McLain, David A.; Gnann, John W.; Bloch, Karen C.

2012-01-01

We report 3 cases of herpes simplex virus encephalitis in patients receiving tumor necrosis factor-alpha (TNF-α) inhibitors for rheumatologic disorders. Although TNF-α inhibitors have been reported to increase the risk of other infectious diseases, to our knowledge, an association between anti–TNF-α drugs and herpes simplex virus encephalitis has not been previously described. PMID:19681709

West Nile virus and other arboviral diseases--United States, 2012.

PubMed

2013-06-28

Arthropod-borne viruses (arboviruses) are transmitted to humans primarily through the bites of infected mosquitoes and ticks. West Nile virus (WNV) is the leading cause of domestically acquired arboviral disease in the United States. However, several other arboviruses also cause sporadic cases and seasonal outbreaks of neuroinvasive disease (e.g., meningitis, encephalitis, and acute flaccid paralysis). In 2012, CDC received reports of 5,780 nationally notifiable arboviral disease cases (excluding dengue). A large multistate outbreak of WNV disease accounted for 5,674 (98%) of reported cases, the highest number reported since 2003. Other reported etiologies included Eastern equine encephalitis virus (EEEV), Powassan virus (POWV), St. Louis encephalitis virus (SLEV), and California serogroup viruses such as La Crosse virus (LACV) and Jamestown Canyon virus (JCV). Arboviruses continue to cause serious illness in substantial numbers of persons in the United States. Maintaining surveillance remains important to identify outbreaks and guide prevention efforts.

Pathogenic effects of Rift Valley fever virus NSs gene are alleviated in cultured cells by expressed antiviral short hairpin RNAs.

PubMed

Scott, Tristan; Paweska, Janusz T; Arbuthnot, Patrick; Weinberg, Marc S

2012-01-01

Rift Valley fever virus (RVFV), a member of the Bunyaviridae family, may cause severe hepatitis, encephalitis and haemorrhagic fever in humans. There are currently no available licensed vaccines or therapies to treat the viral infection in humans. RNA interference (RNAi)-based viral gene silencing offers a promising approach to inhibiting replication of this highly pathogenic virus. The small (S) segment of the RVFV tripartite genome carries the genetic determinates for pathogenicity during infection. This segment encodes the non-structural S (NSs) and essential nucleocapsid (N) genes. To advance RNAi-based inhibition of RVFV replication, we designed several Pol III short hairpin RNA (shRNA) expression cassettes against the NSs and N genes, including a multimerized plasmid vector that included four shRNA expression cassettes. Effective target silencing was demonstrated using full- and partial-length target reporter assays, and confirmed by western blot analysis of exogenous N and NSs expression. Small RNA northern blots showed detectable RNAi guide strand formation from single and multimerized shRNA constructs. Using a cell culture model of RVFV replication, shRNAs targeting the N gene decreased intracellular nucleocapsid protein concentration and viral replication. The shRNAs directed against the NSs gene reduced NSs protein concentrations and alleviated NSs-mediated cytotoxicity, which may be caused by host transcription suppression. These data are the first demonstration that RNAi activators have a potential therapeutic benefit for countering RVFV infection.

[The clinico-epidemiological characteristics of Powassan encephalitis in the southern Soviet Far East].

PubMed

Leonova, G N; Sorokina, M N; Krugliak, S P

1991-03-01

The present communication deals with the analysis of 14 cases of Powassan encephalitis. As shown in this study, the course of this infection may be accompanied by symptoms indicating the presence of cerebral and meningeal lesions (in 7 cases meningoencephalitic forms with one fatal outcome and in 2 cases meningeal forms were registered) or take febrile and inapparent forms (5 cases). Powassan encephalitis was found to give characteristic symptoms of cerebellovestibular lesions, differentiating this disease from tick-borne encephalitis (TBE). The cases of mixed infections caused by TBE virus, Powassan encephalitis virus and tick-born Borrelia were found to be possible.

Alisporivir Has Limited Antiviral Effects Against Ebola Virus Strains Makona and Mayinga.

PubMed

Chiramel, Abhilash I; Banadyga, Logan; Dougherty, Jonathan D; Falzarano, Darryl; Martellaro, Cynthia; Brees, Dominique; Taylor, R Travis; Ebihara, Hideki; Best, Sonja M

2016-10-15

Antiviral therapeutics with existing clinical safety profiles would be highly desirable in an outbreak situation, such as the 2013-2016 emergence of Ebola virus (EBOV) in West Africa. Although, the World Health Organization declared the end of the outbreak early 2016, sporadic cases of EBOV infection have since been reported. Alisporivir is the most clinically advanced broad-spectrum antiviral that functions by targeting a host protein, cyclophilin A (CypA). A modest antiviral effect of alisporivir against contemporary (Makona) but not historical (Mayinga) EBOV strains was observed in tissue culture. However, this effect was not comparable to observations for an alisporivir-susceptible virus, the flavivirus tick-borne encephalitis virus. Thus, EBOV does not depend on (CypA) for replication, in contrast to many other viruses pathogenic to humans. Published by Oxford University Press for the Infectious Diseases Society of America 2016. This work is written by (a) US Government employee(s) and is in the public domain in the US.

CSF herpes virus and autoantibody profiles in the evaluation of encephalitis

PubMed Central

Linnoila, Jenny J.; Binnicker, Matthew J.; Majed, Masoud; Klein, Christopher J.

2016-01-01

Objective: To report the frequency of coexisting herpes viruses (herpes simplex virus 1 [HSV-1] or HSV-2, varicella zoster virus, Epstein-Barr virus [EBV], cytomegalovirus, or human herpes virus 6 [HHV-6]) and autoantibodies in patients with encephalitis (herpes or autoimmune) in clinical laboratory service. Methods: Three groups were evaluated for herpes viruses and antibodies: group 1—patients whose CSF was positive for a herpes virus by real-time PCR over a period of 6 months; group 2—patients whose CSF was positive for an autoimmune encephalitis–associated antibody over 5 years (e.g., NMDA receptor [NMDA-R] antibody), and the same number of controls without autoimmune/infectious disease; and group 3—incidental autoimmune parainfectious encephalitis cases encountered over 1 year. Results: In group 1, antibodies were detected in 27 of 100 herpes PCR-positive CSF specimens (CSFs), either unclassified neural or nonneural in all but one patient with NMDA-R antibody detected after EBV infection. Antibodies were also detected in 3 of 7 CSFs submitted for repeat PCR testing (unclassified, 2; AMPA receptor, 1). In group 2, herpes viruses were detected in 1 of 77 controls (HHV-6) and 4 of 77 patients with autoimmune encephalitis (EBV, 2; HHV-6, 2); autoantibodies targeted NMDA-R in 3/4 and GABAB-R in 1/4. In group 3, NMDA-R antibody was detected in 7 patients post–HSV-1 encephalitis. Of the remaining 3 patients, 2 had unclassified neural antibodies detected, and one had GABAB-R autoimmunity. Concomitant neoplasms were discovered in 2 patients each from groups 2 and 3. Conclusions: Autoantibodies and herpes virus DNA frequently coexist in encephalitic CSF. Some patients develop parainfectious autoimmunity following viral CNS infection (usually HSV-1 encephalitis). The significance of detecting herpes nucleic acids in others remains unclear. PMID:27308306

Postviral autoimmune encephalitis: manifestations in children and adults.

PubMed

Prüss, Harald

2017-06-01

Autoimmune encephalitis is an increasingly recognized neuropsychiatric condition seen in patients of all ages. Herpes virus infections of the brain can antedate the development of pathogenic autoantibodies against N-methyl-D-aspartate receptors and further neuronal surface proteins, leading to neuronal dysfunction and relapsing symptoms. This review will recapitulate the recent scientific progress, clinical manifestations in children and adults, therapeutic options, and etiological concepts on how autoimmunity develops. Postviral autoimmune encephalitis has been established as disease mechanism after herpes simplex virus encephalitis. Relapsing symptoms in the absence of virus occur in up to 20% of cases. The clinical presentation is relatively stereotyped in children, consisting of choreoathetosis and reduced levels of consciousness. Adults commonly present with psychiatric abnormalities and cognitive changes. Virus-induced antibody generation seems to be a widespread mechanism not confined to Herpesviridae and N-methyl-D-aspartate receptor antibodies SUMMARY: The presence of prolonged, atypical, or relapsing symptoms after virus encephalitis must be actively determined, requiring early follow-up visits of patients, and should always prompt the search for underlying autoantibodies. Relapsing symptoms can markedly improve with immunotherapy, thus treatment, including corticosteroids, plasma separation, immunoglobulins, and rituximab is usually recommended, even if no specific antibody was detected.

Japanese encephalitis in a French traveler to Nepal.

PubMed

Lagarde, S; Lagier, J-C; Charrel, R; Quérat, G; Vanhomwegen, J; Desprès, P; Pelletier, J; Kaphan, E

2014-02-01

Japanese encephalitis is frequent in Asia, with a severe prognosis, but rare in travelers. Culex mosquitoes transmit Japanese encephalitis virus. Risk factors are destination, duration of stay, summer and fall seasons, outdoor activities, and type of accommodation. We report the case of a French traveler to Nepal with neutralization-based serological confirmed Japanese encephalitis. He presented classical clinical (viral syndrome before an encephalitis status with behavioral disorder, global hypotonia, mutism, movement disorders, seizure, and coma), radiological (lesions of thalami, cortico-spinal tracts, and brainstem) and biological features (lymphocytic meningitis). Nowadays, the presence of Japanese encephalitis virus in Nepal, including mountain areas, is established but Japanese encephalitis remains rare in travelers returning from this area and neurologist physicians need to become familiar with this. We recommend vaccination for travelers spending a long period of time in Nepal and having at-risk outdoor activities.

Host factor SPCS1 regulates the replication of Japanese encephalitis virus through interactions with transmembrane domains of NS2B.

PubMed

Ma, Le; Li, Fang; Zhang, Jing-Wei; Li, Wei; Zhao, Dong-Ming; Wang, Han; Hua, Rong-Hong; Bu, Zhi-Gao

2018-03-28

Signal peptidase complex subunit 1 (SPCS1) is a newly identified host factor that regulates flavivirus replication, but the molecular mechanism is not fully understood. Herein, using Japanese encephalitis virus (JEV) as a model, we investigated the mechanism through which host factor SPCS1 regulates the replication of flaviviruses. We first validated the regulatory function of SPCS1 in JEV propagation by knocking down and knocking out endogenous SPCS1. Loss of SPCS1 function markedly reduced intracellular virion assembly and production of infectious JEV particles, but did not affect virus cell entry, RNA replication, or translation. SPCS1 was found to interact with NS2B, which is involved in post-translational protein processing and viral assembly. Serial deletion mutation of the JEV NS2B protein revealed that two transmembrane domains, NS2B (1-49) and NS2B (84-131), interact with SPCS1. Further mutagenesis analysis of conserved flavivirus residues in two SPCS1 interaction domains of NS2B demonstrated that G12A, G37A, and G47A in NS2B (1-49), and P112A in NS2B (84-131), weakened the interaction with SPCS1. Deletion mutation of SPCS1 revealed that SPCS1 (91-169) which containing two transmembrane domains was involved in the interaction with both NS2B (1-49) and NS2B (84-131). Taken together, the results demonstrate that SPCS1 affects viral replication by interacting with NS2B, thereby influencing post-translational processing of JEV proteins and the assembly of virions. IMPORTANCE Understanding viral-host interactions is important for elucidating the molecular mechanisms of viral propagation, and identifying potential anti-viral targets. Previous reports demonstrated that SPCS1 is involved in the flavivirus life cycle, but the mechanism remains unknown. In this study, we confirmed that SPCS1 participates in the post-translational protein processing and viral assembly stages of the JEV lifecycle, but not in the cell entry, genome RNA replication, or translation stages. Furthermore, we found that SPCS1 interacts with two independent transmembrane domains of the Flavivirus NS2B protein. NS2B also interacts with NS2A, which is proposed to mediate viral assembly. Therefore, we propose a protein-protein interaction model showing how SPCS1 participates in the assembly of JEV particles. The findings expand our understanding of how host factors participate in the flavivirus replication lifecycle, and identify potential anti-viral targets for combatting flavivirus infection. Copyright © 2018 American Society for Microbiology.

Characterization of a siberian virus isolated from a patient with progressive chronic tick-borne encephalitis.

PubMed

Gritsun, T S; Frolova, T V; Zhankov, A I; Armesto, M; Turner, S L; Frolova, M P; Pogodina, V V; Lashkevich, V A; Gould, E A

2003-01-01

A strain of Tick-borne encephalitis virus designated Zausaev (Za) was isolated in Siberia from a patient who died of a progressive (2-year) form of tick-borne encephalitis 10 years after being bitten by a tick. The complete genomic sequence of this virus was determined, and an attempt was made to correlate the sequence with the biological characteristics of the virus. Phylogenetic analysis demonstrated that this virus belongs to the Siberian subtype of Tick-borne encephalitis virus. Comparison of Za virus with two related viruses, a Far Eastern isolate, Sofjin, and a Siberian isolate, Vasilchenko, revealed differences among the three viruses in pathogenicity for Syrian hamsters, cytopathogenicity for PS cells, plaque morphology, and the electrophoretic profiles of virus-specific nonstructural proteins. Comparative amino acid alignments revealed 10 individual amino acid substitutions in the Za virus polyprotein sequence that were different from those of other tick-borne flaviviruses. Notably, the dimeric form of the Za virus NS1 protein migrated in polyacrylamide gels as a heterogeneous group of molecules with a significantly higher electrophoretic mobility than those of the Sofjin and Vasilchenko viruses. Two amino acid substitutions, T(277)-->V and E(279)-->G, within the NS1 dimerization domain are probably responsible for the altered oligomerization of Za virus NS1. These studies suggest that the patient from whom Za virus was isolated died due to increased pathogenicity of the latent virus following spontaneous mutagenesis.

Characterization of a Siberian Virus Isolated from a Patient with Progressive Chronic Tick-Borne Encephalitis

PubMed Central

Gritsun, T. S.; Frolova, T. V.; Zhankov, A. I.; Armesto, M.; Turner, S. L.; Frolova, M. P.; Pogodina, V. V.; Lashkevich, V. A.; Gould, E. A.

2003-01-01

A strain of Tick-borne encephalitis virus designated Zausaev (Za) was isolated in Siberia from a patient who died of a progressive (2-year) form of tick-borne encephalitis 10 years after being bitten by a tick. The complete genomic sequence of this virus was determined, and an attempt was made to correlate the sequence with the biological characteristics of the virus. Phylogenetic analysis demonstrated that this virus belongs to the Siberian subtype of Tick-borne encephalitis virus. Comparison of Za virus with two related viruses, a Far Eastern isolate, Sofjin, and a Siberian isolate, Vasilchenko, revealed differences among the three viruses in pathogenicity for Syrian hamsters, cytopathogenicity for PS cells, plaque morphology, and the electrophoretic profiles of virus-specific nonstructural proteins. Comparative amino acid alignments revealed 10 individual amino acid substitutions in the Za virus polyprotein sequence that were different from those of other tick-borne flaviviruses. Notably, the dimeric form of the Za virus NS1 protein migrated in polyacrylamide gels as a heterogeneous group of molecules with a significantly higher electrophoretic mobility than those of the Sofjin and Vasilchenko viruses. Two amino acid substitutions, T277→V and E279→G, within the NS1 dimerization domain are probably responsible for the altered oligomerization of Za virus NS1. These studies suggest that the patient from whom Za virus was isolated died due to increased pathogenicity of the latent virus following spontaneous mutagenesis. PMID:12477807

Granulomatous herpes simplex encephalitis in an infant with multicystic encephalopathy: a distinct clinicopathologic entity?

PubMed

Schutz, Peter W; Fauth, Clarissa T; Al-Rawahi, Ghada N; Pugash, Denise; White, Valerie A; Stockler, Sylvia; Dunham, Christopher P

2014-04-01

Herpes simplex virus encephalitis can manifest as a range of clinical presentations including classic adult, neonatal, and biphasic chronic-granulomatous herpes encephalitis. We report an infant with granulomatous herpes simplex virus type 2 encephalitis with a subacute course and multicystic encephalopathy. A 2-month-old girl presented with lethargy and hypothermia. Computed tomography scan of the head showed multicystic encephalopathy and calcifications. Cerebrospinal fluid analysis by polymerase chain reaction testing for herpes simplex virus 1 and 2, enterovirus, and cytomegalovirus was negative. Normal cerebrospinal fluid interferon-α levels argued against Aicardi-Goutières syndrome. The patient died 2 weeks after presentation. At autopsy, multicystic encephalopathy was confirmed with bilateral gliosis, granulomatous inflammation with multinucleated giant cells, and calcifications. Bilateral healing necrotizing retinitis suggested a viral etiology, but retina and brain were free of viral inclusions and immunohistochemically negative for herpes simplex virus-2 and cytomegalovirus. However, polymerase chain reaction analysis showed herpes simplex virus-2 DNA in four cerebral paraffin blocks. Subsequent repeat testing of the initial cerebrospinal fluid sample using a different polymerase chain reaction assay was weakly positive for herpes simplex virus-2 DNA. Granulomatous herpes simplex virus encephalitis in infants can present with subacute course and result in multicystic encephalopathy with mineralization and minimal cerebrospinal fluid herpes simplex virus DNA load. Infectious etiologies should be carefully investigated in the differential diagnosis of multicystic encephalopathy with mineralization, in particular if multinucleated giant cells are present. Copyright © 2014 Elsevier Inc. All rights reserved.

[The clinico-laboratory characteristics of cases of diseases connected with viruses of the California encephalitis complex in the inhabitants of Moscow].

PubMed

Kolobukhina, L V; L'vov, D K; Butenko, A M; Kuznetsov, A A; Galkina, I V

1989-10-01

To study the role of viruses of the California encephalitis virus complex (the family Bunyaviridae) in infectious pathology, 187 fever patients admitted to the Clinical Infectious Hospital in May-September 1986 were examined. In 10 of these patients the neutralization test revealed the presence of diagnostically significant changes in neutralizing antibodies (neutralization indices), which was indicative of the role played by Tahyna virus or other related viruses belonging to the California encephalitis virus complex in the etiology of the diseases. The analysis of the clinical picture showed that in all patients the disease took an acute course in its initial stage, starting with shivering and characterized by high fever, headache, pronounced toxicosis, the possibility of the formation of intracerebral hypertension and pneumonia.

Neurologic Complications of Influenza B Virus Infection in Adults, Romania.

PubMed

Popescu, Corneliu P; Florescu, Simin A; Lupulescu, Emilia; Zaharia, Mihaela; Tardei, Gratiela; Lazar, Mihaela; Ceausu, Emanoil; Ruta, Simona M

2017-04-01

We characterized influenza B virus-related neurologic manifestations in an unusually high number of hospitalized adults at a tertiary care facility in Romania during the 2014-15 influenza epidemic season. Of 32 patients with a confirmed laboratory diagnosis of influenza B virus infection, neurologic complications developed in 7 adults (median age 31 years). These complications were clinically diagnosed as confirmed encephalitis (4 patients), possible encephalitis (2 patients), and cerebellar ataxia (1 patient). Two of the patients died. Virus sequencing identified influenza virus B (Yam)-lineage clade 3, which is representative of the B/Phuket/3073/2013 strain, in 4 patients. None of the patients had been vaccinated against influenza. These results suggest that influenza B virus can cause a severe clinical course and should be considered as an etiologic factor for encephalitis.

Neuro-Immune Mechanisms in Response to Venezuelan equine encephalitis Virus Infection

DTIC Science & Technology

2000-05-01

horses . They were subsequently shown to be previously unrecognized viral agents of severe equine encephalitis (Smith et al., 1997). One member of...iii ABSTRACT NEURO-IMMUNE MECHANISMS IN RESPONSE TO VENEZUELAN EQUINE ENCEPHALITIS VIRUS INFECTION Major Bruce A. Schoneboom directed by Franziska B...Grieder, DVM, Ph.D., Assistant Professor of Microbiology and Immunology, Molecular and Cellular Biology, and Neuroscience Venezuelan equine

Serologic Evidence of Tick-Borne Encephalitis Virus Infection in a Patient with Suspected Lyme Disease in Japan.

PubMed

Yoshii, Kentaro; Sato, Kozue; Ishizuka, Mariko; Kobayashi, Shintaro; Kariwa, Hiroaki; Kawabata, Hiroki

2018-05-29

Tick-borne encephalitis (TBE) is widely prevalent on the Eurasian continent, including Japan, but four cases of TBE have been reported in Japan. To inspect unconfirmed TBE cases in Japan, we conducted a retrospective seroepidemiological study of a total of 158 samples from 81 meningoencephalitis patients suspected as Lyme disease. Two serum samples from one patient showed neutralizing antibodies against TBE virus. The patient with severe and progressive encephalitis had a history of tick bite in Hokkaido in 2012. These results demonstrated that tick-borne encephalitis virus (TBEV) case was actually unconfirmed in Japan. Further seroepidemiological surveys are required to identify unconfirmed TBEV infections to consider the pros and cons of introducing specific countermeasures including vaccination in Japan.

West Nile Virus Encephalitis in a Barbary Macaque (Macaca sylvanus)

PubMed Central

Barker, Ian K.; Crawshaw, Graham J.; Bertelsen, Mads F.; Drebot, Michael A.; Andonova, Maya

2004-01-01

An aged Barbary ape (Macaca sylvanus) at the Toronto Zoo became infected with naturally acquired West Nile virus (WNV) encephalitis that caused neurologic signs, which, associated with other medical problems, led to euthanasia. The diagnosis was based on immunohistochemical assay of brain lesions, reverse transcriptase–polymerase chain reaction, and virus isolation. PMID:15200866

Diagnosis of Fatal Human Case of St. Louis Encephalitis Virus Infection by Metagenomic Sequencing, California, 2016.

PubMed

Chiu, Charles Y; Coffey, Lark L; Murkey, Jamie; Symmes, Kelly; Sample, Hannah A; Wilson, Michael R; Naccache, Samia N; Arevalo, Shaun; Somasekar, Sneha; Federman, Scot; Stryke, Doug; Vespa, Paul; Schiller, Gary; Messenger, Sharon; Humphries, Romney; Miller, Steve; Klausner, Jeffrey D

2017-10-01

We used unbiased metagenomic next-generation sequencing to diagnose a fatal case of meningoencephalitis caused by St. Louis encephalitis virus in a patient from California in September 2016. This case is associated with the recent 2015-2016 reemergence of this virus in the southwestern United States.

Unrecognized Subclinical Infection with Tickborne Encephalitis Virus, Japan

PubMed Central

Yoshii, Kentaro; Kojima, Reiji

2017-01-01

During early 2017, we conducted a seroepidemiologic investigation for tickborne encephalitis virus among 291 Japan Self-Defense Forces members in Hokkaido. Two (0.7%) tested positive. Neither had clinically apparent symptoms after removing ticks. PMID:28930025

Genetic Diversity of Venezuelan Alphaviruses and Circulation of a Venezuelan Equine Encephalitis Virus Subtype IAB Strain During an Interepizootic Period

PubMed Central

Medina, Gladys; Garzaro, Domingo J.; Barrios, Miguel; Auguste, Albert J.; Weaver, Scott C.; Pujol, Flor H.

2015-01-01

Several species of alphaviruses have been previously described in the Americas, some of which are associated with encephalitis and others are associated with arthralgia. Venezuelan equine encephalitis virus (VEEV) and eastern equine encephalitis virus (EEEV) are endemic to Venezuela, with the former being responsible for major outbreaks of severe and often fatal disease in animals and humans. The aim of this study was to analyze the genetic diversity of Venezuelan alphaviruses isolated during two decades (1973–1999) of surveillance in northern Venezuela. Phylogenetic analysis indicated the circulation of a VEEV subtype IAB strain 8 years after the last reported outbreak. Thirteen strains within two subclades of South American lineage III of EEEV were also found in Venezuela. Considerable genetic variability was observed among Venezuelan Una virus strains, which were widely distributed among the clades. The first Venezuelan Mayaro sequence was also characterized. PMID:25940191

Study on the occurrence of tick-borne encephalitis virus RNA in European bison (Bison bonasus) eliminated at Białowieza Primeval Forest (north-eastern Poland) in 2005-2009.

PubMed

Biernat, Beata; Karbowiak, Grzegorz

2014-01-01

Tick-borne encephalitis virus (TBEV) (Flaviviridae, Flavivirus) is an arthropod-borne virus, an etiologic agent of tick-borne encephalitis (TBE), an infection involving the central nervous system. The disease is endemic in a large region in Eurasia where it is transmitted mainly by Ixodes ricinus in Europe and I. persulcatus ticks in Asia. This is the most important tick-transmitted arbovirus of human pathogenicity in Europe. The Białowieza Primeval Forest is a well-known endemic focus of tick-borne encephalitis. The aim of this study was to identify the prevalence of tickborne encephalitis virus (TBEV) in European bison, the important hosts of ticks in the Białowieza Primeval Forest. In the years 2005-2009, 95 blood samples were collected from European bison and examined for the presence of TBEV using nRT-PCR method. No positive results were obtained. For better understanding of TBEV vertebrate reservoir hosts in Poland, further investigations are needed.

[Epidemiology of encephalitis caused by arbovirus in the Brazilian Amazonia].

PubMed

Vasconcelos, P F; Da Rosa, J F; Da Rosa, A P; Dégallier, N; Pinheiro, F de P; Sá Filho, G C

1991-01-01

An overview of ecological, epidemiological and clinical findings of potential arthropod-borne encephalitis viruses circulating in the Amazon Region of Brazil are discussed. These viruses are the Eastern Equine Encephalitis (EEE), Western Equine Encephalitis (WEE), St. Louis Encephalitis (SLE), Mucambo (MUC) and Pixuna (PIX). These last two are subtypes (III and IV) of Venezuelan Equine Encephalitis virus. The areas of study were the highways and projects of development, as well as places where outbreaks of human diseases caused by arboviruses had been detected. These viruses are widespread in all Amazonia, and at least four of them, EEE, WEE, SLE and MUC are pathogenic to man. EEE and WEE infections were detected by serology, while SLE and MUC by either serology and virus isolation. The PIX virus has the lowest prevalence and, it was isolated in only a few cases, one being from a laboratory infection. Wild birds are the main hosts for all these viruses, except MUC, whose major hosts are rodents. The symptoms presented by infected people were generally a mild febrile illness. Although, jaundice was observed in two individuals from whom SLE was isolated. A comparison of the clinical symptoms presented by the patients in the Amazon Region and other areas of America, especially in the USA is made. In Brazilian Amazon region epidemics have not been detected although, at least, one EEE epizootic was recorded in Bragança, Para State, in 1960. At that time, of 500 horses that were examined 61% were positive to EEE by HI and of them 8.2% died. On the other hand, SLE has caused four epizootics in a forest near Belem. Wild birds and sentinel monkeys were infected, but no human cases were reported.

Present and Future Arboviral Threats

PubMed Central

Weaver, Scott C.; Reisen, William K.

2009-01-01

Arthropod-borne viruses (arboviruses) are important causes of human disease nearly worldwide. All arboviruses circulate among wild animals, and many cause disease after spillover transmission to humans and agriculturally important domestic animals that are incidental or dead-end hosts. Viruses such as dengue (DENV) and chikungunya (CHIKV) viruses that have lost the requirement for enzootic amplification now produce extensive epidemics in tropical urban centers. Many arboviruses recently have increased in importance as human and veterinary pathogens using a variety of mechanisms. Beginning in 1999, West Nile virus (WNV) underwent a dramatic geographic expansion into the Americas. High amplification associated with avian virulence coupled with adaptation for replication at higher temperatures in mosquito vectors, it has caused the largest epidemic of arboviral encephalitis ever reported in the Americas. Japanese encephalitis virus (JEV), the most frequent arboviral cause of encephalitis worldwide, has spread throughout most of Asia and as far south as Australia from its putative origin in Indonesia and Malaysia. JEV has caused major epidemics as it invaded new areas, often enabled by rice culture and amplification in domesticated swine. Rift Valley fever virus (RVFV), another arbovirus that infects humans after amplification in domesticated animals, undergoes epizootic transmission during wet years following droughts. Warming of the Indian Ocean, linked to the El Niño-Southern Oscillation in the Pacific, leads to heavy rainfall in east Africa inundating surface pools and vertically-infected mosquito eggs laid during previous seasons. Like WNV, JEV and RVFV could become epizootic and epidemic in the Americas if introduced unintentionally via commerce or intentionally for nefarious purposes. Climate warming also could facilitate the expansion of the distributions of many arboviruses, as documented for bluetongue viruses (BTV), major pathogens of ruminants. BTV, especially BTV-8, invaded Europe after climate warming enabled the major midge vector to expand is distribution northward into southern Europe and extended the transmission season and vectorial capacity of local midge species. Perhaps the greatest health risk of arboviral emergence comes from extensive tropical urbanization and the colonization of this expanding habitat by the highly anthropophilic (attracted to humans) mosquito, Aedes aegypti. These factors led to the emergence of permanent endemic cycles of urban DENV and chikungunya virus (CHIKV), as well as seasonal interhuman transmission of yellow fever and Zika viruses. The recent invasion into the Americas, Europe and Africa of Ae. albopictus, an important CHIKV and secondary DENV vector, could enhance urban transmission of these viruses in tropical as well as temperate regions. The minimal requirements for sustained endemic arbovirus transmission, adequate human viremia and vector competence of Ae. aegypti and/or Ae. albopictus, may be met by two other viruses with the potential to become major human pathogens: Venezuelan equine encephalitis virus, already an important cause of neurological disease in humans and equids throughout the Americas, and Mayaro virus, a close relative of CHIKV that produces a comparably debilitating arthralgic disease in South America. Further research is needed to understand the potential of these and other arboviruses to emerge in the future, invade new geographic areas, and become important public and veterinary health problems. PMID:19857523

Attenuation of pathogenic Rift Valley fever virus strain through the chimeric S-segment encoding sandfly fever phlebovirus NSs or a dominant-negative PKR

PubMed Central

Nishiyama, Shoko; Slack, Olga A. L.; Lokugamage, Nandadeva; Hill, Terence E.; Juelich, Terry L.; Zhang, Lihong; Smith, Jennifer K.; Perez, David; Gong, Bin; Freiberg, Alexander N.; Ikegami, Tetsuro

2016-01-01

ABSTRACT Rift Valley fever is a mosquito-borne zoonotic disease affecting ruminants and humans. Rift Valley fever virus (RVFV: family Bunyaviridae, genus Phlebovirus) causes abortions and fetal malformations in ruminants, and hemorrhagic fever, encephalitis, or retinitis in humans. The live-attenuated MP-12 vaccine is conditionally licensed for veterinary use in the US. However, this vaccine lacks a marker for the differentiation of vaccinated from infected animals (DIVA). NSs gene is dispensable for RVFV replication, and thus, rMP-12 strains lacking NSs gene is applicable to monitor vaccinated animals. However, the immunogenicity of MP-12 lacking NSs was not as high as parental MP-12. Thus, chimeric MP-12 strains encoding NSs from either Toscana virus (TOSV), sandfly fever Sicilian virus (SFSV) or Punta Toro virus Adames strain (PTA) were characterized previously. Although chimeric MP-12 strains are highly immunogenic, the attenuation through the S-segment remains unknown. Using pathogenic ZH501 strain, we aimed to demonstrate the attenuation of ZH501 strain through chimeric S-segment encoding either the NSs of TOSV, SFSV, PTA, or Punta Toro virus Balliet strain (PTB). In addition, we characterized rZH501 encoding a human dominant-negative PKR (PKRΔE7), which also enhances the immunogenicity of MP-12. Study done on mice revealed that attenuation of rZH501 occurred through the S-segment encoding either PKRΔE7 or SFSV NSs. However, rZH501 encoding either TOSV, PTA, or PTB NSs in the S-segment uniformly caused lethal encephalitis. Our results indicated that the S-segments encoding PKRΔE7 or SFSV NSs are attenuated and thus applicable toward next generation MP-12 vaccine candidates that encode a DIVA marker. PMID:27248570

Attenuation of pathogenic Rift Valley fever virus strain through the chimeric S-segment encoding sandfly fever phlebovirus NSs or a dominant-negative PKR.

PubMed

Nishiyama, Shoko; Slack, Olga A L; Lokugamage, Nandadeva; Hill, Terence E; Juelich, Terry L; Zhang, Lihong; Smith, Jennifer K; Perez, David; Gong, Bin; Freiberg, Alexander N; Ikegami, Tetsuro

2016-11-16

Rift Valley fever is a mosquito-borne zoonotic disease affecting ruminants and humans. Rift Valley fever virus (RVFV: family Bunyaviridae, genus Phlebovirus) causes abortions and fetal malformations in ruminants, and hemorrhagic fever, encephalitis, or retinitis in humans. The live-attenuated MP-12 vaccine is conditionally licensed for veterinary use in the US. However, this vaccine lacks a marker for the differentiation of vaccinated from infected animals (DIVA). NSs gene is dispensable for RVFV replication, and thus, rMP-12 strains lacking NSs gene is applicable to monitor vaccinated animals. However, the immunogenicity of MP-12 lacking NSs was not as high as parental MP-12. Thus, chimeric MP-12 strains encoding NSs from either Toscana virus (TOSV), sandfly fever Sicilian virus (SFSV) or Punta Toro virus Adames strain (PTA) were characterized previously. Although chimeric MP-12 strains are highly immunogenic, the attenuation through the S-segment remains unknown. Using pathogenic ZH501 strain, we aimed to demonstrate the attenuation of ZH501 strain through chimeric S-segment encoding either the NSs of TOSV, SFSV, PTA, or Punta Toro virus Balliet strain (PTB). In addition, we characterized rZH501 encoding a human dominant-negative PKR (PKRΔE7), which also enhances the immunogenicity of MP-12. Study done on mice revealed that attenuation of rZH501 occurred through the S-segment encoding either PKRΔE7 or SFSV NSs. However, rZH501 encoding either TOSV, PTA, or PTB NSs in the S-segment uniformly caused lethal encephalitis. Our results indicated that the S-segments encoding PKRΔE7 or SFSV NSs are attenuated and thus applicable toward next generation MP-12 vaccine candidates that encode a DIVA marker.

Interim Report on SNP analysis and forensic microarray probe design for South American hemorrhagic fever viruses, tick-borne encephalitis virus, henipaviruses, Old World Arenaviruses, filoviruses, Crimean-Congo hemorrhagic fever viruses, Rift Valley fever

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

Jaing, C; Gardner, S

The goal of this project is to develop forensic genotyping assays for select agent viruses, enhancing the current capabilities for the viral bioforensics and law enforcement community. We used a multipronged approach combining bioinformatics analysis, PCR-enriched samples, microarrays and TaqMan assays to develop high resolution and cost effective genotyping methods for strain level forensic discrimination of viruses. We have leveraged substantial experience and efficiency gained through year 1 on software development, SNP discovery, TaqMan signature design and phylogenetic signature mapping to scale up the development of forensics signatures in year 2. In this report, we have summarized the whole genomemore » wide SNP analysis and microarray probe design for forensics characterization of South American hemorrhagic fever viruses, tick-borne encephalitis viruses and henipaviruses, Old World Arenaviruses, filoviruses, Crimean-Congo hemorrhagic fever virus, Rift Valley fever virus and Japanese encephalitis virus.« less

Modulation of neuronal proteome profile in response to Japanese encephalitis virus infection.

PubMed

Sengupta, Nabonita; Ghosh, Sourish; Vasaikar, Suhas V; Gomes, James; Basu, Anirban

2014-01-01

In this study we have reported the in vivo proteomic changes during Japanese Encephalitis Virus (JEV) infection in combination with in vitro studies which will help in the comprehensive characterization of the modifications in the host metabolism in response to JEV infection. We performed a 2-DE based quantitative proteomic study of JEV-infected mouse brain as well as mouse neuroblastoma (Neuro2a) cells to analyze the host response to this lethal virus. 56 host proteins were found to be differentially expressed post JEV infection (defined as exhibiting ≥ 1.5-fold change in protein abundance upon JEV infection). Bioinformatics analyses were used to generate JEV-regulated host response networks which reported that the identified proteins were found to be associated with various cellular processes ranging from intracellular protein transport, cellular metabolism and ER stress associated unfolded protein response. JEV was found to invade the host protein folding machinery to sustain its survival and replication inside the host thereby generating a vigorous unfolded protein response, subsequently triggering a number of pathways responsible for the JEV associated pathologies. The results were also validated using a human cell line to correlate them to the human response to JEV. The present investigation is the first report on JEV-host interactome in in vivo model and will be of potential interest for future antiviral research in this field.

Herpesvirus-associated central nervous system diseases after allogeneic hematopoietic stem cell transplantation.

PubMed

Wu, Meiqing; Huang, Fen; Jiang, Xinmiao; Fan, Zhiping; Zhou, Hongsheng; Liu, Can; Jiang, Qianli; Zhang, Yu; Zhao, Ke; Xuan, Li; Zhai, Xiao; Zhang, Fuhua; Yin, Changxin; Sun, Jing; Feng, Ru; Liu, Qifa

2013-01-01

Herpesvirus infections of the central nervous system (CNS) are associated with encephalitis/myelitis and lymphoproliferative diseases in immunocompromised individuals. As of now, data of herpesvirus-associated CNS diseases in transplant recipients is limited. Hence, in this prospective study, we investigated the incidence of herpesvirus-associated CNS diseases and explored the diagnosis of these diseases in 281 allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. Herpesvirus-DNA and cerebrospinal fluid (CSF) cells were sampled from 58 recipients with herpesvirus-associated diseases or with unexplainable CNS manifestations. Results showed that 23 patients were diagnosed as herpesvirus-associated CNS diseases, including 15 Epstein-Barr virus (EBV)-associated diseases (4 encephalitis and 11 lymphoproliferative diseases), 5 herpes simplex virus type 1 encephalitis, 2 cytomegalovirus encephalitis/myelitis and 1 varicella zoster virus encephalitis. The median time of diseases onset was 65 (range 22-542) days post-transplantation. The 3-year cumulative incidence of herpesvirus-associated encephalitis/myelitis and post-transplant lymphoproliferative disorder (PTLD) was 6.3% ± 1.9% and 4.1% ± 1.2%, respectively. Of the evaluable cases, CSF cells mainly consisted of CD19(+)CD20(+) B cells (7/11) and had clonal rearrangement of immunoglobulin genes (3/11) in patients with CNS-PTLD. On the contrary, in patients with encephalitis/myelitis, CSF cells were comprised of different cell populations and none of the gene rearrangement was detected. Herpesvirus-associated CNS diseases are common in the early stages of allo-HSCT, wherein EBV is the most frequent causative virus. The immunophenotypic and clonal analysis of CSF cells might be helpful in the differential diagnosis between encephalitis and lymphoproliferative diseases.

The role of birds in the epizootiology of eastern encephalitis

USGS Publications Warehouse

Herman, C.M.

1962-01-01

Eastern encephalitis is a disease of horses, man, birds, and reptiles caused by a virus that in some hosts results in an inflammation of the brain. The causative virus belongs to a group classified as mosquito-borne encephalitides. This disease, more commonly called eastern equine encephalitis in the past, occurs from Wisconsin and Texas to the Atlantic coast and is particularly prevalent on our eastern seaboard.

Surveillance for Western Equine Encephalitis, St. Louis Encephalitis, and West Nile Viruses Using Reverse Transcription Loop-Mediated Isothermal Amplification

PubMed Central

Wheeler, Sarah S.; Ball, Cameron S.; Langevin, Stanley A.; Fang, Ying; Coffey, Lark L.; Meagher, Robert J.

2016-01-01

Collection of mosquitoes and testing for vector-borne viruses is a key surveillance activity that directly influences the vector control efforts of public health agencies, including determining when and where to apply insecticides. Vector control districts in California routinely monitor for three human pathogenic viruses including West Nile virus (WNV), Western equine encephalitis virus (WEEV), and St. Louis encephalitis virus (SLEV). Reverse transcription quantitative polymerase chain reaction (RT-qPCR) offers highly sensitive and specific detection of these three viruses in a single multiplex reaction, but this technique requires costly, specialized equipment that is generally only available in centralized public health laboratories. We report the use of reverse transcription loop-mediated isothermal amplification (RT-LAMP) to detect WNV, WEEV, and SLEV RNA extracted from pooled mosquito samples collected in California, including novel primer sets for specific detection of WEEV and SLEV, targeting the nonstructural protein 4 (nsP4) gene of WEEV and the 3’ untranslated region (3’-UTR) of SLEV. Our WEEV and SLEV RT-LAMP primers allowed detection of <0.1 PFU/reaction of their respective targets in <30 minutes, and exhibited high specificity without cross reactivity when tested against a panel of alphaviruses and flaviviruses. Furthermore, the SLEV primers do not cross-react with WNV, despite both viruses being closely related members of the Japanese encephalitis virus complex. The SLEV and WEEV primers can also be combined in a single RT-LAMP reaction, with discrimination between amplicons by melt curve analysis. Although RT-qPCR is approximately one order of magnitude more sensitive than RT-LAMP for all three targets, the RT-LAMP technique is less instrumentally intensive than RT-qPCR and provides a more cost-effective method of vector-borne virus surveillance. PMID:26807734

MEK/ERK activation plays a decisive role in yellow fever virus replication: implication as an antiviral therapeutic target.

PubMed

Albarnaz, Jonas D; De Oliveira, Leonardo C; Torres, Alice A; Palhares, Rafael M; Casteluber, Marisa C; Rodrigues, Claudiney M; Cardozo, Pablo L; De Souza, Aryádina M R; Pacca, Carolina C; Ferreira, Paulo C P; Kroon, Erna G; Nogueira, Maurício L; Bonjardim, Cláudio A

2014-11-01

Exploiting the inhibition of host signaling pathways aiming for discovery of potential antiflaviviral compounds is clearly a beneficial strategy for the control of life-threatening diseases caused by flaviviruses. Here we describe the antiviral activity of the MEK1/2 inhibitor U0126 against Yellow fever virus 17D vaccine strain (YFV-17D). Infection of VERO cells with YFV-17D stimulates ERK1/2 phosphorylation early during infection. Pharmacological inhibition of MEK1/2 through U0126 treatment of VERO cells blockades not only the YFV-stimulated ERK1/2 phosphorylation, but also inhibits YFV replication by ∼99%. U0126 was also effective against dengue virus (DENV-2 and -3) and Saint-Louis encephalitis virus (SLEV). Levels of NS4AB, as detected by immunofluorescence, are diminished upon treatment with the inhibitor, as well as the characteristic endoplasmic reticulum membrane invagination stimulated during the infection. Though not protective, treatment of YFV-infected, adult BALB/c mice with U0126 resulted in significant reduction of virus titers in brains. Collectively, our data suggest the potential targeting of the MEK1/2 kinase as a therapeutic tool against diseases caused by flaviviruses such as yellow fever, adverse events associated with yellow fever vaccination and dengue. Copyright © 2014 Elsevier B.V. All rights reserved.

ST. LOUIS ENCEPHALITIS

PubMed Central

Smith, Margaret G.; Blattner, Russell J.; Heys, Florence M.

1946-01-01

A colony of chicken mites (Dermanyssus gallinae) was established from a single adult female mite and her offspring. This colony of mites was shown to be free of the virus of St. Louis encephalitis. Infection of mites from this homogeneous colony with the virus of St. Louis encephalitis was accomplished by feeding on chickens having viremia. The virus was recovered as readily from mites which had not been allowed to feed for 8 days as from mites freshly engorged, showing that the demonstration of virus in the mites does not depend on the presence of fresh infective chicken blood. Transovarian passage of the St. Louis virus into the second generation has been demonstrated in mites infected experimentally. The female mite infected as an adult can pass the St. Louis virus through eggs laid after additional feeding on normal blood. Persistence of the virus for a period of 6 months has been shown in a colony of mites infected experimentally in the laboratory. PMID:19871548

Medically important arboviruses of the United States and Canada.

PubMed Central

Calisher, C H

1994-01-01

Of more than 500 arboviruses recognized worldwide, 5 were first isolated in Canada and 58 were first isolated in the United States. Six of these viruses are human pathogens: western equine encephalitis (WEE) and eastern equine encephalitis (EEE) viruses (family Togaviridae, genus Alphavirus), St. Louis encephalitis (SLE) and Powassan (POW) viruses (Flaviviridae, Flavivirus), LaCrosse (LAC) virus (Bunyaviridae, Bunyavirus), and Colorado tick fever (CTF) virus (Reoviridae, Coltivirus). Their scientific histories, geographic distributions, virology, epidemiology, vectors, vertebrate hosts, transmission, pathogenesis, clinical and differential diagnoses, control, treatment, and laboratory diagnosis are reviewed. In addition, mention is made of the Venezuelan equine encephalitis (VEE) complex viruses (family Togaviridae, genus Alphavirus), which periodically cause human and equine disease in North America. WEE, EEE, and SLE viruses are transmitted by mosquitoes between birds; POW and CTF viruses, between wild mammals by ticks; LAC virus, between small mammals by mosquitoes; and VEE viruses, between small or large mammals by mosquitoes. Human infections are tangential to the natural cycle. Such infections range from rare to focal but are relatively frequent where they occur. Epidemics of WEE, EEE, VEE, and SLE viruses have been recorded at periodic intervals, but prevalence of infections with LAC and CTF viruses typically are constant, related to the degree of exposure to infected vectors. Infections with POW virus appear to be rare. Adequate diagnostic tools are available, but treatment is mainly supportive, and greater efforts at educating the public and the medical community are suggested if infections are to be prevented. PMID:8118792

Immunogenicity of Japanese encephalitis virus envelope protein by Hyphantria cunea nuclear polyhedrosis virus vector in guinea pig.

PubMed

Lee, Hyung-Hoan; Hong, Seung-Kuk; Yoon, Sang-Ho; Jang, Sung-Jae; Bahk, Young-Yil; Song, Min-Dong; Park, Pyo-Jam; Lee, Kwang-Ho; Kim, Chan-Gil; Kim, Bokyung; Park, Tae-Kyu; Kang, Hyun

2012-05-01

Japanese encephalitis virus (JEV) is an important pathogen causing febrile syndrome, encephalitis, and death. Envelop (E) glycoprotein is the major target of inducing neutralizing antibodies and protective immunity in host. In this study, E glycoprotein of JEV was expressed in Spodoptera frugiperd 9 cells as a fusion protein containing a gX signal sequence of pseudorabies virus. This purified HcE recombinant protein was evaluated for their immunogenicity and protective efficacy in guinea pig. The survival rates of guinea pig immunized with HcE protein was significantly increased over that of JE vaccine. This result indicates helpful information for developing a subunit vaccine against JEV.

Influence of Sex and Age on Natural Resistance to St. Louis Encephalitis Virus Infection in Mice

PubMed Central

Andersen, Arthur A.; Hanson, Robert P.

1974-01-01

A difference was observed in susceptibility of adult male and female mice to St. Louis encephalitis (SLE) virus as measured by the death rate after intravenous challenge. Female mice that had susceptibility similar to that of males at 2 months of age had increased resistance to SLE virus at 3 and 4 months of age. The increased resistance occurred after sexual maturity, indicating that the resistance factor possibly was related to an aging process in the female. The susceptibility of male mice remained unchanged over the 2- to 4-month period. Neither pregnancy nor castration had any effect on resistance of adult mice to St. Louis encephalitis virus. PMID:4857422

Preclinical and clinical development of YFV 17D-based chimeric vaccines against dengue, West Nile and Japanese encephalitis viruses.

PubMed

Guy, Bruno; Guirakhoo, Farshad; Barban, Veronique; Higgs, Stephen; Monath, Thomas P; Lang, Jean

2010-01-08

Dengue viruses (DENV), West Nile virus (WNV) and Japanese encephalitis virus (JEV) are major global health and growing medical problems. While a live-attenuated vaccine exists since decades against the prototype flavivirus, yellow fever virus (YFV), there is an urgent need for vaccines against dengue or West Nile diseases, and for improved vaccines against Japanese encephalitis. Live-attenuated chimeric viruses were constructed by replacing the genes coding for Premembrane (prM) and Envelope (E) proteins from YFV 17D vaccine strain with those of heterologous flaviviruses (ChimeriVax technology). This technology has been used to produce vaccine candidates for humans, for construction of a horse vaccine for West Nile fever, and as diagnostic reagents for dengue, Japanese encephalitis, West Nile and St. Louis encephalitis infections. This review focuses on human vaccines and their characterization from the early stages of research through to clinical development. Phenotypic and genetic properties and stability were examined, preclinical evaluation through in vitro or animal models, and clinical testing were carried out. Theoretical environmental concerns linked to the live and genetically modified nature of these vaccines have been carefully addressed. Results of the extensive characterizations are in accordance with the immunogenicity and excellent safety profile of the ChimeriVax-based vaccine candidates, and support their development towards large-scale efficacy trials and registration.

Arboviruses associated with human disease in Australia.

PubMed

Russell, R C; Dwyer, D E

2000-11-01

Mosquito-borne arboviruses are an important public health issue in Australia. The alphaviruses Ross River and Barmah Forest virus are widespread and active annually, and cause debilitating polyarthritis. The flaviviruses Murray Valley encephalitis, Kunjin and Japanese encephalitis virus are restricted in distribution and activity but may cause life-threatening illness, and dengue viruses are active in some areas.

Rab5 and Rab11 Are Required for Clathrin-Dependent Endocytosis of Japanese Encephalitis Virus in BHK-21 Cells.

PubMed

Liu, Chun-Chun; Zhang, Yun-Na; Li, Zhao-Yao; Hou, Jin-Xiu; Zhou, Jing; Kan, Lin; Zhou, Bin; Chen, Pu-Yan

2017-10-01

During infection Japanese encephalitis virus (JEV) generally enters host cells via receptor-mediated clathrin-dependent endocytosis. The trafficking of JEV within endosomes is controlled by Rab GTPases, but which Rab proteins are involved in JEV entry into BHK-21 cells is unknown. In this study, entry and postinternalization of JEV were analyzed using biochemical inhibitors, RNA interference, and dominant negative (DN) mutants. Our data demonstrate that JEV entry into BHK-21 cells depends on clathrin, dynamin, and cholesterol but not on caveolae or macropinocytosis. The effect on JEV infection of dominant negative (DN) mutants of four Rab proteins that regulate endosomal trafficking was examined. Expression of DN Rab5 and DN Rab11, but not DN Rab7 and DN Rab9, significantly inhibited JEV replication. These results were further tested by silencing Rab5 or Rab11 expression before viral infection. Confocal microscopy showed that virus particles colocalized with Rab5 or Rab11 within 15 min after virus entry, suggesting that after internalization JEV moves to early and recycling endosomes before the release of the viral genome. Our findings demonstrate the roles of Rab5 and Rab11 on JEV infection of BHK-21 cells through the endocytic pathway, providing new insights into the life cycle of flaviviruses. IMPORTANCE Although Japanese encephalitis virus (JEV) utilizes different endocytic pathways depending on the cell type being infected, the detailed mechanism of its entry into BHK-21 cells is unknown. Understanding the process of JEV endocytosis and postinternalization will advance our knowledge of JEV infection and pathogenesis as well as provide potential novel drug targets for antiviral intervention. With this objective, we used systematic approaches to dissect this process. The results show that entry of JEV into BHK-21 cells requires a low-pH environment and that the process occurs through dynamin-, actin-, and cholesterol-dependent clathrin-mediated endocytosis that requires Rab5 and Rab11. Our work provides a detailed picture of the entry of JEV into BHK-21 cells and the cellular events that follow. Copyright © 2017 American Society for Microbiology.

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).

Modulation of the immune-related gene responses to protect mice against Japanese encephalitis virus using the antimicrobial peptide, tilapia hepcidin 1-5.

PubMed

Huang, Han-Ning; Rajanbabu, Venugopal; Pan, Chieh-Yu; Chan, Yi-Lin; Hui, Cho-Fat; Chen, Jyh-Yih; Wu, Chang-Jer

2011-10-01

Japanese encephalitis virus (JEV), a neurotropic flavivirus, is one of the major causes of acute encephalitis in humans. After infection, it is commonly associated with inflammatory reactions and neurological disease. There is still no effective antiviral drug available against Japanese encephalitis virus infection. Recently, a number of investigators found that antimicrobial peptide (AMPs) present a broad range of biological activities including antimicrobial and immunomodulatory activities. In this study, we found that an AMP, tilapia hepcidin (TH)1-5, caused no harm to either cells or test animals during the test course and could control JEV viral infection in BHK-21 cells. Mice co-injected with TH1-5/JEV and subsequently subjected to JEV re-challenge survived and behaved normally. The neuroprotective effects were associated with marked decreases in: (i) the viral load and viral replication within the brain, (ii) neuronal death, and (iii) secondary inflammation resulting from microglial activation. TH1-5 was also determined to enhance adaptive immunity by elevating levels of anti-JEV-neutralizing antibodies in the serum. The microarray data also showed that TH1-5 modulated Socs-6, interleukin (IL)-6, Toll-like receptor (TLR)-1, TLR-7, caspase-4, interferon (IFN)-β1, ATF-3, and several immune-responsive genes to protect mice against JEV infection. In addition, TH1-5 was confirmed to modulate the expressions of several proinflammatory and immune-responsive genes, such as IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, tumor necrosis factor (TNF)-α, IFN-γ and monocyte chemoattractant protein (MCP)-1 at both the transcriptional and translational levels in JEV-infected mice. In conclusion, our findings provide mechanistic insights into the actions of TH1-5 against JEV. Results from our in vivo and in vitro experiments clearly indicate that TH1-5 has antiviral, neuroprotective, anti-inflammatory, and immunomodulatory activities. Furthermore, TH1-5 successfully reduced the severity of disease induced by JEV. Our results point out that TH1-5 is a promising candidate for further development as an antiviral agent against JEV infection. Copyright © 2011 Elsevier Ltd. All rights reserved.

Powassan virus encephalitis resembling herpes simplex encephalitis.

PubMed

Embil, J A; Camfield, P; Artsob, H; Chase, D P

1983-02-01

A boy from New York traveling in Nova Scotia had olfactory hallucinations and other signs of temporal lobe involvement, leading to a diagnosis of herpes simplex encephalitis. The patient was treated with vidarabine and made a complete recovery. However, hemagglutination inhibition, complement fixation, and neutralization tests identified Powassan virus (POW) as the pathogen. Shortly before his trip to Nova Scotia, the patient had traveled in an area where POW encephalitis had occurred in humans (the eastern part of the state of New York), and he also came in contact with a known reservoir of POW infection (a groundhog) at home.

Pathogenesis of Borna disease in rats: evidence that intra-axonal spread is the major route for virus dissemination and the determinant for disease incubation.

PubMed

Carbone, K M; Duchala, C S; Griffin, J W; Kincaid, A L; Narayan, O

1987-11-01

Borna disease virus is an uncharacterized agent that causes sporadic but fatal neurological disease in horses and sheep in Europe. Studies of the infection in rats have shown that the agent has a strict tropism for neural tissues, in which it persists indefinitely. Inoculated rats developed encephalitis after an incubation period of 17 to 90 days. This report shows that the incubation period is the time required for transport of the agent in dendritic-axonal processes from the site of inoculation to the hippocampus. The immune responses to the agent had no effect on replication or transport of the virus. The neural conduit to the brain was proven by intranasal inoculation of virus that resulted in rapid transport of the agent via olfactory nerves to the hippocampus and in development of disease in 20 days. Virus inoculation into the feet resulted in spread along nerve fibers from neuron to neuron. There was sequential replication in neurons of the dorsal root ganglia adjacent to the lumbar spinal cord, the gracilis nucleus in the medulla, and pyramidal cells in the cerebral cortex, followed by infection of the hippocampal neurons and onset of disease. This progression required 50 to 60 days. The exclusiveness of the neural conduit was proven by failure to cause infection after injection of the virus intravenously or into the feet of neurectomized rats.

Hantavirus pulmonary syndrome: encephalitis caused by virus Andes.

PubMed

Talamonti, Lionel; Padula, Paula J; Canteli, María Sol; Posner, Federico; Marczeski, Fanny Pires; Weller, Carlos

2011-04-01

Hemorrhagic fever with renal syndrome and hantavirus pulmonary syndrome (HPS) are rodent-borne emerging diseases caused by members of the genus Hantavirus, family Bunyaviridae. Some species of hantavirus may cause encephalitis, but this is the first report in Andes virus associated to HPS.

Rapid Detection of Powassan Virus in a Patient With Encephalitis by Metagenomic Sequencing.

PubMed

Piantadosi, Anne; Kanjilal, Sanjat; Ganesh, Vijay; Khanna, Arjun; Hyle, Emily P; Rosand, Jonathan; Bold, Tyler; Metsky, Hayden C; Lemieux, Jacob; Leone, Michael J; Freimark, Lisa; Matranga, Christian B; Adams, Gordon; McGrath, Graham; Zamirpour, Siavash; Telford, Sam; Rosenberg, Eric; Cho, Tracey; Frosch, Matthew P; Goldberg, Marcia B; Mukerji, Shibani S; Sabeti, Pardis C

2018-02-10

We describe a patient with severe and progressive encephalitis of unknown etiology. We performed rapid metagenomic sequencing from cerebrospinal fluid and identified Powassan virus, an emerging tick-borne flavivirus that has been increasingly detected in the United States.

A Protective Role for Interleukin-1 Signaling during Mouse Adenovirus Type 1-Induced Encephalitis.

PubMed

Castro-Jorge, Luiza A; Pretto, Carla D; Smith, Asa B; Foreman, Oded; Carnahan, Kelly E; Spindler, Katherine R

2017-02-15

Interleukin-1β (IL-1β), an inflammatory cytokine and IL-1 receptor ligand, has diverse activities in the brain. We examined whether IL-1 signaling contributes to the encephalitis observed in mouse adenovirus type 1 (MAV-1) infection, using mice lacking the IL-1 receptor (Il1r1 -/- mice). Il1r1 -/- mice demonstrated reduced survival, greater disruption of the blood-brain barrier (BBB), higher brain viral loads, and higher brain inflammatory cytokine and chemokine levels than control C57BL/6J mice. We also examined infections of mice defective in IL-1β production (Pycard -/- mice) and mice defective in trafficking of Toll-like receptors to the endosome (Unc93b1 -/- mice). Pycard -/- and Unc93b1 -/- mice showed lower survival (similar to Il1r1 -/- mice) than control mice but, unlike Il1r1 -/- mice, did not have increased brain viral loads or BBB disruption. Based on the brain cytokine levels, MAV-1-infected Unc93b1 -/- mice had a very different inflammatory profile from infected Il1r1 -/- and Pycard -/- mice. Histological examination demonstrated pathological findings consistent with encephalitis in control and knockout mice; however, intranuclear viral inclusions were seen only in Il1r1 -/- mice. A time course of infection of control and Il1r1 -/- mice evaluating the kinetics of viral replication and cytokine production revealed differences between the mouse strains primarily at 7 to 8 days after infection, when mice began succumbing to MAV-1 infection. In the absence of IL-1 signaling, we noted an increase in the transcription of type I interferon (IFN)-stimulated genes. Together, these results indicate that IL-1 signaling is important during MAV-1 infection and suggest that, in its absence, increased IFN-β signaling may result in increased neuroinflammation. The investigation of encephalitis pathogenesis produced by different viruses is needed to characterize virus and host-specific factors that contribute to disease. MAV-1 produces viral encephalitis in its natural host, providing a good model for studying factors involved in encephalitis development. We investigated the role of IL-1 signaling during MAV-1-induced encephalitis. Unexpectedly, the lack of IL-1 signaling increased the mortality and inflammation in mice infected with MAV-1. Also, there was an increase in the transcription of type I IFN-stimulated genes that correlated with the observed increased mortality and inflammation. The findings highlight the complex nature of encephalitis and suggests that IL-1 has a protective effect for the development of MAV-1-induced encephalitis. Copyright © 2017 American Society for Microbiology.

West nile virus disease and other arboviral diseases - United States, 2011.

PubMed

2012-07-13

Arthropodborne viruses (arboviruses) are transmitted to humans primarily through the bites of infected mosquitoes and ticks. Symptomatic infections most often manifest as a systemic febrile illness and, less commonly, as neuroinvasive disease (e.g., meningitis, encephalitis, or acute flaccid paralysis). West Nile virus (WNV) is the leading cause of domestically acquired arboviral disease in the United States. However, several other arboviruses also cause seasonal outbreaks and sporadic cases. In 2011, CDC received reports of 871 cases of nationally notifiable arboviral diseases (excluding dengue); etiological agents included WNV (712 cases), La Crosse virus (LACV) (130), Powassan virus (POWV) (16), St. Louis encephalitis virus (SLEV) (six), Eastern equine encephalitis virus (EEEV) (four), and Jamestown Canyon virus (JCV) (three). Of these, 624 (72%) were classified as neuroinvasive disease, for a national incidence of 0.20 per 100,000 population. WNV and other arboviruses continue to cause focal outbreaks and severe illness in substantial numbers of persons in the United States.

Animal models of highly pathogenic RNA viral infections: encephalitis viruses.

PubMed

Holbrook, Michael R; Gowen, Brian B

2008-04-01

The highly pathogenic RNA viruses that cause encephalitis include a significant number of emerging or re-emerging viruses that are also considered potential bioweapons. Many of these viruses, including members of the family Flaviviridae, the genus Alphavirus in the family Togaviridae, and the genus Henipavirus in the family Paramyxoviridae, circulate widely in their endemic areas, where they are transmitted by mosquitoes or ticks. They use a variety of vertebrate hosts, ranging from birds to bats, in their natural life cycle. As was discovered in the United States, the introduction of a mosquito-borne encephalitis virus such as West Nile virus can cause significant health and societal concerns. There are no effective therapeutics for treating diseases caused by any of these viruses and there is limited, if any, vaccine availability for most. In this review we provide a brief summary of the current status of animal models used to study highly pathogenic encephalitic RNA viruses for the development of antiviral therapeutics and vaccines.

Distribution of mosquitoes and mosquito-borne arboviruses in Yunnan Province near the China-Myanmar-Laos border.

PubMed

Wang, Jinglin; Zhang, Hailin; Sun, Xiaohong; Fu, Shihong; Wang, Huanqin; Feng, Yun; Wang, Huanyu; Tang, Qing; Liang, Guo-Dong

2011-05-01

Economic development and increased tourism in the southern region of Yunnan Province in China, adjacent to several countries in Southeast Asia, has increased the likelihood of import and export of vectors and vector-borne diseases. We report the results of surveillance of mosquitoes and mosquito-borne arboviruses along the border of China-Myanmar-Laos in 2005 and 2006, and information associating several arboviruses with infections and possibly disease in local human populations. Seventeen mosquito species representing four genera were obtained, and 14 strains of mosquito-borne viruses representing six viruses in five genera were isolated from Culex tritaeniorhynchus. In addition, IgM against Japanese encephalitis virus, Sindbis virus, Yunnan orbivirus and novel Banna virus was detected in acute-phase serum samples obtained from hospitalized patients with fever and encephalitis near the areas where the viruses were isolated. This investigation suggests that Japanese encephalitis virus, Sindbis virus, and lesser-known arboviruses circulate and may be infecting humans in the China-Myanmar-Laos border region.

[Analysis of pathogen spectrum of Encephalitis/Meningitis in northwestern area of China].

PubMed

Zhang, Xiao-shu; Wang, Xu-xia; Yu, De-shan; Jiang, Jian-xiang; Zhang, Guang-ye; Wang, Fang; Li, Hui

2013-10-01

To learn the characteristics of pathogen spectrum of Encephalitis /Meningitis in northwestern area of China. Between January 1st 2009 and March 31st 2011, a total of 569 patients with clinical symptoms of Encephalitis/Meningitis were selected from the hospitals in Gansu, Qinghai,Inner Mongolia and Xinjiang province. 1514 samples of specimen were collected from the 515 patients, to detect the IgM of Japanese encephalitis virus (JEV), enterovirus (EV, including Coxsackie virus, ECHO virus and enterovirus 71), Mumps virus, Herpes simplex virus (HSV) in blood and cerebrospinal fluid. Meanwhile, Neisseria meningitis (Nm), Haemophilus influenzae Type B (Hib), Staphylococcus, Streptococcus pneumonia, Streptococcus Suis, E. Coli and Cryptococci were also identified. The detection results were analyzed by different region, time and age range. Pathogenic bacteria were identified in the specimen from 16 patients, with the rate at 3.65%, of which the dominant ones were Streptococcus pneumonia (7 patients, 43.75%). Virus were identified in the specimen from 132 patients, with the rate at 27.05%, of which the dominant types were EV and HSV, accounting for 33.33% (44 cases) and 31.82% (42 cases) respectively. The detection rate of virus showed a significant seasonal trend, with the peak appearing between June and November each year. The peak of EV detection was between July and September, with 24 cases detected out; the peak of HSV was between June and August (11 cases detected out); mumps virus was mainly found between July and December (25 cases). There was no significant time-distribution found in the detection of bacteria. The EV and HSV were mainly distributed in Gansu and Qinghai province (70 cases) ;most of mumps virus were found in Gansu province (24 cases);and JEV were only found in Gansu province (20 cases). The viral pathogen spectrum was identified in all ages, and the EV and mumps virus were mainly found in children aged 0-14 years old (42 and 17 cases respectively) ; JEV were identified in people over 15 years old, with 13 detected out of the 20 patients. The main pathogen of acute encephalitis and meningitis in northwestern area of China was virus, and the main pathogens of encephalitis and meningitis in children under 15 years were Herpes simplex virus and Mumps virus.

A case of Powassan virus encephalitis

PubMed Central

Rossier, Edmond; Harrison, Robert J.; Lemieux, Bernard

1974-01-01

A case of encephalitis due to Powassan virus, probably transmitted through tick-bite, is reported in an 8-year-old boy. There was a 50-fold increase in neutralization titre against Powassan virus, but the virus could not be isolated. Other virological investigations were negative. The patient survived and early physiotherapy and speech re-education could be instituted. Nine months after onset of illness the patient showed moderate sequelae, despite a very severe illness. PMID:4829843

A case of Powassan virus encephalitis.

PubMed

Rossier, E; Harrison, R J; Lemieux, B

1974-05-18

A case of encephalitis due to Powassan virus, probably transmitted through tick-bite, is reported in an 8-year-old boy. There was a 50-fold increase in neutralization titre against Powassan virus, but the virus could not be isolated. Other virological investigations were negative.The patient survived and early physiotherapy and speech re-education could be instituted. Nine months after onset of illness the patient showed moderate sequelae, despite a very severe illness.

Present and future arboviral threats.

PubMed

Weaver, Scott C; Reisen, William K

2010-02-01

Arthropod-borne viruses (arboviruses) are important causes of human disease nearly worldwide. All arboviruses circulate among wild animals, and many cause disease after spillover transmission to humans and agriculturally important domestic animals that are incidental or dead-end hosts. Viruses such as dengue (DENV) and chikungunya (CHIKV) that have lost the requirement for enzootic amplification now produce extensive epidemics in tropical urban centers. Many arboviruses recently have increased in importance as human and veterinary pathogens using a variety of mechanisms. Beginning in 1999, West Nile virus (WNV) underwent a dramatic geographic expansion into the Americas. High amplification associated with avian virulence coupled with adaptation for replication at higher temperatures in mosquito vectors, has caused the largest epidemic of arboviral encephalitis ever reported in the Americas. Japanese encephalitis virus (JEV), the most frequent arboviral cause of encephalitis worldwide, has spread throughout most of Asia and as far south as Australia from its putative origin in Indonesia and Malaysia. JEV has caused major epidemics as it invaded new areas, often enabled by rice culture and amplification in domesticated swine. Rift Valley fever virus (RVFV), another arbovirus that infects humans after amplification in domesticated animals, undergoes epizootic transmission during wet years following droughts. Warming of the Indian Ocean, linked to the El Niño-Southern Oscillation in the Pacific, leads to heavy rainfall in east Africa inundating surface pools and vertically infected mosquito eggs laid during previous seasons. Like WNV, JEV and RVFV could become epizootic and epidemic in the Americas if introduced unintentionally via commerce or intentionally for nefarious purposes. Climate warming also could facilitate the expansion of the distributions of many arboviruses, as documented for bluetongue viruses (BTV), major pathogens of ruminants. BTV, especially BTV-8, invaded Europe after climate warming and enabled the major midge vector to expand is distribution northward into southern Europe, extending the transmission season and vectorial capacity of local midge species. Perhaps the greatest health risk of arboviral emergence comes from extensive tropical urbanization and the colonization of this expanding habitat by the highly anthropophilic (attracted to humans) mosquito, Aedes aegypti. These factors led to the emergence of permanent endemic cycles of urban DENV and CHIKV, as well as seasonal interhuman transmission of yellow fever virus. The recent invasion into the Americas, Europe and Africa by Aedes albopictus, an important CHIKV and secondary DENV vector, could enhance urban transmission of these viruses in tropical as well as temperate regions. The minimal requirements for sustained endemic arbovirus transmission, adequate human viremia and vector competence of Ae. aegypti and/or Ae. albopictus, may be met by two other viruses with the potential to become major human pathogens: Venezuelan equine encephalitis virus, already an important cause of neurological disease in humans and equids throughout the Americas, and Mayaro virus, a close relative of CHIKV that produces a comparably debilitating arthralgic disease in South America. Further research is needed to understand the potential of these and other arboviruses to emerge in the future, invade new geographic areas, and become important public and veterinary health problems. Copyright 2009 Elsevier B.V. All rights reserved.

Inefficient Mechanical Transmission of Langat (Tick-Borne Encephalitis Virus Complex) Virus by Blood-Feeding Mites (Acari) to Laboratory Mice

DTIC Science & Technology

1993-05-01

AD--A269 706 SPSSHORT C:OMMNUNICATION 8 Inefficient Mechanical Transmission of Langat (Tick-Bornee Encephalitis Virus Complex) Virus by Blood-Feeding...I d after a . iremic blood meal. but onhv immediatelIy after the vi re muo. LANGAT (LGT) VIRUS is a member of the tick- No isolations of LCT virus...Use of ulatus collected in the Ulu Langat Forest re- Laboratory Animals." as promulgated by the Committee on serve, Malaysia. in l959’(Struth 1956

The Frequency of Autoimmune N-Methyl-D-Aspartate Receptor Encephalitis Surpasses That of Individual Viral Etiologies in Young Individuals Enrolled in the California Encephalitis Project

PubMed Central

Sheriff, Heather; Dalmau, Josep; Tilley, Drake H.; Glaser, Carol A.

2012-01-01

Background. In 2007, the California Encephalitis Project (CEP), which was established to study the epidemiology of encephalitis, began identifying cases of anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis. Increasing numbers of anti-NMDAR encephalitis cases have been identified at the CEP, and this form rivals commonly known viral etiologies as a causal agent. We report here the relative frequency and differences among encephalitides caused by anti-NMDAR and viral etiologies within the CEP experience. Methods. Demographic, frequency, and clinical data from patients with anti-NMDAR encephalitis are compared with those with viral encephalitic agents: enterovirus, herpes simplex virus type 1 (HSV-1), varicella-zoster virus (VZV), and West Nile virus (WNV). All examined cases presented to the CEP between September 2007 and February 2011 and are limited to individuals aged ≤30 years because of the predominance of anti-NMDAR encephalitis in this group. The diagnostic costs incurred in a single case are also included. Results. Anti-NMDAR encephalitis was identified >4 times as frequently as HSV-1, WNV, or VZV and was the leading entity identified in our cohort. We found that 65% of anti-NMDAR encephalitis occurred in patients aged ≤18 years. This disorder demonstrated a predilection, which was not observed with viral etiologies, for females (P < .01). Seizures, language dysfunction, psychosis, and electroencephalographic abnormalities were significantly more frequent in patients with anti-NMDAR encephalitis (P < .05), and autonomic instability occurred exclusively in this group. Discussion. Anti-NMDAR encephalitis rivals viral etiologies as a cause of encephalitis within the CEP cohort. This entity deserves a prominent place on the encephalitic differential diagnosis to avoid unnecessary diagnostic and treatment costs, and to permit a more timely treatment. PMID:22281844

IL-1β Signaling Promotes CNS-Intrinsic Immune Control of West Nile Virus Infection

PubMed Central

Ramos, Hilario J.; Lanteri, Marion C.; Blahnik, Gabriele; Negash, Amina; Suthar, Mehul S.; Brassil, Margaret M.; Sodhi, Khushbu; Treuting, Piper M.; Busch, Michael P.; Norris, Philip J.; Gale, Michael

2012-01-01

West Nile virus (WNV) is an emerging flavivirus capable of infecting the central nervous system (CNS) and mediating neuronal cell death and tissue destruction. The processes that promote inflammation and encephalitis within the CNS are important for control of WNV disease but, how inflammatory signaling pathways operate to control CNS infection is not defined. Here, we identify IL-1β signaling and the NLRP3 inflammasome as key host restriction factors involved in viral control and CNS disease associated with WNV infection. Individuals presenting with acute WNV infection displayed elevated levels of IL-1β in their plasma over the course of infection, suggesting a role for IL-1β in WNV immunity. Indeed, we found that in a mouse model of infection, WNV induced the acute production of IL-1β in vivo, and that animals lacking the IL-1 receptor or components involved in inflammasome signaling complex exhibited increased susceptibility to WNV pathogenesis. This outcome associated with increased accumulation of virus within the CNS but not peripheral tissues and was further associated with altered kinetics and magnitude of inflammation, reduced quality of the effector CD8+ T cell response and reduced anti-viral activity within the CNS. Importantly, we found that WNV infection triggers production of IL-1β from cortical neurons. Furthermore, we found that IL-1β signaling synergizes with type I IFN to suppress WNV replication in neurons, thus implicating antiviral activity of IL-1β within neurons and control of virus replication within the CNS. Our studies thus define the NLRP3 inflammasome pathway and IL-1β signaling as key features controlling WNV infection and immunity in the CNS, and reveal a novel role for IL-1β in antiviral action that restricts virus replication in neurons. PMID:23209411

Initiation, extension, and termination of RNA synthesis by a paramyxovirus polymerase.

PubMed

Jordan, Paul C; Liu, Cheng; Raynaud, Pauline; Lo, Michael K; Spiropoulou, Christina F; Symons, Julian A; Beigelman, Leo; Deval, Jerome

2018-02-01

Paramyxoviruses represent a family of RNA viruses causing significant human diseases. These include measles virus, the most infectious virus ever reported, in addition to parainfluenza virus, and other emerging viruses. Paramyxoviruses likely share common replication machinery but their mechanisms of RNA biosynthesis activities and details of their complex polymerase structures are unknown. Mechanistic and functional details of a paramyxovirus polymerase would have sweeping implications for understanding RNA virus replication and for the development of new antiviral medicines. To study paramyxovirus polymerase structure and function, we expressed an active recombinant Nipah virus (NiV) polymerase complex assembled from the multifunctional NiV L protein bound to its phosphoprotein cofactor. NiV is an emerging highly pathogenic virus that causes severe encephalitis and has been declared a global public health concern due to its high mortality rate. Using negative-stain electron microscopy, we demonstrated NiV polymerase forms ring-like particles resembling related RNA polymerases. We identified conserved sequence elements driving recognition of the 3'-terminal genomic promoter by NiV polymerase, and leading to initiation of RNA synthesis, primer extension, and transition to elongation mode. Polyadenylation resulting from NiV polymerase stuttering provides a mechanistic basis for transcription termination. It also suggests a divergent adaptation in promoter recognition between pneumo- and paramyxoviruses. The lack of available antiviral therapy for NiV prompted us to identify the triphosphate forms of R1479 and GS-5734, two clinically relevant nucleotide analogs, as substrates and inhibitors of NiV polymerase activity by delayed chain termination. Overall, these findings provide low-resolution structural details and the mechanism of an RNA polymerase from a previously uncharacterized virus family. This work illustrates important functional differences yet remarkable similarities between the polymerases of nonsegmented negative-strand RNA viruses.

Powassan encephalitis and Colorado tick fever.

PubMed

Romero, José R; Simonsen, Kari A

2008-09-01

This article discusses two tick-borne illnesses: Powassan encephalitis, a rare cause of central nervous system infection caused by the Powassan virus, and Colorado tick fever, an acute febrile illness caused by the Colorado tick fever virus common to the Rocky Mountain region of North America.

Current status of flavivirus vaccines.

PubMed

Barrett, A D

2001-12-01

Although there are approximately 68 flaviviruses recognized, vaccines have been developed to control very few human flavivirus diseases. Licensed live attenuated vaccines have been developed for yellow fever (strain 17D) and Japanese encephalitis (strain SA14-14-2) viruses, and inactivated vaccines have been developed for Japanese encephalitis and tick-borne encephalitis viruses. The yellow fever live attenuated 17D vaccine is one of the most efficacious and safe vaccines developed to date and has been used to immunize more than 300 million people. A number of experimental vaccines are being developed, most notably for dengue. Candidate tetravalent live attenuated dengue vaccines are undergoing clinical trials. Other vaccines are being developed using reverse genetics, DNA vaccines, and recombinant immunogens. In addition, the yellow fever 17D vaccine has been used as a backbone to generate chimeric viruses containing the premembrane and envelope protein genes from other flaviviruses. The "Chimerivax" platform has been used to construct chimeric Japanese encephalitis and dengue viruses that are in different phases of development. Similar strategies are being used by other laboratories.

Potential role of deer tick virus in Powassan encephalitis cases in Lyme disease-endemic areas of New York, U.S.A.

PubMed

El Khoury, Marc Y; Camargo, Jose F; White, Jennifer L; Backenson, Bryon P; Dupuis, Alan P; Escuyer, Kay L; Kramer, Laura; St George, Kirsten; Chatterjee, Debarati; Prusinski, Melissa; Wormser, Gary P; Wong, Susan J

2013-12-01

Powassan virus, a member of the tick-borne encephalitis group of flaviviruses, encompasses 2 lineages with separate enzootic cycles. The prototype lineage of Powassan virus (POWV) is principally maintained between Ixodes cookei ticks and the groundhog (Marmota momax) or striped skunk (Mephitis mephitis), whereas the deer tick virus (DTV) lineage is believed to be maintained between Ixodes scapularis ticks and the white-footed mouse (Peromyscus leucopus). We report 14 cases of Powassan encephalitis from New York during 2004-2012. Ten (72%) of the patients were residents of the Lower Hudson Valley, a Lyme disease-endemic area in which I. scapularis ticks account for most human tick bites. This finding suggests that many of these cases were caused by DTV rather than POWV. In 2 patients, DTV infection was confirmed by genetic sequencing. As molecular testing becomes increasingly available, more cases of Powassan encephalitis may be determined to be attributable to the DTV lineage.

Potential Role of Deer Tick Virus in Powassan Encephalitis Cases in Lyme Disease–endemic Areas of New York, USA

PubMed Central

Camargo, Jose F.; White, Jennifer L.; Backenson, Bryon P.; Dupuis, Alan P.; Escuyer, Kay L.; Kramer, Laura; St. George, Kirsten; Chatterjee, Debarati; Prusinski, Melissa; Wormser, Gary P.; Wong, Susan J.

2013-01-01

Powassan virus, a member of the tick-borne encephalitis group of flaviviruses, encompasses 2 lineages with separate enzootic cycles. The prototype lineage of Powassan virus (POWV) is principally maintained between Ixodes cookei ticks and the groundhog (Marmota momax) or striped skunk (Mephitis mephitis), whereas the deer tick virus (DTV) lineage is believed to be maintained between Ixodes scapularis ticks and the white-footed mouse (Peromyscus leucopus). We report 14 cases of Powassan encephalitis from New York during 2004–2012. Ten (72%) of the patients were residents of the Lower Hudson Valley, a Lyme disease–endemic area in which I. scapularis ticks account for most human tick bites. This finding suggests that many of these cases were caused by DTV rather than POWV. In 2 patients, DTV infection was confirmed by genetic sequencing. As molecular testing becomes increasingly available, more cases of Powassan encephalitis may be determined to be attributable to the DTV lineage. PMID:24274334

Genetic diversity of Venezuelan alphaviruses and circulation of a Venezuelan equine encephalitis virus subtype IAB strain during an interepizootic period.

PubMed

Medina, Gladys; Garzaro, Domingo J; Barrios, Miguel; Auguste, Albert J; Weaver, Scott C; Pujol, Flor H

2015-07-01

Several species of alphaviruses have been previously described in the Americas, some of which are associated with encephalitis and others are associated with arthralgia. Venezuelan equine encephalitis virus (VEEV) and eastern equine encephalitis virus (EEEV) are endemic to Venezuela, with the former being responsible for major outbreaks of severe and often fatal disease in animals and humans. The aim of this study was to analyze the genetic diversity of Venezuelan alphaviruses isolated during two decades (1973-1999) of surveillance in northern Venezuela. Phylogenetic analysis indicated the circulation of a VEEV subtype IAB strain 8 years after the last reported outbreak. Thirteen strains within two subclades of South American lineage III of EEEV were also found in Venezuela. Considerable genetic variability was observed among Venezuelan Una virus strains, which were widely distributed among the clades. The first Venezuelan Mayaro sequence was also characterized. © The American Society of Tropical Medicine and Hygiene.

Nipah encephalitis - an update.

PubMed

Sherrini, B A; Chong, T T

2014-08-01

Between September 1998 to May 1999, Malaysia and Singapore were hit by an outbreak of fatal encephalitis caused by a novel virus from the paramyxovirus family. This virus was subsequently named as Nipah virus, after the Sungei Nipah village in Negeri Sembilan, where the virus was first isolated. The means of transmission was thought to be from bats-topigs and subsequently pigs-to-human. Since 2001, almost yearly outbreak of Nipah encephalitis has been reported from Bangladesh and West Bengal, India. These outbreaks were characterized by direct bats-to-human, and human-to-human spread of infection. Nipah virus shares many similar characteristics to Hendra virus, first isolated in an outbreak of respiratory illness involving horses in Australia in 1994. Because of their homology, a new genus called Henipavirus (Hendra + Nipah) was introduced. Henipavirus infection is a human disease manifesting most often as acute encephalitis (which may be relapsing or late-onset) or pneumonia, with a high mortality rate. Pteropus bats act as reservoir for the virus, which subsequently lead to human spread. Transmission may be from consumption of food contaminated by bats secretion, contact with infected animals, or human-to-human spread. With wide geographical distribution of Pteropus bats, Henipavirus infection has become an important emerging human infection with worldwide implication.

Modification of the Host Cell Lipid Metabolism Induced by Hypolipidemic Drugs Targeting the Acetyl Coenzyme A Carboxylase Impairs West Nile Virus Replication

PubMed Central

Merino-Ramos, Teresa; Vázquez-Calvo, Ángela; Casas, Josefina; Sobrino, Francisco; Saiz, Juan-Carlos

2015-01-01

West Nile virus (WNV) is a neurotropic flavivirus transmitted by the bite of mosquitoes that causes meningitis and encephalitis in humans, horses, and birds. Several studies have highlighted that flavivirus infection is highly dependent on cellular lipids for virus replication and infectious particle biogenesis. The first steps of lipid synthesis involve the carboxylation of acetyl coenzyme A (acetyl-CoA) to malonyl-CoA that is catalyzed by the acetyl-CoA carboxylase (ACC). This makes ACC a key enzyme of lipid synthesis that is currently being evaluated as a therapeutic target for different disorders, including cancers, obesity, diabetes, and viral infections. We have analyzed the effect of the ACC inhibitor 5-(tetradecyloxy)-2-furoic acid (TOFA) on infection by WNV. Lipidomic analysis of TOFA-treated cells confirmed that this drug reduced the cellular content of multiple lipids, including those directly implicated in the flavivirus life cycle (glycerophospholipids, sphingolipids, and cholesterol). Treatment with TOFA significantly inhibited the multiplication of WNV in a dose-dependent manner. Further analysis of the antiviral effect of this drug showed that the inhibitory effect was related to a reduction of viral replication. Furthermore, treatment with another ACC inhibitor, 3,3,14,14-tetramethylhexadecanedioic acid (MEDICA 16), also inhibited WNV infection. Interestingly, TOFA and MEDICA 16 also reduced the multiplication of Usutu virus (USUV), a WNV-related flavivirus. These results point to the ACC as a druggable cellular target suitable for antiviral development against WNV and other flaviviruses. PMID:26503654

Modification of the Host Cell Lipid Metabolism Induced by Hypolipidemic Drugs Targeting the Acetyl Coenzyme A Carboxylase Impairs West Nile Virus Replication.

PubMed

Merino-Ramos, Teresa; Vázquez-Calvo, Ángela; Casas, Josefina; Sobrino, Francisco; Saiz, Juan-Carlos; Martín-Acebes, Miguel A

2016-01-01

West Nile virus (WNV) is a neurotropic flavivirus transmitted by the bite of mosquitoes that causes meningitis and encephalitis in humans, horses, and birds. Several studies have highlighted that flavivirus infection is highly dependent on cellular lipids for virus replication and infectious particle biogenesis. The first steps of lipid synthesis involve the carboxylation of acetyl coenzyme A (acetyl-CoA) to malonyl-CoA that is catalyzed by the acetyl-CoA carboxylase (ACC). This makes ACC a key enzyme of lipid synthesis that is currently being evaluated as a therapeutic target for different disorders, including cancers, obesity, diabetes, and viral infections. We have analyzed the effect of the ACC inhibitor 5-(tetradecyloxy)-2-furoic acid (TOFA) on infection by WNV. Lipidomic analysis of TOFA-treated cells confirmed that this drug reduced the cellular content of multiple lipids, including those directly implicated in the flavivirus life cycle (glycerophospholipids, sphingolipids, and cholesterol). Treatment with TOFA significantly inhibited the multiplication of WNV in a dose-dependent manner. Further analysis of the antiviral effect of this drug showed that the inhibitory effect was related to a reduction of viral replication. Furthermore, treatment with another ACC inhibitor, 3,3,14,14-tetramethylhexadecanedioic acid (MEDICA 16), also inhibited WNV infection. Interestingly, TOFA and MEDICA 16 also reduced the multiplication of Usutu virus (USUV), a WNV-related flavivirus. These results point to the ACC as a druggable cellular target suitable for antiviral development against WNV and other flaviviruses. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Purification and crystallization of dengue and West Nile virus NS2B-NS3 complexes.

PubMed

D'Arcy, Allan; Chaillet, Maxime; Schiering, Nikolaus; Villard, Frederic; Lim, Siew Pheng; Lefeuvre, Peggy; Erbel, Paul

2006-02-01

Both dengue and West Nile virus infections are an increasing risk to humans, not only in tropical and subtropical areas, but also in North America and parts of Europe. These viral infections are generally transmitted by mosquitoes, but may also be tick-borne. Infection usually results in mild flu-like symptoms, but can also cause encephalitis and fatalities. Approximately 2799 severe West Nile virus cases were reported this year in the United States, resulting in 102 fatalities. With this alarming increase in the number of West Nile virus infections in western countries and the fact that dengue virus already affects millions of people per year in tropical and subtropical climates, there is a real need for effective medicines. A possible therapeutic target to combat these viruses is the protease, which is essential for virus replication. In order to provide structural information to help to guide a lead identification and optimization program, crystallizations of the NS2B-NS3 protease complexes from both dengue and West Nile viruses have been initiated. Crystals that diffract to high resolution, suitable for three-dimensional structure determinations, have been obtained.

Type-1 angiotensin receptor signaling in central nervous system myeloid cells is pathogenic during fatal alphavirus encephalitis in mice.

PubMed

Blakely, Pennelope K; Huber, Amanda K; Irani, David N

2016-08-25

Alphaviruses can cause fatal encephalitis in humans. Natural infections occur via the bite of infected mosquitos, but aerosol transmissibility makes some of these viruses potential bioterrorism agents. Central nervous system (CNS) host responses contribute to alphavirus pathogenesis in experimental models and are logical therapeutic targets. We investigated whether reactive oxygen species (ROS) generated by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox) activity within the CNS contributes to fatal alphavirus encephalitis in mice. Infected animals were treated systemically with the angiotensin receptor-blocking drug, telmisartan, given its ability to cross the blood-brain barrier, selectively block type-1 angiotensin receptors (AT1R), and inhibit Nox-derived ROS production in vascular smooth muscle and other extraneural tissues. Clinical, virological, biochemical, and histopathological outcomes were followed over time. The importance of the angiotensin II (Ang II)/AT1R axis in disease pathogenesis was confirmed by demonstrating increased Ang II levels in the CNS following infection, enhanced disease survival when CNS Ang II production was suppressed, increased AT1R expression on microglia and tissue-infiltrating myeloid cells, and enhanced disease survival in AT1R-deficient mice compared to wild-type (WT) controls. Systemic administration of telmisartan protected WT mice from lethal encephalitis caused by two different alphaviruses in a dose-dependent manner without altering virus replication or exerting any anti-inflammatory effects in the CNS. Infection triggered up-regulation of multiple Nox subunits in the CNS, while drug treatment inhibited local Nox activity, ROS production, and oxidative neuronal damage. Telmisartan proved ineffective in Nox-deficient mice, demonstrating that this enzyme is its main target in this experimental setting. Nox-derived ROS, likely arising from CNS myeloid cells triggered by AT1R signaling, are pathogenic during fatal alphavirus encephalitis in mice. Systemically administered telmisartan at non-hypotensive doses targets Nox activity in the CNS to exert a neuroprotective effect. Disruption of this pathway may have broader implications for the treatment of related infections as well as for other CNS diseases driven by oxidative injury.

Microbial study of meningitis and encephalitis cases.

PubMed

Selim, Heba S; El-Barrawy, Mohamed A; Rakha, Magda E; Yingst, Samuel L; Baskharoun, Magda F

2007-01-01

Meningitis and/or encephalitis can pose a serious public health problem especially during outbreaks. A rapid and accurate diagnosis is important for effective earlier treatment. This study aimed to identify the possible microbial causes of meningitis and/or encephalitis cases. CSF and serum samples were collected from 322 patients who had signs and symptoms suggestive of meningitis and/or encephalitis. Out of 250 cases with confirmed clinical diagnosis, 83 (33.2%) were definitely diagnosed as bacterial meningitis and/or encephalitis cases (by using CSF culture, biochemical tests, latex agglutination test, and CSF stain), 17 (6.8%) were definitely diagnosed as having viral causes ( by viral isolation on tissue culture, PCR and ELISA), and one (0.4%) was diagnosed as fungal meningitis case (by India ink stain, culture, and biochemical tests). Also, there was one encephalitis case with positive serum ELISA IgM antibodies against Sandfly scilian virus. N. meningitidis, S. pneumonia and M. tuberculosis were the most frequently detected bacterial agents, while Enteroviruses, herpes simplex viruses and varicella zoster viruses were the most common viral agents encountered. Further studies are needed to assess the role of different microbial agents in CNS infections and their effective methods of diagnosis.

Dendritic transport of tick-borne flavivirus RNA by neuronal granules affects development of neurological disease.

PubMed

Hirano, Minato; Muto, Memi; Sakai, Mizuki; Kondo, Hirofumi; Kobayashi, Shintaro; Kariwa, Hiroaki; Yoshii, Kentaro

2017-09-12

Neurological diseases caused by encephalitic flaviviruses are severe and associated with high levels of mortality. However, little is known about the detailed mechanisms of viral replication and pathogenicity in the brain. Previously, we reported that the genomic RNA of tick-borne encephalitis virus (TBEV), a member of the genus Flavivirus , is transported and replicated in the dendrites of neurons. In the present study, we analyzed the transport mechanism of the viral genome to dendrites. We identified specific sequences of the 5' untranslated region of TBEV genomic RNA that act as a cis -acting element for RNA transport. Mutated TBEV with impaired RNA transport in dendrites caused a reduction in neurological symptoms in infected mice. We show that neuronal granules, which regulate the transport and local translation of dendritic mRNAs, are involved in TBEV genomic RNA transport. TBEV genomic RNA bound an RNA-binding protein of neuronal granules and disturbed the transport of dendritic mRNAs. These results demonstrated a neuropathogenic virus hijacking the neuronal granule system for the transport of viral genomic RNA in dendrites, resulting in severe neurological disease.

Herpes encephalitis is a disease of middle aged and elderly people: polymerase chain reaction for detection of herpes simplex virus in the CSF of 516 patients with encephalitis. The Study Group.

PubMed

Koskiniemi, M; Piiparinen, H; Mannonen, L; Rantalaiho, T; Vaheri, A

1996-02-01

To assess the diagnostic potential of the polymerase chain reaction (PCR) in herpes simplex virus (HSV) encephalitis. Samples of CSF from 516 patients with encephalitis were studied for HSV-DNA by PCR. Samples taken one to 29 days from the onset of symptoms from 38 patients (7.4%) were positive, 32 (6.2%) for HSV-1 and six (1.2%) for HSV-2. At follow up, eight of 28 patients studied were still HSV-PCR positive. A diagnostic serum:CSF antibody ratio to HSV but not to other viruses was detected in 25 of the 38 HSV-PCR positive patients thus supporting the initial PCR findings. Patients positive by HSV-PCR were concentrated in the age group > or = 40 years, and especially in patients aged 60-64 years, of whom nine of 24 (37.5%) were positive. The HSV-PCR was negative in all other patients with encephalitis of known or unknown aetiology. This group included 34 patients with a diagnostic serum:CSF antibody ratio to other viruses. A dual infection, HSV and another microbe, was considered possible in seven patients. The HSV-PCR is a rapid and useful diagnostic method during the early phase of encephalitis. It may be useful in monitoring the efficacy of treatment and allowing the recognition of new features in the appearance of herpes encephalitis. The HSV-PCR test and antibody determinations from serum and CSF are complementary methods, which should both be applied in pursuit of clinical laboratory diagnosis of these conditions.

Susceptibility of a North American Culex quinquefasciatus to Japanese encephalitis virus

USDA-ARS?s Scientific Manuscript database

Japanese encephalitis virus (JEV) is a flavivirus that is transmitted by Culex (Cx.) tritaeniorhynchus in tropical and subtropical regions of Asia. The endemic transmission cycle involves domestic pigs and avian species that serve as amplification hosts; humans are incidental hosts that cannot devel...

Rapid Detection of Powassan Virus in a Patient With Encephalitis by Metagenomic Sequencing

PubMed Central

Piantadosi, Anne; Kanjilal, Sanjat; Ganesh, Vijay; Khanna, Arjun; Hyle, Emily P; Rosand, Jonathan; Bold, Tyler; Metsky, Hayden C; Lemieux, Jacob; Leone, Michael J; Freimark, Lisa; Matranga, Christian B; Adams, Gordon; McGrath, Graham; Zamirpour, Siavash; Telford, Sam; Rosenberg, Eric; Cho, Tracey; Frosch, Matthew P; Goldberg, Marcia B; Mukerji, Shibani S; Sabeti, Pardis C

2018-01-01

Abstract We describe a patient with severe and progressive encephalitis of unknown etiology. We performed rapid metagenomic sequencing from cerebrospinal fluid and identified Powassan virus, an emerging tick-borne flavivirus that has been increasingly detected in the United States. PMID:29020227

Utilisation of ISA Reverse Genetics and Large-Scale Random Codon Re-Encoding to Produce Attenuated Strains of Tick-Borne Encephalitis Virus within Days.

PubMed

de Fabritus, Lauriane; Nougairède, Antoine; Aubry, Fabien; Gould, Ernest A; de Lamballerie, Xavier

2016-01-01

Large-scale codon re-encoding is a new method of attenuating RNA viruses. However, the use of infectious clones to generate attenuated viruses has inherent technical problems. We previously developed a bacterium-free reverse genetics protocol, designated ISA, and now combined it with large-scale random codon-re-encoding method to produce attenuated tick-borne encephalitis virus (TBEV), a pathogenic flavivirus which causes febrile illness and encephalitis in humans. We produced wild-type (WT) and two re-encoded TBEVs, containing 273 or 273+284 synonymous mutations in the NS5 and NS5+NS3 coding regions respectively. Both re-encoded viruses were attenuated when compared with WT virus using a laboratory mouse model and the relative level of attenuation increased with the degree of re-encoding. Moreover, all infected animals produced neutralizing antibodies. This novel, rapid and efficient approach to engineering attenuated viruses could potentially expedite the development of safe and effective new-generation live attenuated vaccines.

Outbreak of Japanese encephalitis on the island of Saipan, 1990.

PubMed

Paul, W S; Moore, P S; Karabatsos, N; Flood, S P; Yamada, S; Jackson, T; Tsai, T F

1993-05-01

During October 1990, an outbreak of encephalitis occurred on Saipan. Although no virus was isolated, patients seroconverted to Japanese encephalitis (JE) virus, indicating the first known occurrence of JE on US territory since 1947. Ten cases occurred among a population of 40,000. The prevalence of antibody to JE virus among 234 lifelong Saipan residents surveyed after the outbreak was 4.2%. Age, household crowding, and lack of air conditioning were risk factors for infection. The seroprevalence in pigs, which are important amplifying hosts of JE virus, was 96% (n = 52). None of 288 stored serum specimens from lifelong Saipan residents sampled in 1984 were seropositive. These data suggest that JE virus was recently introduced onto Saipan and that peridomestic factors affected the risk of human infection. Transmission of JE virus probably ended with exhaustion of the supply of susceptible amplifying hosts. Surveillance for human cases and seroconversions in pigs during 1991 revealed no evidence of ongoing JE virus transmission.

Comparisons of Venezuelan encephalitis virus strains by hemagglutination-inhibition tests with chicken antibodies.

PubMed Central

Scherer, W F; Pancake, B A

1977-01-01

Twenty strains of Venezuelan encephalitis (VE) virus inoculated intravenously in large doses into roosters produced hemagglutination-inhibition (HI) antibodies detectable in plasmas within 7 to 10 days. No signs of illness occurred, and there was no evidence of viral growth in tissues since blood concentrations of infectious virus steadily decreased after inoculation. HI antibodies in early plasmas were specific for VE virus and did not cross-react significantly with two other North American alphaviruses, eastern and western encephalitis viruses. VE virus strains could be distinquished by virus-dilution, short-incubation HI, but not by plasma-dilution neutralization tests, by using early rooster antibodies. The distinctions by HI test were similar with some strains to, but different with other strains from, those described by Young and Johnson with the spiny rat antisera used to establish their subtype classifications of VE virus (14, 28). Nevertheless, results of HI tests with rooster antibodies correlated with equine virulence, as did results with spiny rat antibodies, and distinguished the new strains of virus that appeared in Middle America during the VE outbreak of 1969 from preexisting strains. PMID:591629

Emergence or improved detection of Japanese encephalitis virus in the Himalayan highlands?

PubMed Central

Baylis, Matthew; Barker, Christopher M.; Caminade, Cyril; Joshi, Bhoj R.; Pant, Ganesh R.; Rayamajhi, Ajit; Reisen, William K.; Impoinvil, Daniel E.

2016-01-01

The emergence of Japanese encephalitis virus (JEV) in the Himalayan highlands is of significant veterinary and public health concern and may be related to climate warming and anthropogenic landscape change, or simply improved surveillance. To investigate this phenomenon, a One Health approach focusing on the phylogeography of JEV, the distribution and abundance of the mosquito vectors, and seroprevalence in humans and animal reservoirs would be useful to understand the epidemiology of Japanese encephalitis in highland areas. PMID:26956778

Genetically Engineered, Live Attenuated Vaccines Protect Nonhuman Primates Against Aerosol Challenge with a Virulent IE Strain of Venezuelan Equine Encephalitis Virus

DTIC Science & Technology

2005-01-21

integrated moving average ( ARIMA ) model [15,19]. Fore- casted values for the postexposure time periods were based on the training model extrapolated...Smith JF. Genetically engineered, live attenuated vaccines or Venezuelan equine encephalitis: testing in animal models . Vaccine 2003;21(25–26):3854–62...encephalitis: testing in animal models . Vaccine 2003;21(25-26):3854-62] and IE strains of VEE viruses. 15. SUBJECT TERMS Venezuelan equine

Proteomics analysis of BHK-21 cells infected with a fixed strain of rabies virus.

PubMed

Zandi, Fatemeh; Eslami, Naser; Soheili, Masoomeh; Fayaz, Ahmad; Gholami, Alireza; Vaziri, Behrouz

2009-05-01

Rabies is a neurotropic virus that causes a life threatening acute viral encephalitis. The complex relationship of rabies virus (RV) with the host leads to its replication and spreading toward the neural network, where viral pathogenic effects appeared as neuronal dysfunction. In order to better understand the molecular basis of this relationship, a proteomics study on baby hamster kidney cells infected with challenge virus standard strain of RV was performed. This cell line is an in vitro model for rabies infection and is commonly used for viral seed preparation. The direct effect of the virus on cellular protein machinery was investigated by 2-DE proteome mapping of infected versus control cells followed by LC-MS/MS identification. This analysis revealed significant changes in expression of 14 proteins, seven of these proteins were viral and the remaining were host proteins with different known functions: cytoskeletal (capping protein, vimentin), anti-oxidative stress (superoxide dismutase), regulatory (Stathmin), and protein synthesis (P0). Despite of limited changes appeared upon rabies infection, they present a set of interesting biochemical pathways for further investigation on viral-host interaction.

Surveillance for Western equine encephalitis St. Louis encephalitis and West Nile viruses using reverse transcription loop-mediated isothermal amplification

DOE PAGES

Meagher, Robert J.; Ball, Cameron Scott; Langevin, Stanley A.; ...

2016-01-25

In this study, collection of mosquitoes and testing for vector-borne viruses is a key surveillance activity that directly influences the vector control efforts of public health agencies, including determining when and where to apply insecticides. Vector control districts in California routinely monitor for three human pathogenic viruses including West Nile virus (WNV), Western equine encephalitis virus (WEEV), and St. Louis encephalitis virus (SLEV). Reverse transcription quantitative polymerase chain reaction (RT-qPCR) offers highly sensitive and specific detection of these three viruses in a single multiplex reaction, but this technique requires costly, specialized equipment that is generally only available in centralized publicmore » health laboratories. We report the use of reverse transcription loop-mediated isothermal amplification (RT-LAMP) to detect WNV, WEEV, and SLEV RNA extracted from pooled mosquito samples collected in California, including novel primer sets for specific detection of WEEV and SLEV, targeting the nonstructural protein 4 (nsP4) gene of WEEV and the 3’ untranslated region (3’-UTR) of SLEV. Our WEEV and SLEV RT-LAMP primers allowed detection of <0.1 PFU/reaction of their respective targets in <30 minutes, and exhibited high specificity without cross reactivity when tested against a panel of alphaviruses and flaviviruses. Furthermore, the SLEV primers do not cross-react with WNV, despite both viruses being closely related members of the Japanese encephalitis virus complex. The SLEV and WEEV primers can also be combined in a single RT-LAMP reaction, with discrimination between amplicons by melt curve analysis. Although RT-qPCR is approximately one order of magnitude more sensitive than RT-LAMP for all three targets, the RT-LAMP technique is less instrumentally intensive than RT-qPCR and provides a more cost-effective method of vector-borne virus surveillance.« less

Can Herpes Simplex Virus Encephalitis Cause Aphasia?

ERIC Educational Resources Information Center

Naude, H.; Pretorius, E.

2003-01-01

Aphasia implies the loss or impairment of language caused by brain damage. The key to understanding the nature of aphasic symptoms is the neuro-anatomical site of brain damage, and not the causative agent. However, because "Herpes simplex" virus (HSV) encephalitis infection usually affects the frontal and temporal lobes, subcortical…

Direct Activation of Adenosine Monophosphate-Activated Protein Kinase (AMPK) by PF-06409577 Inhibits Flavivirus Infection through Modification of Host-Cell Lipid Metabolism.

PubMed

Jiménez de Oya, Nereida; Blázquez, Ana-Belén; Casas, Josefina; Saiz, Juan-Carlos; Martín Acebes, Miguel A

2018-04-30

Mosquito-borne flaviviruses are a group of RNA viruses that constitute global threats for human and animal health. Replication of these pathogens is strictly dependent on cellular lipid metabolism. We have evaluated the effect of the pharmacological activation of Adenosine Monophosphate-activated Protein Kinase (AMPK), a master regulator of lipid metabolism, on the infection of three medically relevant flaviviruses: West Nile virus (WNV), Zika virus (ZIKV) and dengue virus (DENV). WNV is responsible for recurrent outbreaks of meningitis and encephalitis affecting humans and horses worldwide. ZIKV has caused a recent pandemic associated with birth defects (microcephaly), reproductive disorders, and severe neurological complications (Guillain-Barré syndrome). DENV is the etiological agent of the most prevalent mosquito-borne viral disease that can induce a potentially lethal complication called severe dengue. Our results showed, for the first time, that activation of AMPK using the specific small molecule activator PF-06409577 reduced both WNV, ZIKV, and DENV infection. This antiviral effect was associated to an impairment of viral replication due to the modulation of host cell lipid metabolism exerted by the compound. These results support that the pharmacological activation of AMPK, which currently constitutes an important pharmacological target for human diseases, could also provide a feasible approach for broad-spectrum host-directed antiviral discovery. Copyright © 2018 American Society for Microbiology.

Variability of interferon-λ induction and antiviral activity in Nipah virus infected differentiated human bronchial epithelial cells of two human donors.

PubMed

Sauerhering, Lucie; Müller, Helena; Behner, Laura; Elvert, Mareike; Fehling, Sarah Katharina; Strecker, Thomas; Maisner, Andrea

2017-10-01

Highly pathogenic Nipah virus (NiV) generally causes severe encephalitis in humans. Respiratory symptoms are infrequently observed, likely reflecting variations in infection kinetics in human airways. Supporting this idea, we recently identified individual differences in NiV replication kinetics in cultured airway epithelia from different human donors. As type III interferons (IFN-λ) represent major players in the defence mechanism against viral infection of the respiratory mucosa, we studied IFN-λ induction and antiviral activity in NiV-infected primary differentiated human bronchial epithelial cells (HBEpCs) cultured under air-liquid interface conditions. Our studies revealed that IFN-λ was upregulated in airway epithelia upon NiV infection. We also show that IFN-λ pretreatment efficiently inhibited NiV replication. Interestingly, the antiviral activity of IFN-λ varied in HBEpCs from two different donors. Increased sensitivity to IFN-λ was associated with higher expression levels of IFN-λ receptors, enhanced phosphorylation of STAT1, as well as enhanced induction of interferon-stimulated gene expression. These findings suggest that individual variations in IFN-λ receptor expression affecting IFN responsiveness can play a functional role for NiV replication kinetics in human respiratory epithelial cells of different donors.

Pathology of whooper swans (Cygnus cygnus) infected with H5N1 avian influenza virus in Akita, Japan, in 2008.

PubMed

Ogawa, Shuji; Yamamoto, Yu; Yamada, Manabu; Mase, Masaji; Nakamura, Kikuyasu

2009-10-01

Two (1 adult and 1 young bird) of 4 H5N1-highly-pathogenic-avian-influenza (HPAI)-virus-infected whooper swans in Akita, Japan, in 2008 were investigated pathologically. Macroscopically, white spots with hemorrhages were scattered in the pancreas in the adult bird. Histologically, the adult bird had severe necrotizing pancreatitis and mild nonpurulent encephalitis. The young bird had severe nonpurulent encephalitis and nonpurulent enteric ganglionitis, and intestinal venous wall thickening. Virus antigens were detected in the lesions of pancreatitis in the adult bird and of encephalitis in adult and young birds. These findings suggest that the swans died or became moribund due to neurological disorders and necrotizing pancreatitis caused by H5N1 HPAI virus infection.

SIV/Macaque Model of HIV Infection in Cocaine Users: Minimal Effects of Cocaine on Behavior, Virus Replication, and CNS Inflammation

PubMed Central

Weed, Michael; Adams, Robert J.; Hienz, Robert D.; Meulendyke, Kelly A.; Linde, Michael E.; Clements, Janice E.; Mankowski, Joseph L.; Zink, M. Christine

2011-01-01

Studies of the effects of drugs of abuse on HIV immune status, disease progression, and neuroAIDS have produced conflicting data and have not definitively shown whether this combination promotes cognitive impairment or disease progression. Using a consistent SIV–macaque model, we investigated the effects of cocaine on behavior, virologic parameters, and CNS inflammation. Macaques received either vehicle or chronic administration of behaviorally active doses of cocaine (1.7 or 3.2 mg/kg/day). Chronic cocaine administration reduced CD8+ T cell counts during acute and late stage infection but had no effect on CD4+ T cell counts. Low-dose cocaine-treated animals had lower CSF vRNA levels late in infection, but cocaine did not alter plasma viral load or vRNA or protein in brain. There were no differences in CSF CCL-2 or interleukin (IL)-6 levels or severity of encephalitis in cocaine-treated as compared to vehicle-treated macaques. There were no differences in brain inflammation or neurodegeneration markers, as determined by interferon (IFN)-β, MxA, CCL2, IL-6, TNFα, IFNγ, and indolamine 2,3-deoxygenase mRNA levels. APP levels also were not altered. The executive function of inhibitory control was not impaired in cocaine-treated or control animals following SIV infection. However, animals receiving 3.2 mg/kg/day cocaine performed more slowly in a bimanual motor test. Thus, chronic administration of cocaine produced only minor changes in behavior, encephalitis severity, CNS inflammation/neurodegeneration, and virus replication in SIV-infected pigtailed macaques, suggesting that cocaine would have only modest effects on the progression of neuroAIDS in HIV-infected individuals. PMID:21626125

Eastern equine encephalitis cases among horses in Brazil between 2005 and 2009.

PubMed

de Novaes Oliveira, Rafael; Iamamoto, Keila; Silva, Maria Luana Cristiny Rodrigues; Achkar, Samira Maria; Castilho, Juliana Galera; Ono, Ekaterina Durymanova; Lobo, Renata Spinelli Vaz; Brandão, Paulo Eduardo; Carnieli, Pedro; Carrieri, Maria Luiza; Kotait, Ivanete; Macedo, Carla Isabel

2014-10-01

Eastern equine encephalitis is a viral zoonosis that exhibits complex distribution and epidemiology, and greater importance should be given to this disease by the public-health authorities. In Brazil, although eastern equine encephalitis virus (EEEV) has been identified in vectors and antibodies are sometimes detected in horses and humans, there have been no records of equine encephalitis in horses caused by this virus during the last 24 years. This study describes eighteen cases of eastern equine encephalomyelitis that occurred in six Brazilian states between 2005 and 2009. Viral RNA was identified using semi-nested RT-PCR to detect members of the genus Alphavirus, and by genetic sequencing. The gene encoding NSP1 was partially amplified, and after genetic sequencing, eighteen sequences were generated. All eighteen strains were classified as belonging to lineage III of American EEEV. These findings could be an indication of the importance of this virus in animal and human public health.

Deployable Pan-Flavivirus and Pan-alphavirus Assays for Screening Pools of Medically Relevant Arthropod

DTIC Science & Technology

2011-09-01

Venezuelan equine encephalitis virus (TC-83 strain). The flaviviruses included West Nile Virus and Dengue 3 virus. We chose these organisms because these...and Venezuelan Equine Encephalitis (VEE, TC-83 strain). Flaviviruses: Dengue 3 and West Nile Virus (WNV). We purified these lysates using the...mixed 1:1 with 6xSSC. 30ul of each of these PCR mixes were incubated for 30 minutes in separate sectors of a 4x2k microarray with detection probes

Viperin targets flavivirus virulence by inducing assembly of non-infectious capsid particles.

PubMed

Vonderstein, Kirstin; Nilsson, Emma; Hubel, Philipp; Nygård Skalman, Lars; Upadhyay, Arunkumar; Pasto, Jenny; Pichlmair, Andreas; Lundmark, Richard; Överby, Anna K

2017-10-18

Efficient antiviral immunity requires interference with virus replication at multiple layers targeting diverse steps in the viral life cycle. Here we describe a novel flavivirus inhibition mechanism that results in interferon-mediated obstruction of tick-borne encephalitis virus particle assembly, and involves release of malfunctional membrane associated capsid (C) particles. This mechanism is controlled by the activity of the interferon-induced protein viperin, a broad spectrum antiviral interferon stimulated gene. Through analysis of the viperin-interactome, we identified the Golgi Brefeldin A resistant guanine nucleotide exchange factor 1 (GBF1), as the cellular protein targeted by viperin. Viperin-induced antiviral activity as well as C-particle release was stimulated by GBF1 inhibition and knock down, and reduced by elevated levels of GBF1. Our results suggest that viperin targets flavivirus virulence by inducing the secretion of unproductive non-infectious virus particles, by a GBF1-dependent mechanism. This yet undescribed antiviral mechanism allows potential therapeutic intervention. Importance The interferon response can target viral infection on almost every level, however, very little is known about interference of flavivirus assembly. Here we show that interferon, through the action of viperin, can disturb assembly of tick-borne encephalitis virus. The viperin protein is highly induced after viral infection and exhibit broad-spectrum antiviral activity. However, the mechanism of action is still elusive and appear to vary between the different viruses, indicating that cellular targets utilized by several viruses might be involved. In this study we show that viperin induce capsid particle release by interacting and inhibiting the function of the cellular protein Golgi Brefeldin A resistant guanine nucleotide exchange factor 1 (GBF1). GBF1 is a key protein in the cellular secretory pathway and essential in the life cycle of many viruses, also targeted by viperin, implicating GBF1 as a novel putative drug target. Copyright © 2017 Vonderstein et al.

Identification of Western Equine Encephalitis Virus Structural Proteins That Confer Protection after DNA Vaccination▿

PubMed Central

Gauci, Penelope J.; Wu, Josh Q. H.; Rayner, George A.; Barabé, Nicole D.; Nagata, Leslie P.; Proll, David F.

2010-01-01

DNA vaccines encoding different portions of the structural proteins of western equine encephalitis virus were tested for the efficacy of their protection in a 100% lethal mouse model of the virus. The 6K-E1 structural protein encoded by the DNA vaccine conferred complete protection against challenge with the homologous strain and limited protection against challenge with a heterologous strain. PMID:19923571

Role of Autoantibodies to N-Methyl-d-Aspartate (NMDA) Receptor in Relapsing Herpes Simplex Encephalitis: A Retrospective, One-Center Experience.

PubMed

Sutcu, Murat; Akturk, Hacer; Somer, Ayper; Tatli, Burak; Torun, Selda Hancerli; Yıldız, Edibe Pembegul; Şık, Guntulu; Citak, Agop; Agacfidan, Ali; Salman, Nuran

2016-03-01

Post-herpes simplex virus encephalitis relapses have been recently associated with autoimmunity driven by autoantibodies against N-methyl-d-aspartate (NMDA) receptors. Because it offers different treatment options, determination of this condition is important. Between 2011 and 2014, 7 children with proven diagnosis of herpes simplex virus encephalitis were identified in a university hospital of Istanbul. Two patients had neurologic relapse characterized mainly by movement disorders 2 to 3 weeks after initial encephalitis. The first patient received a second 14 days of acyclovir treatment together with antiepileptic drugs and left with severe neurologic sequelae. The second patient was found to be NMDA receptors antibody positive in the cerebrospinal fluid. She was treated with intravenous immunoglobulin and prednisolone. She showed substantial improvement, gradually regaining lost neurologic abilities. Post-herpes simplex virus encephalitis relapses may frequently be immune-mediated rather than a viral reactivation, particularly in children displaying movement disorders like choreoathetosis. Immunotherapy may provide benefit for this potentially devastating condition, like the case described in this report. © The Author(s) 2015.

Fulminant encephalitis associated with a vaccine strain of rubella virus.

PubMed

Gualberto, Felipe Augusto Souza; de Oliveira, Maria Isabel; Alves, Venancio A F; Kanamura, Cristina T; Rosemberg, Sérgio; Sato, Helena Keico; Arantes, Benedito A F; Curti, Suely Pires; Figueiredo, Cristina Adelaide

2013-12-01

Involvement of the central nervous system is common in measles, but rare in rubella. However, rubella virus (RV) can cause a variety of central nervous system syndromes, including meningitis, encephalitis, Guillain-Barré syndrome and sub acute sclerosing panencephalitis. We report the occurrence of one fatal case of the encephalitis associated with measles-rubella (MR) vaccine during an immunization campaign in São Paulo, Brazil. A 31 year-old-man, previously in good health, was admitted at emergency room, with confusion, agitation, inability to stand and hold his head up. Ten days prior to admission, he was vaccinated with combined MR vaccine (Serum Institute of India) and three days later he developed 'flu-like' illness with fever, myalgia and headache. Results of clinical and laboratory exams were consistent with a pattern of viral encephalitis. During hospitalization, his condition deteriorated rapidly with tetraplegia and progression to coma. On the 3rd day of hospitalization he died. Histopathology confirmed encephalitis and immunohistochemistry was positive for RV on brain tissue. RV was also detected by qPCR and virus isolation in cerebrospinal fluid, brain and other clinical samples. The sequence obtained from the isolated virus was identical to that of the RA 27/3 vaccine strain. Copyright © 2013 Elsevier B.V. All rights reserved.

West Nile Virus and Other Nationally Notifiable Arboviral Diseases - United States, 2014.

PubMed

Lindsey, Nicole P; Lehman, Jennifer A; Staples, J Erin; Fischer, Marc

2015-09-04

Arthropod-borne viruses (arboviruses) are transmitted to humans primarily through the bites of infected mosquitoes and ticks. West Nile virus (WNV) is the leading cause of domestically acquired arboviral disease in the United States (1). However, several other arboviruses also cause sporadic cases and seasonal outbreaks. This report summarizes surveillance data reported to CDC in 2014 for WNV and other nationally notifiable arboviruses, excluding dengue. Forty-two states and the District of Columbia (DC) reported 2,205 cases of WNV disease. Of these, 1,347 (61%) were classified as WNV neuroinvasive disease (e.g., meningitis, encephalitis, or acute flaccid paralysis), for a national incidence of 0.42 cases per 100,000 population. After WNV, the next most commonly reported cause of arboviral disease was La Crosse virus (80 cases), followed by Jamestown Canyon virus (11), St. Louis encephalitis virus (10), Powassan virus (8), and Eastern equine encephalitis virus (8). WNV and other arboviruses cause serious illness in substantial numbers of persons each year. Maintaining surveillance programs is important to help direct prevention activities.

Viral Etiology of Encephalitis in Children in Southern Vietnam: Results of a One-Year Prospective Descriptive Study

PubMed Central

Tan, Le Van; Qui, Phan Tu; Ha, Do Quang; Hue, Nguyen Bach; Bao, Lam Quoi; Cam, Bach Van; Khanh, Truong Huu; Hien, Tran Tinh; Vinh Chau, Nguyen Van; Tram, Tran Tan; Hien, Vo Minh; Nga, Tran Vu Thieu; Schultsz, Constance; Farrar, Jeremy; van Doorn, H. Rogier; de Jong, Menno D.

2010-01-01

Background Acute encephalitis is an important and severe disease in children in Vietnam. However, little is known about the etiology while such knowledge is essential for optimal prevention and treatment. To identify viral causes of encephalitis, in 2004 we conducted a one-year descriptive study at Children's Hospital Number One, a referral hospital for children in southern Vietnam including Ho Chi Minh City. Methodology/Principal Findings Children less than 16 years of age presenting with acute encephalitis of presumed viral etiology were enrolled. Diagnostic efforts included viral culture, serology and real time (RT)-PCRs. A confirmed or probable viral causative agent was established in 41% of 194 enrolled patients. The most commonly diagnosed causative agent was Japanese encephalitis virus (n = 50, 26%), followed by enteroviruses (n = 18, 9.3%), dengue virus (n = 9, 4.6%), herpes simplex virus (n = 1), cytomegalovirus (n = 1) and influenza A virus (n = 1). Fifty-seven (29%) children died acutely. Fatal outcome was independently associated with patient age and Glasgow Coma Scale (GCS) on admission. Conclusions/Significance Acute encephalitis in children in southern Vietnam is associated with high mortality. Although the etiology remains unknown in a majority of the patients, the result from the present study may be useful for future design of treatment and prevention strategies of the disease. The recognition of GCS and age as predictive factors may be helpful for clinicians in managing the patient. PMID:21049060

Controlling Nipah virus encephalitis in Bangladesh: Policy options.

PubMed

Dhillon, Jasmine; Banerjee, Arinjay

2015-08-01

Nipah virus (NiV) encephalitis is endemic in Bangladesh, with yearly seasonal outbreaks occurring since 2003. NiV has a notable case fatality rate, 75-100 per cent depending on the strain. In Bangladesh, primary transmission to humans is believed to be because of consumption of bat-contaminated date palm sap (DPS). Both the disease and the virus have been investigated extensively, however efforts to implement preventive strategies have met social and cultural challenges. Here we present a variety of community approaches to control the spread of Nipah encephalitis, along with advantages and disadvantages of each. This information may be useful to health workers and policymakers in potential NiV outbreak areas in Southeast Asia.

West Nile encephalitis outbreak in Kerala, India, 2011.

PubMed

Anukumar, B; Sapkal, Gajanan N; Tandale, Babasheb V; Balasubramanian, R; Gangale, Daya

2014-09-01

An outbreak of acute encephalitis syndrome (AES) was reported in Kerala in India in May 2011. The outbreak features were unusual in terms of seasonality, geographical distribution, age group, and clinical manifestations in comparison to the epidemiological features of Japanese Encephalitis. To detect the etiology of the acute encephalitis syndrome outbreak. Investigation of outbreak was undertaken by collection of brief clinical history and epidemiological details along with the specimens for viral diagnosis. The serum/CSF samples (patients=208) received from the sentinel hospitals were subjected to IgM capture ELISA and RT-PCR specific for Japanese encephalitis (JE) virus and West Nile virus (WNV). The JE/WN IgM positive samples were further tested by serum neutralization assay for the presence of JE and WNV specific neutralizing antibody. Most of the affected patients were aged above 15 years. No spatial clustering of the disease was noticed. Cases were observed in premonsoon and early monsoon season and in JE non-endemic area of Kerala. A total of 47 patient samples were positive for in-house JE IgM capture ELISA and WNV IgM capture ELISA. Serum neutralization assay result revealed that 32 of 42 (76.19%) sera were positive for WNV neutralization antibodies. WNV was isolated from a clinical specimen. Phylogenetic analysis of WNV envelope gene revealed 99% homology with Russian Lineage 1 WNV. West Nile virus (WNV) etiology was confirmed by virus isolation and detection of virus specific antibody from clinical specimen. Phylogenetic analysis grouped the current strain in lineage I West Nile virus. Copyright © 2014 Elsevier B.V. All rights reserved.

Usutu virus: an emerging flavivirus in Europe.

PubMed

Ashraf, Usama; Ye, Jing; Ruan, Xindi; Wan, Shengfeng; Zhu, Bibo; Cao, Shengbo

2015-01-19

Usutu virus (USUV) is an African mosquito-borne flavivirus belonging to the Japanese encephalitis virus serocomplex. USUV is closely related to Murray Valley encephalitis virus, Japanese encephalitis virus, and West Nile virus. USUV was discovered in South Africa in 1959. In Europe, the first true demonstration of circulation of USUV was reported in Austria in 2001 with a significant die-off of Eurasian blackbirds. In the subsequent years, USUV expanded to neighboring countries, including Italy, Germany, Spain, Hungary, Switzerland, Poland, England, Czech Republic, Greece, and Belgium, where it caused unusual mortality in birds. In 2009, the first two human cases of USUV infection in Europe have been reported in Italy, causing meningoencephalitis in immunocompromised patients. This review describes USUV in terms of its life cycle, USUV surveillance from Africa to Europe, human cases, its cellular tropism and pathogenesis, its genetic relationship with other flaviviruses, genetic diversity among USUV strains, its diagnosis, and a discussion of the potential future threat to Asian countries.

Viral encephalitis of tilapia larvae: primary characterization of a novel herpes-like virus.

PubMed

Shlapobersky, Mark; Sinyakov, Michael S; Katzenellenbogen, Mark; Sarid, Ronit; Don, Jeremy; Avtalion, Ramy R

2010-04-10

We report here an outbreak of an acute disease that caused high mortality rate in laboratory-reared tilapia larvae. The disease was initially observed in inbred gynogenetic line of blue tilapia larvae (Oreochromis aureus) and could be transmitted to larvae of other tilapia species. Based on the clinical manifestation (a whirling syndrome), we refer to the disease as viral encephalitis of tilapia larvae. The disease-associated DNA virus is described and accordingly designated tilapia larvae encephalitis virus (TLEV). A primary morphological, biophysical and molecular characterization of TLEV is presented. By virtue of these properties, the newly discovered virus is a herpes-like virus. Phylogenetic analysis, albeit limited, confirms this assumption and places TLEV within the family of Herpesviridae and distantly from the families Alloherpesviridae and Iridoviridae. By using PCR with virus-specific primers, diseased larvae and adult TLEV carriers were also identified in tilapia delivered from external hatcheries. Copyright 2010 Elsevier Inc. All rights reserved.

Anti-N-methyl-D-aspartate receptor encephalitis after Herpes simplex virus-associated encephalitis: an emerging disease with diagnosis and therapeutic challenges.

PubMed

Schein, Flora; Gagneux-Brunon, Amandine; Antoine, Jean-Christophe; Lavernhe, Sylvie; Pillet, Sylvie; Paul, Stéphane; Frésard, Anne; Boutet, Claire; Grange, Rémi; Cazorla, Céline; Lucht, Frédéric; Botelho-Nevers, Elisabeth

2017-08-01

Morbidity and mortality of Herpes simplex virus encephalitis (HSE) remain high. Relapses of neurological signs may occur after initial clinical improvement under acyclovir treatment. We report here a case of post-HSE anti-N-methyl-d-aspartate receptor-mediated encephalitis in an adult and perform a systematic search on PubMed to identify other cases in adults. We identified 11 previously published cases, to discuss diagnostic and therapeutic management. Symptoms in adults are often inappropriate behaviors, confusion and agitation. Diagnosis of anti-NMDA-R encephalitis after HSE is often delayed. Treatment consists in steroids, plasma exchange, and rituximab. Prognosis is often favorable. Anti-NMDA-R antibodies should be searched in cerebrospinal fluid of patients with unexpected evolution of HSE. This emerging entity reopens the hot debate about steroids in HSE.

Insights into host-finding by Culex mosquitoes: New tools for surveillance?

USDA-ARS?s Scientific Manuscript database

Culex mosquitoes are important vectors of pathogens and parasites causing diseases such as West Nile virus, St. Louis encephalitis, Japanese encephalitis, Venezuelan equine encephalitis and bancroftian filariasis. Surveillance of these species is based on traps using conventional mosquito attractan...

Novel indole-2-carboxamide compounds are potent broad-spectrum antivirals active against western equine encephalitis virus in vivo.

PubMed

Delekta, Phillip C; Dobry, Craig J; Sindac, Janice A; Barraza, Scott J; Blakely, Pennelope K; Xiang, Jianming; Kirchhoff, Paul D; Keep, Richard F; Irani, David N; Larsen, Scott D; Miller, David J

2014-10-01

Neurotropic alphaviruses, including western, eastern, and Venezuelan equine encephalitis viruses, cause serious and potentially fatal central nervous system infections in humans for which no currently approved therapies exist. We previously identified a series of thieno[3,2-b]pyrrole derivatives as novel inhibitors of neurotropic alphavirus replication, using a cell-based phenotypic assay (W. Peng et al., J. Infect. Dis. 199:950-957, 2009, doi:http://dx.doi.org/10.1086/597275), and subsequently developed second- and third-generation indole-2-carboxamide derivatives with improved potency, solubility, and metabolic stability (J. A. Sindac et al., J. Med. Chem. 55:3535-3545, 2012, doi:http://dx.doi.org/10.1021/jm300214e; J. A. Sindac et al., J. Med. Chem. 56:9222-9241, 2013, http://dx.doi.org/10.1021/jm401330r). In this report, we describe the antiviral activity of the most promising third-generation lead compound, CCG205432, and closely related analogs CCG206381 and CCG209023. These compounds have half-maximal inhibitory concentrations of ∼1 μM and selectivity indices of >100 in cell-based assays using western equine encephalitis virus replicons. Furthermore, CCG205432 retains similar potency against fully infectious virus in cultured human neuronal cells. These compounds show broad inhibitory activity against a range of RNA viruses in culture, including members of the Togaviridae, Bunyaviridae, Picornaviridae, and Paramyxoviridae families. Although their exact molecular target remains unknown, mechanism-of-action studies reveal that these novel indole-based compounds target a host factor that modulates cap-dependent translation. Finally, we demonstrate that both CCG205432 and CCG209023 dampen clinical disease severity and enhance survival of mice given a lethal western equine encephalitis virus challenge. These studies demonstrate that indole-2-carboxamide compounds are viable candidates for continued preclinical development as inhibitors of neurotropic alphaviruses and, potentially, of other RNA viruses. IMPORTANCE There are currently no approved drugs to treat infections with alphaviruses. We previously identified a novel series of compounds with activity against these potentially devastating pathogens (J. A. Sindac et al., J. Med. Chem. 55:3535-3545, 2012, doi:http://dx.doi.org/10.1021/jm300214e; W. Peng et al., J. Infect. Dis. 199:950-957, 2009, doi:http://dx.doi.org/10.1086/597275; J. A. Sindac et al., J. Med. Chem. 56:9222-9241, 2013, http://dx.doi.org/10.1021/jm401330r). We have now produced third-generation compounds with enhanced potency, and this manuscript provides detailed information on the antiviral activity of these advanced-generation compounds, including activity in an animal model. The results of this study represent a notable achievement in the continued development of this novel class of antiviral inhibitors. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Novel Indole-2-Carboxamide Compounds Are Potent Broad-Spectrum Antivirals Active against Western Equine Encephalitis Virus In Vivo

PubMed Central

Delekta, Phillip C.; Dobry, Craig J.; Sindac, Janice A.; Barraza, Scott J.; Blakely, Pennelope K.; Xiang, Jianming; Kirchhoff, Paul D.; Keep, Richard F.; Irani, David N.; Larsen, Scott D.

2014-01-01

ABSTRACT Neurotropic alphaviruses, including western, eastern, and Venezuelan equine encephalitis viruses, cause serious and potentially fatal central nervous system infections in humans for which no currently approved therapies exist. We previously identified a series of thieno[3,2-b]pyrrole derivatives as novel inhibitors of neurotropic alphavirus replication, using a cell-based phenotypic assay (W. Peng et al., J. Infect. Dis. 199:950–957, 2009, doi:http://dx.doi.org/10.1086/597275), and subsequently developed second- and third-generation indole-2-carboxamide derivatives with improved potency, solubility, and metabolic stability (J. A. Sindac et al., J. Med. Chem. 55:3535–3545, 2012, doi:http://dx.doi.org/10.1021/jm300214e; J. A. Sindac et al., J. Med. Chem. 56:9222–9241, 2013, http://dx.doi.org/10.1021/jm401330r). In this report, we describe the antiviral activity of the most promising third-generation lead compound, CCG205432, and closely related analogs CCG206381 and CCG209023. These compounds have half-maximal inhibitory concentrations of ∼1 μM and selectivity indices of >100 in cell-based assays using western equine encephalitis virus replicons. Furthermore, CCG205432 retains similar potency against fully infectious virus in cultured human neuronal cells. These compounds show broad inhibitory activity against a range of RNA viruses in culture, including members of the Togaviridae, Bunyaviridae, Picornaviridae, and Paramyxoviridae families. Although their exact molecular target remains unknown, mechanism-of-action studies reveal that these novel indole-based compounds target a host factor that modulates cap-dependent translation. Finally, we demonstrate that both CCG205432 and CCG209023 dampen clinical disease severity and enhance survival of mice given a lethal western equine encephalitis virus challenge. These studies demonstrate that indole-2-carboxamide compounds are viable candidates for continued preclinical development as inhibitors of neurotropic alphaviruses and, potentially, of other RNA viruses. IMPORTANCE There are currently no approved drugs to treat infections with alphaviruses. We previously identified a novel series of compounds with activity against these potentially devastating pathogens (J. A. Sindac et al., J. Med. Chem. 55:3535–3545, 2012, doi:http://dx.doi.org/10.1021/jm300214e; W. Peng et al., J. Infect. Dis. 199:950–957, 2009, doi:http://dx.doi.org/10.1086/597275; J. A. Sindac et al., J. Med. Chem. 56:9222–9241, 2013, http://dx.doi.org/10.1021/jm401330r). We have now produced third-generation compounds with enhanced potency, and this manuscript provides detailed information on the antiviral activity of these advanced-generation compounds, including activity in an animal model. The results of this study represent a notable achievement in the continued development of this novel class of antiviral inhibitors. PMID:25031353

West Nile virus infection in killer whale, Texas, USA, 2007.

PubMed

St Leger, Judy; Wu, Guang; Anderson, Mark; Dalton, Les; Nilson, Erika; Wang, David

2011-08-01

In 2007, nonsuppurative encephalitis was identified in a killer whale at a Texas, USA, marine park. Panviral DNA microarray of brain tissue suggested West Nile virus (WNV); WNV was confirmed by reverse transcription PCR and sequencing. Immunohistochemistry demonstrated WNV antigen within neurons. WNV should be considered in cases of encephalitis in cetaceans.

Novel Variant of Tickborne Encephalitis Virus, Russia

PubMed Central

Ternovoi, Vladimir A.; Protopopova, Elena V.; Chausov, Eugene V.; Novikov, Dmitry V.; Leonova, Galina N.; Netesov, Sergey V.

2007-01-01

We isolated a novel strain of tickborne encephalitis virus (TBEV), Glubinnoe/2004, from a patient with a fatal case in Russia. We sequenced the strain, whose landmark features included 57 amino acid substitutions and 5 modified cleavage sites. Phylogenetically, Glubinnoe/2004 is a novel variant that belongs to the Eastern type of TBEV. PMID:18258012

Virulence of Japanese Encephalitis Virus Genotypes I and III, Taiwan

PubMed Central

Fan, Yi-Chin; Lin, Jen-Wei; Liao, Shu-Ying; Chen, Jo-Mei; Chen, Yi-Ying; Chiu, Hsien-Chung; Shih, Chen-Chang; Chen, Chi-Ming; Chang, Ruey-Yi; King, Chwan-Chuen; Chen, Wei-June; Ko, Yi-Ting; Chang, Chao-Chin

2017-01-01

The virulence of genotype I (GI) Japanese encephalitis virus (JEV) is under debate. We investigated differences in the virulence of GI and GIII JEV by calculating asymptomatic ratios based on serologic studies during GI- and GIII-JEV endemic periods. The results suggested equal virulence of GI and GIII JEV among humans. PMID:29048288

A comparative analysis on the physicochemical properties of tick-borne encephalitis virus envelope protein residues that affect its antigenic properties.

PubMed

Bukin, Yu S; Dzhioev, Yu P; Tkachev, S E; Kozlova, I V; Paramonov, A I; Ruzek, D; Qu, Z; Zlobin, V I

2017-06-15

This work is dedicated to the study of the variability of the main antigenic envelope protein E among different strains of tick-borne encephalitis virus at the level of physical and chemical properties of the amino acid residues. E protein variants were extracted from then NCBI database. Four amino acid residues properties in the polypeptide sequences were investigated: the average volume of the amino acid residue in the protein tertiary structure, the number of amino acid residue hydrogen bond donors, the charge of amino acid residue lateral radical and the dipole moment of the amino acid residue. These physico-chemical properties are involved in antigen-antibody interactions. As a result, 103 different variants of the antigenic determinants of the tick-borne encephalitis virus E protein were found, significantly different by physical and chemical properties of the amino acid residues in their structure. This means that some strains among the natural variants of tick-borne encephalitis virus can potentially escape the immune response induced by the standard vaccine. Copyright © 2017 Elsevier B.V. All rights reserved.

Epidemiological and clinical aspects on West Nile virus, a globally emerging pathogen.

PubMed

David, Shoba; Abraham, Asha Mary

2016-08-01

Since the isolation of West Nile virus (WNV) in 1937, in Uganda, it has spread globally, causing significant morbidity and mortality. While birds serve as amplifier hosts, mosquitoes of the Culex genus function as vectors. Humans and horses are dead end hosts. The clinical manifestations of West Nile infection in humans range from asymptomatic illness to West Nile encephalitis. The laboratory offers an array of tests, the preferred method being detection of RNA and serum IgM for WNV, which, if detected, confirms the clinical diagnosis. Although no definitive antiviral therapy and vaccine are available for humans, many approaches are being studied. This article will review the current literature of the natural cycle, geographical distribution, virology, replication cycle, molecular epidemiology, pathogenesis, laboratory diagnosis, clinical manifestations, blood donor screening for WNV, treatment, prevention and vaccines.

Recent progress in henipavirus research: molecular biology, genetic diversity, animal models.

PubMed

Rockx, Barry; Winegar, Richard; Freiberg, Alexander N

2012-08-01

Nipah and Hendra virus are members of a newly identified genus of emerging paramyxoviruses, the henipaviruses. Both viruses have the ability to cause severe pulmonary infection and severe acute encephalitis. Following their discovery in the 1990s, outbreaks caused by these zoonotic paramyxoviruses have been associated with high public health and especially economic threat potential. Currently, only geographic groupings in Asia and Australia have been described for the henipaviruses. However, while few viral isolates are available and more detailed characterization is necessary, there has been recent evidence that divergent henipaviruses might be present on the African continent. This review endeavours to capture recent advances in the field of henipavirus research, with a focus on genome structure and replication mechanisms, reservoir hosts, genetic diversity, pathogenesis and animal models. Copyright © 2012 Elsevier B.V. All rights reserved.

Tick-borne encephalitis: A review of epidemiology, clinical characteristics, and management

PubMed Central

Bogovic, Petra; Strle, Franc

2015-01-01

Tick-borne encephalitis is an infection of central nervous system caused by tick-borne encephalitis virus transmitted to humans predominantly by tick bites. During the last few decades the incidence of the disease has been increasing and poses a growing health problem in almost all endemic European and Asian countries. Most cases occur during the highest period of tick activity, in Central Europe mainly from April to November. Tick-borne encephalitis is more common in adults than in children. Clinical spectrum of the disease ranges from mild meningitis to severe meningoencephalitis with or without paralysis. Rare clinical manifestations are an abortive form of the disease and a chronic progressive form. A post-encephalitic syndrome, causing long-lasting morbidity that often affects the quality of life develops in up to 50% of patients after acute tick-borne encephalitis. Clinical course and outcome vary by subtype of tick-borne encephalitis virus (the disease caused by the European subtype has milder course and better outcome than the disease caused by Siberian and Far-Easter subtypes), age of patients (increasing age is associated with less favorable outcome), and host genetic factors. Since clinical features and laboratory results of blood and cerebrospinal fluid are nonspecific, the diagnosis must be confirmed by microbiologic findings. The routine laboratory confirmation of the tick-borne encephalitis virus infection is based mainly on the detection of specific IgM and IgG antibodies in serum (and cerebrospinal fluid), usually by enzyme-linked immunosorbent assay. There is no specific antiviral treatment for tick-borne encephalitis. Vaccination can effectively prevent the disease and is indicated for persons living in or visiting tick-borne encephalitis endemic areas. PMID:25984517

Fatal Deer Tick Virus Infection in Maine.

PubMed

Cavanaugh, Catherine E; Muscat, Paul L; Telford, Sam R; Goethert, Heidi; Pendlebury, William; Elias, Susan P; Robich, Rebecca; Welch, Margret; Lubelczyk, Charles B; Smith, Robert P

2017-09-15

Deer tick virus (DTV), a genetic variant (lineage II) of Powassan virus, is a rare cause of encephalitis in North America. We report a fatal case of DTV encephalitis following a documented bite from an Ixodes scapularis tick and the erythema migrans rash associated with Lyme disease. © 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.

Ocular histopathology in Eastern equine encephalitis: A case report.

PubMed

Lad, Eleonora M; Ong, Sally S; Proia, Alan D

2017-04-01

To describe the ophthalmic symptoms and histopathological findings in a human case of Eastern equine encephalitis (EEE). The patient was a septuagenarian male whose presentation and clinical course were thought to be most consistent with viral meningoencephalitis. ELISA suggested recent infection with EEE virus. Microscopic analysis of the brain demonstrated perivascular lymphohistiocytic cuffing which was consistent with viral type encephalitis. Similarly, both eyes manifested a lymphohistiocytic infiltrate in the retina and optic nerve and a reduced number of ganglion cells. To our knowledge, this is the first report of ophthalmological and ocular pathology observations in an EEE patient. Interestingly, the inflammatory findings in the retina are reminiscent of the central nervous system effects of EEE virus. These findings are relevant given the recent epidemic of microcephaly and ophthalmic complications secondary to another arboviral virus, the Zika virus.

Nominal dysphasia and euphoria caused by EBV encephalitis

PubMed Central

Carman, Kursat Bora; Yakut, Ayten; Ekici, Arzu; Isikay, Sedat

2013-01-01

Encephalitis is an uncommon neurological complication of Ebstein-Barr virus (EBV) infection and usually presents with confusion, decreased level of consciousness, fever, epileptic seizure, emotional instability and chorea. We present a patient with EBV encephalitis, characterised by nominal dysphasia, euphoria and personality changes. PMID:23307455

[Mono- and mixed infection by the tick-borne encephalitis and Powassan viruses of tissue explants from ticks of the genus Hyalomma].

PubMed

Chunikhin, S P; Khozinskaia, G A; Stefutkina, L F; Korolev, M B

1984-01-01

The paper presents results of virusological and electron microscope studies of the reproduction of viruses of tick-borne encephalitis and Povassan at mono- and mixed persistent infection of explants of imaginal tissues of Hyalomma anatolicum and H. dromedarii with these viruses. The virus reproduction in explants was observed within 208 to 217 days after the infection. Joint reproduction of two model viruses within 1-2 months after the infection can take place and after that the inhibition of the reproduction of one of the viruses. This inhibition can be of cyclic character.

Japanese encephalitis virus invasion of cell: allies and alleys.

PubMed

Nain, Minu; Abdin, Malik Z; Kalia, Manjula; Vrati, Sudhanshu

2016-03-01

The mosquito-borne flavivirus, Japanese encephalitis virus (JEV), is the leading cause of virus-induced encephalitis globally and a major public health concern of several countries in Southeast Asia, with the potential to become a global pathogen. The virus is neurotropic, and the disease ranges from mild fever to severe hemorrhagic and encephalitic manifestations and death. The early steps of the virus life cycle, binding, and entry into the cell are crucial determinants of infection and are potential targets for the development of antiviral therapies. JEV can infect multiple cell types; however, the key receptor molecule(s) still remains elusive. JEV also has the capacity to utilize multiple endocytic pathways for entry into cells of different lineages. This review not only gives a comprehensive update on what is known about the virus attachment and receptor system (allies) and the endocytic pathways (alleys) exploited by the virus to gain entry into the cell and establish infection but also discusses crucial unresolved issues. We also highlight common themes and key differences between JEV and other flaviviruses in these contexts. Copyright © 2015 John Wiley & Sons, Ltd.

West Nile Virus and Other Nationally Notifiable Arboviral Diseases - United States, 2016.

PubMed

Burakoff, Alexis; Lehman, Jennifer; Fischer, Marc; Staples, J Erin; Lindsey, Nicole P

2018-01-12

Arthropod-borne viruses (arboviruses) are transmitted to humans primarily through the bites of infected mosquitoes and ticks. West Nile virus (WNV) is the leading cause of domestically acquired arboviral disease in the continental United States (1,2). Other arboviruses, including La Crosse, Powassan, Jamestown Canyon, St. Louis encephalitis, and eastern equine encephalitis viruses, cause sporadic cases of disease and occasional outbreaks. This report summarizes surveillance data reported to CDC for 2016 for nationally notifiable arboviruses. It excludes dengue, chikungunya, and Zika viruses, as these are primarily nondomestic viruses typically acquired through travel. Forty-seven states and the District of Columbia (DC) reported 2,240 cases of domestic arboviral disease, including 2,150 (96%) WNV disease cases. Of the WNV disease cases, 1,310 (61%) were classified as neuroinvasive disease (e.g., meningitis, encephalitis, acute flaccid paralysis), for a national incidence of 0.41 cases per 100,000 population. After WNV, the most frequently reported arboviruses were La Crosse (35 cases), Powassan (22), and Jamestown Canyon (15) viruses. Because arboviral diseases continue to cause serious illness, maintaining surveillance is important to direct prevention activities.

Characterization of a novel flavivirus isolated from Culex (Melanoconion) ocossa mosquitoes from Iquitos, Peru.

PubMed

Evangelista, Julio; Cruz, Cristhopher; Guevara, Carolina; Astete, Helvio; Carey, Cristiam; Kochel, Tadeusz J; Morrison, Amy C; Williams, Maya; Halsey, Eric S; Forshey, Brett M

2013-06-01

We describe the isolation and characterization of a novel flavivirus, isolated from a pool of Culex (Melanoconion) ocossa Dyar and Knab mosquitoes collected in 2009 in an urban area of the Amazon basin city of Iquitos, Peru. Flavivirus infection was detected by indirect immunofluorescent assay of inoculated C6/36 cells using polyclonal flavivirus antibodies (St. Louis encephalitis virus, yellow fever virus and dengue virus type 1) and confirmed by RT-PCR. Based on partial sequencing of the E and NS5 gene regions, the virus isolate was most closely related to the mosquito-borne flaviviruses but divergent from known species, with less than 45 and 71 % pairwise amino acid identity in the E and NS5 gene products, respectively. Phylogenetic analysis of E and NS5 amino acid sequences demonstrated that this flavivirus grouped with mosquito-borne flaviviruses, forming a clade with Nounané virus (NOUV). Like NOUV, no replication was detected in a variety of mammalian cells (Vero-76, Vero-E6, BHK, LLCMK, MDCK, A549 and RD) or in intracerebrally inoculated newborn mice. We tentatively designate this genetically distinct flavivirus as representing a novel species, Nanay virus, after the river near where it was first detected.

Favipiravir (T-705) protects against Nipah virus infection in the hamster model.

PubMed

Dawes, Brian E; Kalveram, Birte; Ikegami, Tetsuro; Juelich, Terry; Smith, Jennifer K; Zhang, Lihong; Park, Arnold; Lee, Benhur; Komeno, Takashi; Furuta, Yousuke; Freiberg, Alexander N

2018-05-15

Nipah and Hendra viruses are recently emerged bat-borne paramyxoviruses (genus Henipavirus) causing severe encephalitis and respiratory disease in humans with fatality rates ranging from 40-75%. Despite the severe pathogenicity of these viruses and their pandemic potential, no therapeutics or vaccines are currently approved for use in humans. Favipiravir (T-705) is a purine analogue antiviral approved for use in Japan against emerging influenza strains; and several phase 2 and 3 clinical trials are ongoing in the United States and Europe. Favipiravir has demonstrated efficacy against a broad spectrum of RNA viruses, including members of the Paramyxoviridae, Filoviridae, Arenaviridae families, and the Bunyavirales order. We now demonstrate that favipiravir has potent antiviral activity against henipaviruses. In vitro, favipiravir inhibited Nipah and Hendra virus replication and transcription at micromolar concentrations. In the Syrian hamster model, either twice daily oral or once daily subcutaneous administration of favipiravir for 14 days fully protected animals challenged with a lethal dose of Nipah virus. This first successful treatment of henipavirus infection in vivo with a small molecule drug suggests that favipiravir should be further evaluated as an antiviral treatment option for henipavirus infections.

Infection of Macaca Radiata with Viruses of the Tick-Borne Encephalitis Group

DTIC Science & Technology

1992-01-01

3411 IC Microbial Patho genesis 1 992, 13: 399 409 ET AD-A265 505 N9 3U 9312898 I Infection of Macaca radiata with viruses of the tick - borne...Diseases, Frederick, MD 21702-5011, U.SA.), M. K. Rippy, K. T. McKee Jr., P. M. Zack and C. J. Peters. Infection of Macaca radiata with viruses of the tick ...for human disease caused by other, related strains of this group of viruses. Key words: Macaca radiata; tick -borne encephalitis; pathogenesis; Kyasanur

Recombinant vaccinia/Venezuelan equine encephalitis (VEE) virus expresses VEE structural proteins.

PubMed

Kinney, R M; Esposito, J J; Johnson, B J; Roehrig, J T; Mathews, J H; Barrett, A D; Trent, D W

1988-12-01

cDNA molecules encoding the structural proteins of the virulent Trinidad donkey and the TC-83 vaccine strains of Venezuelan equine encephalitis (VEE) virus were inserted under control of the vaccinia virus 7.5K promoter into the thymidine kinase gene of vaccinia virus. Synthesis of the capsid protein and glycoproteins E2 and E1 of VEE virus was demonstrated by immunoblotting of lysates of CV-1 cells infected with recombinant vaccinia/VEE viruses. VEE glycoproteins were detected in recombinant virus-infected cells by fluorescent antibody (FA) analysis performed with a panel of VEE-specific monoclonal antibodies. Seven E2-specific epitopes and two of four E1-specific epitopes were demonstrated by FA.

[Acute encephalitis. Neuropsychiatric manifestations as expression of influenza virus infection].

PubMed

Moreno-Flagge, Noris; Bayard, Vicente; Quirós, Evelia; Alonso, Tomás

2009-01-01

The aim is to review the encephalitis in infants and adolescents as well as its etiology, clinical manifestation, epidemiology, physiopathology, diagnostic methods and treatment, and the neuropsyquiatric signs appearing an influenza epidemy. Encephalitis is an inflammation of the central nervous system (CNS) which involves the brain. The clinical manifestations usually are: headache, fever and confusional stage. It could also be manifested as seizures, personality changes, or psiqyiatric symptoms. The clinical manifestations are related to the virus and the cell type affected in the brain. A meningitis or encephalopathy need to be ruled out. It could be present as an epidemic or isolated form, beeing this the most frequent form. It could be produced by a great variety of infections agents including virus, bacterias, fungal and parasitic. Viral causes are herpesvirus, arbovirus, rabies and enterovirus. Bacterias such as Borrelia burgdorferi, Rickettsia and Mycoplasma neumoniae. Some fungal causes are: Coccidioides immitis and Histoplasma capsulatum. More than 100 agents are related to encephalitis. The diagnosis of encephalitis is a challenge for the clinician and its infectious etiology is clear in only 40 to 70% of all cases. The diagnosis of encephalitis can be established with absolute certainty only by the microscopic examination of brain tissue. Epidemiology is related to age of the patients, geographic area, season, weather or the host immune system. Early intervention can reduce the mortality rate and sequels. We describe four patients with encephalitis and neuropsychiatric symptoms during an influenza epidemic.

West Nile Virus Infection in Killer Whale, Texas, USA, 2007

PubMed Central

Wu, Guang; Anderson, Mark; Dalton, Les; Nilson, Erika; Wang, David

2011-01-01

In 2007, nonsuppurative encephalitis was identified in a killer whale at a Texas, USA, marine park. Panviral DNA microarray of brain tissue suggested West Nile virus (WNV); WNV was confirmed by reverse transcription PCR and sequencing. Immunohistochemistry demonstrated WNV antigen within neurons. WNV should be considered in cases of encephalitis in cetaceans. PMID:21801643

Tick-Borne Encephalitis Virus in Ticks and Roe Deer, the Netherlands.

PubMed

Jahfari, Setareh; de Vries, Ankje; Rijks, Jolianne M; Van Gucht, Steven; Vennema, Harry; Sprong, Hein; Rockx, Barry

2017-06-01

We report the presence of tick-borne encephalitis virus (TBEV) in the Netherlands. Serologic screening of roe deer found TBEV-neutralizing antibodies with a seroprevalence of 2%, and TBEV RNA was detected in 2 ticks from the same location. Enhanced surveillance and awareness among medical professionals has led to the identification of autochthonous cases.

Severe Toxoplasma gondii I/III Recombinant-Genotype Encephalitis in a Human Immunodeficiency Virus Patient▿

PubMed Central

Genot, Séverine; Franck, Jacqueline; Forel, Jean-Marie; Rebaudet, Stanislas; Ajzenberg, Daniel; de Paula, Andre Maues; Dardé, Marie-Laure; Stein, Andreas; Ranque, Stéphane

2007-01-01

The reactivation of an uncommon type I/III recombinant-genotype Toxoplasma gondii strain resulted in unusually severe encephalitis and chorioretinitis associated with a cerebral salt wasting syndrome in an African human immunodeficiency virus patient. This observation suggests an influence of the parasite genotype on disease expression in immunocompromised patients. PMID:17634310

Epidemiologic Survey of Japanese Encephalitis Virus Infection, Tibet, China, 2015

PubMed Central

Zhang, Hui; Rehman, Mujeeb Ur; Li, Kun; Luo, Houqiang; Lan, Yanfang; Nabi, Fazul; Zhang, Lihong; Iqbal, Muhammad Kashif; Zhu, Suolangsi; Javed, Muhammad Tariq; Chamba, Yangzom

2017-01-01

We investigated Japanese encephalitis virus (JEV) prevalence in high-altitude regions of Tibet, China, by using standard assays to test mosquitoes, pigs, and humans. Results confirmed that JEV has spread to these areas. Disease prevention and control strategies should be used along with surveillance to limit spread of JEV in high-altitude regions of Tibet. PMID:28518046

Dual functions of Rift Valley fever virus NSs protein: inhibition of host mRNA transcription and post-transcriptional downregulation of protein kinase PKR.

PubMed

Ikegami, Tetsuro; Narayanan, Krishna; Won, Sungyong; Kamitani, Wataru; Peters, C J; Makino, Shinji

2009-09-01

Rift Valley fever virus (RVFV), which belongs to the genus Phlebovirus, family Bunyaviridae, is a negative-stranded RNA virus carrying a single-stranded, tripartite RNA genome. RVFV is an important zoonotic pathogen transmitted by mosquitoes and causes large outbreaks among ruminants and humans in Africa and the Arabian Peninsula. Human patients develop an acute febrile illness, followed by a fatal hemorrhagic fever, encephalitis, or ocular diseases. A viral nonstructural protein, NSs, is a major viral virulence factor. Past studies showed that NSs suppresses the transcription of host mRNAs, including interferon-beta mRNAs. Here we demonstrated that the NSs protein induced post-transcriptional downregulation of dsRNA-dependent protein kinase (PKR), to prevent phosphorylation of eIF2alpha and promoted viral translation in infected cells. These two biological activities of the NSs most probably have a synergistic effect in suppressing host innate immune functions and facilitate efficient viral replication in infected mammalian hosts.

Rapid Nipah virus entry into the central nervous system of hamsters via the olfactory route

PubMed Central

Munster, Vincent J.; Prescott, Joseph B.; Bushmaker, Trenton; Long, Dan; Rosenke, Rebecca; Thomas, Tina; Scott, Dana; Fischer, Elizabeth R.; Feldmann, Heinz; de Wit, Emmie

2012-01-01

Encephalitis is a hallmark of Nipah virus (NiV) infection in humans. The exact route of entry of NiV into the central nervous system (CNS) is unknown. Here, we performed a spatio-temporal analysis of NiV entry into the CNS of hamsters. NiV initially predominantly targeted the olfactory epithelium in the nasal turbinates. From there, NiV infected neurons were visible extending through the cribriform plate into the olfactory bulb, providing direct evidence of rapid CNS entry. Subsequently, NiV disseminated to the olfactory tubercle and throughout the ventral cortex. Transmission electron microscopy on brain tissue showed extravasation of plasma cells, neuronal degeneration and nucleocapsid inclusions in affected tissue and axons, providing further evidence for axonal transport of NiV. NiV entry into the CNS coincided with the occurrence of respiratory disease, suggesting that the initial entry of NiV into the CNS occurs simultaneously with, rather than as a result of, systemic virus replication. PMID:23071900

Dual Functions of Rift Valley Fever Virus NSs Protein: Inhibition of Host mRNA Transcription and Post-transcriptional Downregulation of Protein Kinase PKR

PubMed Central

Ikegami, Tetsuro; Narayanan, Krishna; Won, Sungyong; Kamitani, Wataru; Peters, C. J.; Makino, Shinji

2011-01-01

Rift Valley fever virus (RVFV), which belongs to the genus Phlebovirus, family Bunyaviridae, is a negative-stranded RNA virus carrying a single-stranded, tripartite RNA genome. RVFV is an important zoonotic pathogen transmitted by mosquitoes and causes large outbreaks among ruminants and humans in Africa and the Arabian Peninsula. Human patients develop an acute febrile illness, followed by a fatal hemorrhagic fever, encephalitis or ocular diseases. A viral nonstructural protein, NSs, is a major viral virulence factor. Past studies showed that NSs suppresses the transcription of host mRNAs, including interferon-β mRNAs. Here we demonstrated that the NSs protein induced post-transcriptional downregulation of dsRNA-dependent protein kinase, PKR, to prevent phosphorylation of eIF2α and promoted viral translation in infected cells. These two biological activities of the NSs most probably have a synergistic effect in suppressing host innate immune functions and facilitate efficient viral replication in infected mammalian hosts. PMID:19751406

Eastern Equine Encephalitis Virus

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

Borucki, M.

2010-08-05

Eastern equine encephalitis virus (EEEV) is a mosquito-borne virus capable of causing large outbreaks of encephalitis in humans and horses. In North America, EEEV infection has a very high mortality rate in humans, and survivors often suffer severe neurological sequelae. Interestingly, EEEV infections from South American isolates are generally subclinical. Although EEEV is divided into two antigenic varieties and four lineages, only eleven isolates have been sequenced and eight of these are from the North American variety (Lineage I). Most sequenced strains were collected from mosquitoes and only one human isolate has been sequenced. EEEV isolates exist from a varietymore » of hosts, vectors, years, and geographical locations and efforts should focus on sequencing strains that represent this diversity.« less

Tick-Borne Encephalitis Virus Structural Proteins Are the Primary Viral Determinants of Non-Viraemic Transmission between Ticks whereas Non-Structural Proteins Affect Cytotoxicity.

PubMed

Khasnatinov, Maxim A; Tuplin, Andrew; Gritsun, Dmitri J; Slovak, Mirko; Kazimirova, Maria; Lickova, Martina; Havlikova, Sabina; Klempa, Boris; Labuda, Milan; Gould, Ernest A; Gritsun, Tamara S

2016-01-01

Over 50 million humans live in areas of potential exposure to tick-borne encephalitis virus (TBEV). The disease exhibits an estimated 16,000 cases recorded annually over 30 European and Asian countries. Conventionally, TBEV transmission to Ixodes spp. ticks occurs whilst feeding on viraemic animals. However, an alternative mechanism of non-viraemic transmission (NVT) between infected and uninfected ticks co-feeding on the same transmission-competent host, has also been demonstrated. Here, using laboratory-bred I. ricinus ticks, we demonstrate low and high efficiency NVT for TBEV strains Vasilchenko (Vs) and Hypr, respectively. These virus strains share high sequence similarity but are classified as two TBEV subtypes. The Vs strain is a Siberian subtype, naturally associated with I. persulcatus ticks whilst the Hypr strain is a European subtype, transmitted by I. ricinus ticks. In mammalian cell culture (porcine kidney cell line PS), Vs and Hypr induce low and high cytopathic effects (cpe), respectively. Using reverse genetics, we engineered a range of viable Vs/Hypr chimaeric strains, with substituted genes. No significant differences in replication rate were detected between wild-type and chimaeric viruses in cell culture. However, the chimaeric strain Vs[Hypr str] (Hypr structural and Vs non-structural genomic regions) demonstrated high efficiency NVT in I. ricinus whereas the counterpart Hypr[Vs str] was not transmitted by NVT, indicating that the virion structural proteins largely determine TBEV NVT transmission efficiency between ticks. In contrast, in cell culture, the extent of cpe was largely determined by the non-structural region of the TBEV genome. Chimaeras with Hypr non-structural genes were more cytotoxic for PS cells when compared with Vs genome-based chimaeras.

Tick-Borne Encephalitis Virus Structural Proteins Are the Primary Viral Determinants of Non-Viraemic Transmission between Ticks whereas Non-Structural Proteins Affect Cytotoxicity

PubMed Central

Khasnatinov, Maxim A.; Tuplin, Andrew; Gritsun, Dmitri J.; Slovak, Mirko; Kazimirova, Maria; Lickova, Martina; Havlikova, Sabina; Klempa, Boris; Gould, Ernest A.

2016-01-01

Over 50 million humans live in areas of potential exposure to tick-borne encephalitis virus (TBEV). The disease exhibits an estimated 16,000 cases recorded annually over 30 European and Asian countries. Conventionally, TBEV transmission to Ixodes spp. ticks occurs whilst feeding on viraemic animals. However, an alternative mechanism of non-viraemic transmission (NVT) between infected and uninfected ticks co-feeding on the same transmission-competent host, has also been demonstrated. Here, using laboratory-bred I. ricinus ticks, we demonstrate low and high efficiency NVT for TBEV strains Vasilchenko (Vs) and Hypr, respectively. These virus strains share high sequence similarity but are classified as two TBEV subtypes. The Vs strain is a Siberian subtype, naturally associated with I. persulcatus ticks whilst the Hypr strain is a European subtype, transmitted by I. ricinus ticks. In mammalian cell culture (porcine kidney cell line PS), Vs and Hypr induce low and high cytopathic effects (cpe), respectively. Using reverse genetics, we engineered a range of viable Vs/Hypr chimaeric strains, with substituted genes. No significant differences in replication rate were detected between wild-type and chimaeric viruses in cell culture. However, the chimaeric strain Vs[Hypr str] (Hypr structural and Vs non-structural genomic regions) demonstrated high efficiency NVT in I. ricinus whereas the counterpart Hypr[Vs str] was not transmitted by NVT, indicating that the virion structural proteins largely determine TBEV NVT transmission efficiency between ticks. In contrast, in cell culture, the extent of cpe was largely determined by the non-structural region of the TBEV genome. Chimaeras with Hypr non-structural genes were more cytotoxic for PS cells when compared with Vs genome-based chimaeras. PMID:27341437

Vaccination against Louping Ill Virus Protects Goats from Experimental Challenge with Spanish Goat Encephalitis Virus.

PubMed

Salinas, L M; Casais, R; García Marín, J F; Dalton, K P; Royo, L J; Del Cerro, A; Gayo, E; Dagleish, M P; Alberdi, P; Juste, R A; de la Fuente, J; Balseiro, A

2017-05-01

Spanish goat encephalitis virus (SGEV) is a recently described member of the genus Flavivirus belonging to the tick-borne encephalitis group of viruses, and is closely related to louping ill virus (LIV). Naturally acquired disease in goats results in severe, acute encephalitis and 100% mortality. Eighteen goats were challenged subcutaneously with SGEV; nine were vaccinated previously against LIV and nine were not. None of the vaccinated goats showed any clinical signs of disease or histological lesions, but all of the non-vaccinated goats developed pyrexia and 5/9 developed neurological clinical signs, primarily tremors in the neck and ataxia. All non-vaccinated animals developed histological lesions restricted to the central nervous system and consistent with a lymphocytic meningomyeloencephalitis. Vaccinated goats had significantly (P <0.003) greater concentrations of serum IgG and lower levels of IgM (P <0.0001) compared with unvaccinated animals. SGEV RNA levels were below detectable limits in the vaccinated goats throughout the experiment, but increased rapidly and were significantly (P <0.0001) greater 2-10 days post challenge in the non-vaccinated group. In conclusion, vaccination of goats against LIV confers highly effective protection against SGEV; this is probably mediated by IgG and prevents an increase in viral RNA load in serum such that vaccinated animals would not be an effective reservoir of the virus. Copyright © 2017 Elsevier Ltd. All rights reserved.

Causes of encephalitis and differences in their clinical presentations in England: a multicentre, population-based prospective study.

PubMed

Granerod, Julia; Ambrose, Helen E; Davies, Nicholas Ws; Clewley, Jonathan P; Walsh, Amanda L; Morgan, Dilys; Cunningham, Richard; Zuckerman, Mark; Mutton, Ken J; Solomon, Tom; Ward, Katherine N; Lunn, Michael Pt; Irani, Sarosh R; Vincent, Angela; Brown, David Wg; Crowcroft, Natasha S

2010-12-01

Encephalitis has many causes, but for most patients the cause is unknown. We aimed to establish the cause and identify the clinical differences between causes in patients with encephalitis in England. Patients of all ages and with symptoms suggestive of encephalitis were actively recruited for 2 years (staged start between October, 2005, and November, 2006) from 24 hospitals by clinical staff. Systematic laboratory testing included PCR and antibody assays for all commonly recognised causes of infectious encephalitis, investigation for less commonly recognised causes in immunocompromised patients, and testing for travel-related causes if indicated. We also tested for non-infectious causes for acute encephalitis including autoimmunity. A multidisciplinary expert team reviewed clinical presentation and hospital tests and directed further investigations. Patients were followed up for 6 months after discharge from hospital. We identified 203 patients with encephalitis. Median age was 30 years (range 0-87). 86 patients (42%, 95% CI 35-49) had infectious causes, including 38 (19%, 14-25) herpes simplex virus, ten (5%, 2-9) varicella zoster virus, and ten (5%, 2-9) Mycobacterium tuberculosis; 75 (37%, 30-44) had unknown causes. 42 patients (21%, 15-27) had acute immune-mediated encephalitis. 24 patients (12%, 8-17) died, with higher case fatality for infections from M tuberculosis (three patients; 30%, 7-65) and varicella zoster virus (two patients; 20%, 2-56). The 16 patients with antibody-associated encephalitis had the worst outcome of all groups-nine (56%, 30-80) either died or had severe disabilities. Patients who died were more likely to be immunocompromised than were those who survived (OR = 3·44). Early diagnosis of encephalitis is crucial to ensure that the right treatment is given on time. Extensive testing substantially reduced the proportion with unknown cause, but the proportion of cases with unknown cause was higher than that for any specific identified cause. The Policy Research Programme, Department of Health, UK. Copyright © 2010 Elsevier Ltd. All rights reserved.

Fatal Powassan Encephalitis (Deer Tick Virus, Lineage II) in a Patient With Fever and Orchitis Receiving Rituximab.

PubMed

Solomon, Isaac H; Spera, Kristyn M; Ryan, Sophia L; Helgager, Jeffrey; Andrici, Juliana; Zaki, Sherif R; Vaitkevicius, Henrikas; Leon, Kristoffer E; Wilson, Michael R; DeRisi, Joseph L; Koo, Sophia; Smirnakis, Stelios M; De Girolami, Umberto

2018-06-01

Powassan virus is a rare but increasingly recognized cause of severe neurological disease. To highlight the diagnostic challenges and neuropathological findings in a fatal case of Powassan encephalitis caused by deer tick virus (lineage II) in a patient with follicular lymphoma receiving rituximab, with nonspecific anti-GAD65 antibodies, who was initially seen with fever and orchiepididymitis. Comparison of clinical, radiological, histological, and laboratory findings, including immunohistochemistry, real-time polymerase chain reaction, antibody detection, and unbiased sequencing assays, in a single case report (first seen in December 2016) at an academic medical center. Infection with Powassan virus. Results of individual assays compared retrospectively. In a 63-year-old man with fatal Powassan encephalitis, serum and cerebrospinal fluid IgM antibodies were not detected via standard methods, likely because of rituximab exposure. Neuropathological findings were extensive, including diffuse leptomeningeal and parenchymal lymphohistiocytic infiltration, microglial proliferation, marked neuronal loss, and white matter microinfarctions most severely involving the cerebellum, thalamus, and basal ganglia. Diagnosis was made after death by 3 independent methods, including demonstration of Powassan virus antigen in brain biopsy and autopsy tissue, detection of viral RNA in serum and cerebrospinal fluid by targeted real-time polymerase chain reaction, and detection of viral RNA in cerebrospinal fluid by unbiased sequencing. Extensive testing for other etiologies yielded negative results, including mumps virus owing to prodromal orchiepididymitis. Low-titer anti-GAD65 antibodies identified in serum, suggestive of limbic encephalitis, were not detected in cerebrospinal fluid. Owing to the rarity of Powassan encephalitis, a high degree of suspicion is required to make the diagnosis, particularly in an immunocompromised patient, in whom antibody-based assays may be falsely negative. Unbiased sequencing assays have the potential to detect uncommon infectious agents and may prove useful in similar scenarios.

9 CFR 121.3 - VS select agents and toxins.

Code of Federal Regulations, 2011 CFR

2011-01-01

... AGRICULTURE VIRUSES, SERUMS, TOXINS, AND ANALOGOUS PRODUCTS; ORGANISMS AND VECTORS POSSESSION, USE, AND...-mouth disease virus; Goat pox virus; Japanese encephalitis virus; Lumpy skin disease virus; Malignant...

9 CFR 121.3 - VS select agents and toxins.

Code of Federal Regulations, 2012 CFR

2012-01-01

... AGRICULTURE VIRUSES, SERUMS, TOXINS, AND ANALOGOUS PRODUCTS; ORGANISMS AND VECTORS POSSESSION, USE, AND...-mouth disease virus; Goat pox virus; Japanese encephalitis virus; Lumpy skin disease virus; Malignant...

Structure of the recombinant alphavirus Western equine encephalitis virus revealed by cryoelectron microscopy.

PubMed

Sherman, Michael B; Weaver, Scott C

2010-10-01

Western equine encephalitis virus (WEEV; Togaviridae, Alphavirus) is an enveloped RNA virus that is typically transmitted to vertebrate hosts by infected mosquitoes. WEEV is an important cause of viral encephalitis in humans and horses in the Americas, and infection results in a range of disease, from mild flu-like illnesses to encephalitis, coma, and death. In addition to spreading via mosquito vectors, human WEEV infections can potentially occur directly via aerosol transmission. Due to its aerosol infectivity and virulence, WEEV is thus classified as a biological safety level 3 (BSL-3) agent. Because of its highly infectious nature and containment requirements, it has not been possible to investigate WEEV's structure or assembly mechanism using standard structural biology techniques. Thus, to image WEEV and other BSL-3 agents, we have constructed a first-of-its-kind BSL-3 cryoelectron microscopy (cryoEM) containment facility. cryoEM images of WEEV were used to determine the first three-dimensional structure of this important human pathogen. The overall organization of WEEV is similar to those of other alphaviruses, consistent with the high sequence similarity among alphavirus structural proteins. Surprisingly, the nucleocapsid of WEEV, a New World virus, is more similar to the Old World alphavirus Sindbis virus than to other New World alphaviruses.

Characterization of Rabensburg Virus, a Flavivirus Closely Related to West Nile Virus of the Japanese Encephalitis Antigenic Group

PubMed Central

Aliota, Matthew T.; Jones, Susan A.; Dupuis, Alan P.; Ciota, Alexander T.; Hubalek, Zdenek; Kramer, Laura D.

2012-01-01

Rabensburg virus (RABV), a Flavivirus with ∼76% nucleotide and 90% amino acid identity with representative members of lineage one and two West Nile virus (WNV), previously was isolated from Culex pipiens and Aedes rossicus mosquitoes in the Czech Republic, and phylogenetic and serologic analyses demonstrated that it was likely a new lineage of WNV. However, no direct link between RABV and human disease has been definitively established and the extent to which RABV utilizes the typical WNV transmission cycle is unknown. Herein, we evaluated vector competence and capacity for vertical transmission (VT) in Cx. pipiens; in vitro growth on avian, mammalian, and mosquito cells; and infectivity and viremia production in birds. RABV infection and replication only were detected on mosquito cells. Experimentally inoculated birds did not become infected. Cx. pipiens had poor peroral vector competence and a higher VT rate as compared to US-WNV in Cx. pipiens. As a result, we postulate that RABV is an intermediate between the mosquito-specific and horizontally transmitted flaviviruses. PMID:22724010

[Expression of EV71-VP1, PSGL-1 and SCARB2 in Tissues of Infants with Brain Stem Encephalitis].

PubMed

Li, Ming; Kong, Xiao-ping; Liu, Hong; Cheng, Ling-xi; Huang, Jing-lu; Quan, Li; Wu, Fang-yu; Hao, Bo; Liu, Chao; Luo, Bin

2015-04-01

To understand the correlation of enterovirus 71 (EV71), P-selectin glycoprotein ligand-1 (PSGL-1), and scavenger receptor B2 (SCARB2) and to explore the possible pathway and mechanism of EV71 infection by observing the expression of EV71, PSGL-1 and SCARB2 in tissues of infants with brain stem encephalitis. The organs and tissues of infants with EV71-VP1 positivity in their brain stems were chosen. Expression and distribution of EV71-VP1, PSGL-1, and SCARB2 were detected and compared by immunohistochemistry. Strong staining of EV71 -VP1 was observed in the neuron, glial cells, the inflammatory cells of perivascular cuffing, parietal cells of the gastric fundus gland while alveolar macrophages, intestinal gland epithelium cells, mucosa lymphoid nodule and lymphocyte of palatine tonsil showed moderate staining and weak staining were displayed in mesenteric lymph nodes and lymphocyte of spleen. PSGL-1 expression was detected in parietal cells of the gastric fundus gland, tonsillar crypt squamous epithelium, alveolar macrophages and leukocytes in each tissue. SCARB2 expression was observed in all the above tissues except the intestines and spleen. The distribution of EV71 correlates with SCARB2 expression. SCARB2 plays an important role in virus infection and replication. Stomach may be an important site for EV71 replication.

Research in Drug Development against Viral Diseases of Military Importance (Biological Testing).

DTIC Science & Technology

HAMSTERS, HEMORRHAGIC FEVERS, KOREA, VIRUSES , SECONDARY, STRAINS(BIOLOGY), VESICULAR STOMATITIS, VIRUS DISEASES, JAPANESE ENCEPHALITIS VIRUSES , MICE...SANDFLY FEVER VIRUS INFECTION, SPECTRA, VACCINIA VIRUS , VENEZUELAN EQUINE ENCEPHALOMYELITIS VIRUS , YELLOW FEVER VIRUS .

Measles-induced encephalitis.

PubMed

Fisher, D L; Defres, S; Solomon, T

2015-03-01

Encephalitis is the most frequent neurological complication of measles virus infection. This review examines the pathophysiology of measles infection and the presentations, diagnosis and treatment of the four types of measles-induced encephalitis including primary measles encephalitis, acute post-measles encephalitis, measles inclusion body encephalitis and subacute sclerosing panencephalitis. The early symptoms of encephalitis may be non-specific and can be mistakenly attributed to a systemic infection leading to a delay in diagnosis. This review provides a summary of the symptoms that should cause health care workers to suspect measles-induced encephalitis. © The Author 2014. Published by Oxford University Press on behalf of the Association of Physicians. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Chandipura virus infection causing encephalitis in a tribal population of Odisha in eastern India.

PubMed

Dwibedi, Bhagirathi; Sabat, Jyotsnamayee; Hazra, Rupenangshu K; Kumar, Anu; Dinesh, Diwakar Singh; Kar, Shantanu K

2015-01-01

The sudden death of 10 children in a tribal village of Kandhamal district, Odisha in eastern India led to this investigation. We conducted a door-to-door survey to identify cases. Antibodies for Chandipura, Japanese encephalitis, dengue, chikungunya and West Nile viruses were tested by ELISA in probable cases. Chandipura virus RNA was tested from both human blood samples and sand flies by reverse transcriptase polymerase chain reaction. We conducted vector surveys in domestic and peridomestic areas, and collected sand flies. Entomological investigations revealed the presence of Phlebotomus argentipes and Sergentomiya sp. Thirty-five patients presented with fever, 12 of them had altered sensorium including 4 who had convulsions. The blood samples of 21 patients were tested; four samples revealed Chandipura virusspecific IgM antibody. Chandipura virus infection causing encephalitis affected this tribal population in eastern India at 1212 m above sea level. Copyright 2015, NMJI.

Immunity to airborne challenge with Venezuelan equine encephalitis virus develops rapidly after immunization with the attenuated vaccine strain TC-83.

PubMed

Phillpotts, R J

1999-05-14

Mice vaccinated subcutaneously with the attenuated vaccine strain of Venezuelan equine encephalitis virus (VEEV) rapidly develop immunity to subcutaneous or airborne challenge with virulent VEEV. The specificity of this immune response was demonstrated by challenge with a heterologous virus (St. Louis encephalitis virus). Examination of the levels of VEEV-specific antibody classes in serum and respiratory secretions suggested that the rapid development of immunity was coincident with the appearance of specific IgM and IgG (but not IgA) in the respiratory tract. In order to confirm the role of respiratory tract antibody, mice were passively immunised either intraperitoneally or intranasally with polyclonal VEEV-specific IgG. Intranasal administration of specific IgG significantly enhanced protection against airborne challenge. These results confirm the need to emphasise local antibody production in the development of improved VEEV vaccines.

Venezuelan encephalitis virus infection in neotropical bats. III. Experimental studies on virus excretion and non-arthropod transmission.

PubMed

Seymour, C; Dickerman, R W

1978-03-01

A total of 80 Neotropical bats of five species was inoculated with one of four strains of Venezuelan encephalitis (VE) virus. Virus was detected in the oropharynges of 56% of bats, and most regularly in Artibeus jamaicensis (75%). Titers of virus in oropharyngeal secretions were occasionally very high (8.5 log10 SMicLD50/ml in one A. jamaicensis). Only 2 of 123 urine samples from 50 bats and 2 of 86 fecal samples from 46 bats yielded VE virus. No contact or aerosol virus transmission from bat to bat was detected. VE virus passed transplacentally from two infected mothers to their fetuses, which were aborted. Virus did not pass from one infected mother to her nursing young.

Herpes simplex virus type 1 encephalitis and unusual retinitis in a patient with systemic lupus erythematosus.

PubMed

Zhang, L; Liu, J J; Li, M T

2013-11-01

In this report we discuss a case of a patient with systemic lupus erythematosus who developed herpes simplex virus type 1(HSV-1) infection presenting with encephalitis as well as necrotic and non-necrotic retinitis. The patient presented with typical clinical symptoms and radiologic abnormalities consistent with HSV-1 encephalitis and HSV-1 retinitis in patients with HIV infection, but lacked cerebrospinal fluid pleocytosis and had bilateral retinitis with poor visual acuity. To the best of our knowledge, this is the first such case reported in the literature.

Naloxone-induced seizures in rats infected with Borna disease virus.

PubMed

Solbrig, M V; Koob, G F; Lipkin, W I

1996-04-01

The opioid antagonist naloxone is widely used in the emergency treatment of nontraumatic coma. Although it is uncommon for serious side effects to result from administration of opiate antagonists, we report that naloxone can have epileptogenic effects in the context of encephalitis. In an experimental model of viral encephalitis, rats infected with Borna disease virus developed myoclonic, generalized clonic, or atonic seizures; behavior arrest; and staring spells when treated with naloxone. These findings suggest a novel neuropharmacologic link, through opioid peptide systems, between epilepsy and encephalitis and disclose a potential contraindication to use of opioid antagonists in nontraumatic coma.

Emergence or improved detection of Japanese encephalitis virus in the Himalayan highlands?

PubMed

Baylis, Matthew; Barker, Christopher M; Caminade, Cyril; Joshi, Bhoj R; Pant, Ganesh R; Rayamajhi, Ajit; Reisen, William K; Impoinvil, Daniel E

2016-04-01

The emergence of Japanese encephalitis virus (JEV) in the Himalayan highlands is of significant veterinary and public health concern and may be related to climate warming and anthropogenic landscape change, or simply improved surveillance. To investigate this phenomenon, a One Health approach focusing on the phylogeography of JEV, the distribution and abundance of the mosquito vectors, and seroprevalence in humans and animal reservoirs would be useful to understand the epidemiology of Japanese encephalitis in highland areas. © The Author 2016. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene.

[Characteristics of long-term persisting strains of tick-borne encephalitis virus in different forms of the chronic process in animals].

PubMed

Frolova, T V; Pogodina, V V; Frolova, M P; Karmysheva, V Ia

1982-01-01

The properties of the Vasilchenko strain of tick-borne encephalitis (TBE) virus and its 3 variants isolated at various stages of persistent infection (383, 453, and 535 days) in Macaca rhesus monkeys and Syrian hamsters with different forms of the chronic TBE were studied. The process characterized by chronic focal inflammatory-degenerative changes in the brains of hamsters without the disturbance of motor functions was associated with persistence of different kinds of virus-specific antigens without virulent virus production. Brain explants of this group of hamsters yielded a virus with cytopathogenic properties but not pathogenic for mice. In a chronic disease developing without the initial acute period, a virus was recovered from hamsters which proved to be virulent for mice and to possess the hemagglutinating and high invasive activity. The most virulent strain was isolated from monkeys with continuously progressive chronic encephalitis with steady paralysis of the extremities. This isolate differed from the parental Vasilchenko strain by a high pathogenicity for hamsters by intracerebral and subcutaneous routes, and thermostability at 50 degrees C.

West Nile Virus and Other Nationally Notifiable Arboviral Diseases - United States, 2015.

PubMed

Krow-Lucal, Elisabeth; Lindsey, Nicole P; Lehman, Jennifer; Fischer, Marc; Staples, J Erin

2017-01-20

Arthropod-borne viruses (arboviruses) are transmitted to humans primarily through the bites of infected mosquitoes and ticks. The leading cause of domestically acquired arboviral disease in the United States is West Nile virus (WNV) (1). Other arboviruses, including La Crosse, St. Louis encephalitis, Jamestown Canyon, Powassan, and eastern equine encephalitis viruses, also cause sporadic cases and outbreaks. This report summarizes surveillance data reported to CDC in 2015 for nationally notifiable arboviruses. It excludes dengue, chikungunya, and Zika viruses, which are primarily nondomestic viruses typically acquired through travel (and are addressed in other CDC reports). In 2015, 45 states and the District of Columbia (DC) reported 2,282 cases of domestic arboviral disease. Among these cases, 2,175 (95%) were WNV disease and 1,455 (67%) of those were classified as neuroinvasive disease (meningitis, encephalitis, or acute flaccid paralysis). The national incidence of WNV neuroinvasive disease was 0.45 cases per 100,000 population. Because arboviral diseases continue to cause serious illness, maintaining surveillance is important to direct prevention activities such as reduction of vector populations and screening of blood donors.

A Single Amino Acid Substitution in the NS2A Protein of Japanese Encephalitis Virus Affects Virus Propagation In Vitro but Not In Vivo.

PubMed

Takamatsu, Yuki; Morita, Kouichi; Hayasaka, Daisuke

2015-06-01

We identified a unique amino acid of NS2A113, phenylalanine, that affects the efficient propagation of two Japanese encephalitis virus strains, JaTH160 and JaOArS982, in neuroblastoma Neuro-2a cells but not in cell lines of extraneural origin. This amino acid did not affect viral loads in the brain or survival curves in mice. These findings suggest that virus propagation in vitro may not reflect the level of virus neuroinvasiveness in vivo. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Molecular detection of flaviviruses and alphaviruses in mosquitoes (Diptera: Culicidae) from coastal ecosystems in the Colombian Caribbean

PubMed Central

Hoyos-López, Richard; Suaza-Vasco, Juan; Rúa-Uribe, Guillermo; Uribe, Sandra; Gallego-Gómez, Juan Carlos

2016-01-01

Arboviruses belonging to the genera Flavivirus and Alphavirus were detected in mosquitoes in a rural area of San Bernardo del Viento (Córdoba, Colombia). A total of 22,180 mosquitoes were collected, sorted into 2,102 pools, and tested by generic/nested reverse transcription-polymerase chain reaction. Venezuelan equine encephalitis virus, dengue virus, West Nile virus, St. Louis encephalitis virus, yellow fever virus, and Culex flavivirus were detected and identified by sequencing. The detection of arboviral pathogens in this zone represents possible circulation and indicates a human health risk, demonstrating the importance of virological surveillance activities. PMID:27706377

Genome-Wide Survey of Host Responses: Use of Computational Analysis to Classify Exposures and Extract Signatures of Unconventional Versus Common Viral Exposures

DTIC Science & Technology

2006-11-01

alpha viruses, among which was Venezuelan equine encephalitis (VEE). The “training sets” were constructed from in vitro exposures to purified...virus and 4 serotypes of Dengue), and the forth group include 2 alpha viruses, among which was Venezuelan equine encephalitis (VEE). We have used...We examined our hypothesis that in vitro exposures can predict exposures in vivo. We have used data from PBMC exposed to Venezuelan equine

Isolation, preliminary characterization, and full-genome analyses of tick-borne encephalitis virus from Mongolia.

PubMed

Frey, Stefan; Mossbrugger, Ilona; Altantuul, Damdin; Battsetseg, Jigjav; Davaadorj, Rendoo; Tserennorov, Damdindorj; Buyanjargal, Tsoodol; Otgonbaatar, Dashdavaa; Zöller, Lothar; Speck, Stephanie; Wölfel, Roman; Dobler, Gerhard; Essbauer, Sandra

2012-12-01

Tick-borne encephalitis virus (TBEV) causes one of the most important inflammatory diseases of the central nervous system, namely severe encephalitis in Europe and Asia. Since the 1980s tick-borne encephalitis is known in Mongolia with increasing numbers of human cases reported during the last years. So far, however, data on TBEV strains are still sparse. We herein report the isolation of a TBEV strain from Ixodes persulcatus ticks collected in Mongolia in 2010. Phylogenetic analysis of the E-gene classified this isolate as Siberian subtype of TBEV. The Mongolian TBEV strain showed differences in virus titers, plaque sizes, and growth properties in two human neuronal cell-lines. In addition, the 10,242 nucleotide long open-reading frame and the corresponding polyprotein sequence were revealed. The isolate grouped in the genetic subclade of the Siberian subtype. The strain Zausaev (AF527415) and Vasilchenko (AF069066) had 97 and 94 % identity on the nucleotide level. In summary, we herein describe first detailed data regarding TBEV from Mongolia. Further investigations of TBEV in Mongolia and adjacent areas are needed to understand the intricate dispersal of this virus.

New Japanese encephalitis vaccines: alternatives to production in mouse brain.

PubMed

Halstead, Scott B; Thomas, Stephen J

2011-03-01

Japanese encephalitis virus (JEV), a flavivirus maintained in a zoonotic cycle and transmitted by the mosquito Culex tritaeniorhynchus, causes epidemics of encephalitis throughout much of Asia. Resident populations, including short- or long-term visitors to enzootic regions, are at risk of infection and disease. For the past several decades, killed viral vaccines prepared in tissue culture or mouse brain have been used effectively to immunize travelers and residents of enzootic countries. Cost, efficacy and safety concerns led to the development of a live-attenuated virus vaccine (SA14-14-2) and more recently, to the licensure in the USA, Europe, Canada, and Australia of a purified inactivated, tissue culture-based Japanese encephalitis vaccine (IXIARO(®), referred to as IC51; Intercell AG, Vienna, Austria). In addition, a live-attenuated yellow fever-Japanese encephalitis chimeric vaccine (IMOJEV™, referred to as Japanese encephalitis-CV; Sanofi Pasteur, Lyon, France) was recently licensed in Australia and is under review in Thailand. A broad portfolio of safe and effective Japanese encephalitis vaccines has become available to meet the needs of at-risk populations; when appropriately delivered, these new vaccines should greatly diminish the burden of disease.

9 CFR 121.9 - Responsible official.

Code of Federal Regulations, 2011 CFR

2011-01-01

...: African horse sickness virus, African swine fever virus, avian influenza virus (highly pathogenic), Bacillus anthracis, bovine spongiform encephalopathy agent, Brucella melitensis, classical swine fever... Valley fever virus, rinderpest virus, swine vesicular disease virus, and Venezuelan equine encephalitis...

9 CFR 121.9 - Responsible official.

Code of Federal Regulations, 2012 CFR

2012-01-01

...: African horse sickness virus, African swine fever virus, avian influenza virus (highly pathogenic), Bacillus anthracis, bovine spongiform encephalopathy agent, Brucella melitensis, classical swine fever... Valley fever virus, rinderpest virus, swine vesicular disease virus, and Venezuelan equine encephalitis...

The interaction of flavivirus M protein with light chain Tctex-1 of human dynein plays a role in late stages of virus replication.

PubMed

Brault, Jean-Baptiste; Kudelko, Mateusz; Vidalain, Pierre-Olivier; Tangy, Frédéric; Desprès, Philippe; Pardigon, Nathalie

2011-09-01

The role of the membrane protein (prM/M) in flavivirus life cycle remains unclear. Here, we identified a cellular interactor to the 40-residue-long ectodomain of prM/M (ectoM) using a yeast two-hybrid screen against a human cDNA library and GST pull-down assays. We showed that dynein light chain Tctex-1 interacts with the ectoM of dengue 1-4, West Nile, and Japanese encephalitis flaviviruses. No interaction was found with yellow fever and tick-borne flaviviruses. This interaction is highly specific since a single amino-acid change in the ectoM abrogates the interaction with Tctex-1. To understand the role of this interaction, silencing of Tctex-1 using siRNA was performed prior to infection. A significant decrease in progeny production was observed for dengue and West Nile viruses. Silencing Tctex-1 inhibited the production of recombinant dengue subviral particles (RSPs). Thus Tctex-1 may play a role in late stages of viral replication through its interaction with the membrane protein. Copyright © 2011 Elsevier Inc. All rights reserved.

Neuronal Vacuolization in Feline Panleukopenia Virus Infection.

PubMed

Pfankuche, Vanessa M; Jo, Wendy K; van der Vries, Erhard; Jungwirth, Nicole; Lorenzen, Stephan; Osterhaus, Albert D M E; Baumgärtner, Wolfgang; Puff, Christina

2018-03-01

Feline panleukopenia virus (FPV) infections are typically associated with anorexia, vomiting, diarrhea, neutropenia, and lymphopenia. In cases of late prenatal or early neonatal infections, cerebellar hypoplasia is reported in kittens. In addition, single cases of encephalitis are described. FPV replication was recently identified in neurons, although it is mainly found in cells with high mitotic activity. A female cat, 2 months old, was submitted to necropsy after it died with neurologic deficits. Besides typical FPV intestinal tract changes, multifocal, randomly distributed intracytoplasmic vacuoles within neurons of the thoracic spinal cord were found histologically. Next-generation sequencing identified FPV-specific sequences within the central nervous system. FPV antigen was detected within central nervous system cells, including the vacuolated neurons, via immunohistochemistry. In situ hybridization confirmed the presence of FPV DNA within the vacuolated neurons. Thus, FPV should be considered a cause for neuronal vacuolization in cats presenting with ataxia.

Molecular cloning, overproduction, purification, and biochemical characterization of the p39 nsp2 protease domains encoded by three alphaviruses

PubMed Central

Zhang, Di; Tözsér, József; Waugh, David S.

2009-01-01

Alphaviruses cause serious diseases that pose a potential health threat to both humans and livestock. The nonstructural protein 2 (nsp2) encoded by alphaviruses is a multifunctional enzyme that is essential for viral replication and maturation. Its 39-kDa C-terminal domain (nsp2pro) is a cysteine protease that is responsible for cleaving a viral polyprotein at three sites to generate nonstructural proteins 1, 2, 3 and 4. In the present study, we evaluated nsp2pro domains from the following three sources as reagents for site-specific cleavage of fusion proteins: Venezuelan Equine Encephalitis Virus (VEEV), Semliki Forest Virus (SFV) and Sindbis Virus (SIN). All three alphavirus proteases cleaved model fusion protein substrates with high specificity but they were much less efficient enzymes than potyviral proteases from tobacco etch virus (TEV) and tobacco vein mottling virus (TVMV). Oligopeptide substrates were also cleaved with very low efficiency by the alphavirus proteases. We conclude that, in general, alphavirus nsp2pro proteases are not very useful tools for the removal of affinity tags from recombinant proteins although they do remain promising therapeutic targets for the treatment of a variety of diseases. PMID:19013248

Dynamic changes in global microRNAome and transcriptome reveal complex miRNA-mRNA regulated host response to Japanese Encephalitis Virus in microglial cells

PubMed Central

Kumari, Bharti; Jain, Pratistha; Das, Shaoli; Ghosal, Suman; Hazra, Bibhabasu; Trivedi, Ashish Chandra; Basu, Anirban; Chakrabarti, Jayprokas; Vrati, Sudhanshu; Banerjee, Arup

2016-01-01

Microglia cells in the brain play essential role during Japanese Encephalitis Virus (JEV) infection and may lead to change in microRNA (miRNA) and mRNA profile. These changes may together control disease outcome. Using Affymetrix microarray platform, we profiled cellular miRNA and mRNA expression at multiple time points during viral infection in human microglial (CHME3) cells. In silico analysis of microarray data revealed a phased pattern of miRNAs expression, associated with JEV replication and provided unique signatures of infection. Target prediction and pathway enrichment analysis identified anti correlation between differentially expressed miRNA and the gene expression at multiple time point which ultimately affected diverse signaling pathways including Notch signaling pathways in microglia. Activation of Notch pathway during JEV infection was demonstrated in vitro and in vivo. The expression of a subset of miRNAs that target multiple genes in Notch signaling pathways were suppressed and their overexpression could affect JEV induced immune response. Further analysis provided evidence for the possible presence of cellular competing endogenous RNA (ceRNA) associated with innate immune response. Collectively, our data provide a uniquely comprehensive view of the changes in the host miRNAs induced by JEV during cellular infection and identify Notch pathway in modulating microglia mediated inflammation. PMID:26838068

Dynamic changes in global microRNAome and transcriptome reveal complex miRNA-mRNA regulated host response to Japanese Encephalitis Virus in microglial cells.

PubMed

Kumari, Bharti; Jain, Pratistha; Das, Shaoli; Ghosal, Suman; Hazra, Bibhabasu; Trivedi, Ashish Chandra; Basu, Anirban; Chakrabarti, Jayprokas; Vrati, Sudhanshu; Banerjee, Arup

2016-02-03

Microglia cells in the brain play essential role during Japanese Encephalitis Virus (JEV) infection and may lead to change in microRNA (miRNA) and mRNA profile. These changes may together control disease outcome. Using Affymetrix microarray platform, we profiled cellular miRNA and mRNA expression at multiple time points during viral infection in human microglial (CHME3) cells. In silico analysis of microarray data revealed a phased pattern of miRNAs expression, associated with JEV replication and provided unique signatures of infection. Target prediction and pathway enrichment analysis identified anti correlation between differentially expressed miRNA and the gene expression at multiple time point which ultimately affected diverse signaling pathways including Notch signaling pathways in microglia. Activation of Notch pathway during JEV infection was demonstrated in vitro and in vivo. The expression of a subset of miRNAs that target multiple genes in Notch signaling pathways were suppressed and their overexpression could affect JEV induced immune response. Further analysis provided evidence for the possible presence of cellular competing endogenous RNA (ceRNA) associated with innate immune response. Collectively, our data provide a uniquely comprehensive view of the changes in the host miRNAs induced by JEV during cellular infection and identify Notch pathway in modulating microglia mediated inflammation.

Emerging Cases of Powassan Virus Encephalitis in New England: Clinical Presentation, Imaging, and Review of the Literature

PubMed Central

Piantadosi, Anne; Rubin, Daniel B.; McQuillen, Daniel P.; Hsu, Liangge; Lederer, Philip A.; Ashbaugh, Cameron D.; Duffalo, Chad; Duncan, Robert; Thon, Jesse; Bhattacharyya, Shamik; Basgoz, Nesli; Feske, Steven K.; Lyons, Jennifer L.

2016-01-01

Background. Powassan virus (POWV) is a rarely diagnosed cause of encephalitis in the United States. In the Northeast, it is transmitted by Ixodes scapularis, the same vector that transmits Lyme disease. The prevalence of POWV among animal hosts and vectors has been increasing. We present 8 cases of POWV encephalitis from Massachusetts and New Hampshire in 2013–2015. Methods. We abstracted clinical and epidemiological information for patients with POWV encephalitis diagnosed at 2 hospitals in Massachusetts from 2013 to 2015. We compared their brain imaging with those in published findings from Powassan and other viral encephalitides. Results. The patients ranged in age from 21 to 82 years, were, for the most part, previously healthy, and presented with syndromes of fever, headache, and altered consciousness. Infections occurred from May to September and were often associated with known tick exposures. In all patients, cerebrospinal fluid analyses showed pleocytosis with elevated protein. In 7 of 8 patients, brain magnetic resonance imaging demonstrated deep foci of increased T2/fluid-attenuation inversion recovery signal intensity. Conclusions. We describe 8 cases of POWV encephalitis in Massachusetts and New Hampshire in 2013–2015. Prior to this, there had been only 2 cases of POWV encephalitis identified in Massachusetts. These cases may represent emergence of this virus in a region where its vector, I. scapularis, is known to be prevalent or may represent the emerging diagnosis of an underappreciated pathogen. We recommend testing for POWV in patients who present with encephalitis in the spring to fall in New England. PMID:26668338

Tick-borne encephalitis among U.S. travelers to Europe and Asia - 2000-2009.

PubMed

2010-03-26

Tick-borne encephalitis virus (TBEV) is the most common arbovirus transmitted by ticks in Europe. Approximately 10,000 cases of tick-borne encephalitis (TBE) are reported annually in Europe and Russia. Although TBE is endemic in parts of China, information regarding its incidence is limited. TBEV is closely related to Powassan virus (POWV), another tick-borne flavivirus that is a rare cause of encephalitis in North America and Russia; TBEV and POWV can cross-react in serologic tests. Before 2000, two cases of TBE in North American travelers to Europe were reported. State health officials or clinicians send specimens from patients with unexplained encephalitis to CDC as part of routine surveillance and diagnostic testing. CDC recently reviewed all 2000-2009 laboratory records to identify cases of TBE among U.S. travelers; the five cases identified are summarized in this report. All five cases had TBEV or POWV immunoglobulin M (IgM) antibodies in serum and were confirmed as acute TBE cases by plaque-reduction neutralization tests against both viruses. All four patients who had traveled to Europe or Russia had biphasic illnesses (a common feature of TBE) and made nearly complete recoveries. The fifth patient, the first reported case of TBE in a U.S. traveler to China, had a monophasic illness with severe encephalitis and neurologic sequelae. Health-care providers should be aware of TBE, should counsel travelers about measures to reduce exposure to tick bites, and should consider the diagnosis of TBE in travelers returning from TBE-endemic countries with meningitis or encephalitis.

Brain Macrophages in Simian Immunodeficiency Virus-Infected, Antiretroviral-Suppressed Macaques: a Functional Latent Reservoir

PubMed Central

Avalos, Claudia R.; Abreu, Celina M.; Queen, Suzanne E.; Li, Ming; Price, Sarah; Shirk, Erin N.; Engle, Elizabeth L.; Forsyth, Ellen; Bullock, Brandon T.; Mac Gabhann, Feilim; Wietgrefe, Stephen W.; Haase, Ashley T.; Zink, M. Christine; Mankowski, Joseph L.; Clements, Janice E.

2017-01-01

ABSTRACT A human immunodeficiency virus (HIV) infection cure requires an understanding of the cellular and anatomical sites harboring virus that contribute to viral rebound upon treatment interruption. Despite antiretroviral therapy (ART), HIV-associated neurocognitive disorders (HAND) are reported in HIV-infected individuals on ART. Biomarkers for macrophage activation and neuronal damage in cerebrospinal fluid (CSF) of HIV-infected individuals demonstrate continued effects of HIV in brain and suggest that the central nervous system (CNS) may serve as a viral reservoir. Using a simian immunodeficiency virus (SIV)/macaque model for HIV encephalitis and AIDS, we evaluated whether infected cells persist in brain despite ART. Eight SIV-infected pig-tailed macaques were virally suppressed with ART, and plasma and CSF viremia levels were analyzed longitudinally. To assess whether virus persisted in brain macrophages (BrMΦ) in these macaques, we used a macrophage quantitative viral outgrowth assay (MΦ-QVOA), PCR, and in situ hybridization (ISH) to measure the frequency of infected cells and the levels of viral RNA and DNA in brain. Viral RNA in brain tissue of suppressed macaques was undetectable, although viral DNA was detected in all animals. The MΦ-QVOA demonstrated that the majority of suppressed animals contained latently infected BrMΦ. We also showed that virus produced in the MΦ-QVOAs was replication competent, suggesting that latently infected BrMΦ are capable of reestablishing productive infection upon treatment interruption. This report provides the first confirmation of the presence of replication-competent SIV in BrMΦ of ART-suppressed macaques and suggests that the highly debated issue of viral latency in macrophages, at least in brain, has been addressed in SIV-infected macaques treated with ART. PMID:28811349

Care beyond the hospital ward: understanding the socio-medical trajectory of herpes simplex virus encephalitis.

PubMed

Cooper, Jessie; Kierans, Ciara; Defres, Sylviane; Easton, Ava; Kneen, Rachel; Solomon, Tom

2017-09-12

Herpes simplex virus (HSV) encephalitis is a life-threatening infection of the brain, which has significant physical, cognitive and social consequences for survivors. Despite increasing recognition of the long-term effects of encephalitis, research and policy remains largely focused on its acute management, meaning there is little understanding of the difficulties people face after discharge from acute care. This paper aims to chart the problems and challenges which people encounter when they return home after treatment for HSV encephalitis. The paper reports on data from 30 narrative interviews with 45 people affected by HSV encephalitis and their significant others. The study was conducted as part of the ENCEPH-UK programme grant on Understanding and Improving the Outcome of Encephalitis. The findings show the diverse challenges which are experienced by people after treatment for HSV encephalitis. We first chart how peoples' everyday lives are fragmented following their discharge from hospital. Second, we document the social consequences which result from the longer-term effects of encephalitis. Finally, we show how the above struggles are exacerbated by the lack of support systems for the post-acute effects of encephalitis, and describe how people are consequently forced to devise their own care routines and strategies for managing their problems. The paper argues that in order to improve long-term outcomes in encephalitis, it is vital that we develop pathways of support for the condition beyond the acute hospital setting. We conclude by making recommendations to enhance communication and care for the post-acute consequences of encephalitis, to ensure those affected are fully supported through the chronic effects of this devastating disease.

Flavivirus Infection of Ixodes scapularis (Black-Legged Tick) Ex Vivo Organotypic Cultures and Applications for Disease Control.

PubMed

Grabowski, Jeffrey M; Tsetsarkin, Konstantin A; Long, Dan; Scott, Dana P; Rosenke, Rebecca; Schwan, Tom G; Mlera, Luwanika; Offerdahl, Danielle K; Pletnev, Alexander G; Bloom, Marshall E

2017-08-22

Ixodes scapularis ticks transmit many infectious agents that cause disease, including tick-borne flaviviruses (TBFVs). TBFV infections cause thousands of human encephalitis cases worldwide annually. In the United States, human TBFV infections with Powassan virus (POWV) are increasing and have a fatality rate of 10 to 30%. Additionally, Langat virus (LGTV) is a TBFV of low neurovirulence and is used as a model TBFV. TBFV replication and dissemination within I. scapularis organs are poorly characterized, and a deeper understanding of virus biology in this vector may inform effective countermeasures to reduce TBFV transmission. Here, we describe short-term, I. scapularis organ culture models of TBFV infection. Ex vivo organs were metabolically active for 9 to 10 days and were permissive to LGTV and POWV replication. Imaging and videography demonstrated replication and spread of green fluorescent protein-expressing LGTV in the organs. Immunohistochemical staining confirmed LGTV envelope and POWV protein synthesis within the infected organs. LGTV- and POWV-infected organs produced infectious LGTV and POWV; thus, the ex vivo cultures were suitable for study of virus replication in individual organs. LGTV- and POWV-infected midgut and salivary glands were subjected to double-stranded RNA (dsRNA) transfection with dsRNA to the LGTV 3' untranslated region (UTR), which reduced infectious LGTV and POWV replication, providing a proof-of-concept use of RNA interference in I. scapularis organ cultures to study the effects on TBFV replication. The results contribute important information on TBFV localization within ex vivo I. scapularis organs and provide a significant translational tool for evaluating recombinant, live vaccine candidates and potential tick transcripts and proteins for possible therapeutic use and vaccine development to reduce TBFV transmission. IMPORTANCE Tick-borne flavivirus (TBFV) infections cause neurological and/or hemorrhagic disease in humans worldwide. There are currently no licensed therapeutics or vaccines against Powassan virus (POWV), the only TBFV known to circulate in North America. Evaluating tick vector targets for antitick vaccines directed at reducing TBFV infection within the arthropod vector is a critical step in identifying efficient approaches to controlling TBFV transmission. This study characterized infection of female Ixodes scapularis tick organ cultures of midgut, salivary glands, and synganglion with the low-neurovirulence Langat virus (LGTV) and the more pathogenic POWV. Cell types of specific organs were susceptible to TBFV infection, and a difference in LGTV and POWV replication was noted in TBFV-infected organs. This tick organ culture model of TBFV infection will be useful for various applications, such as screening of tick endogenous dsRNA corresponding to potential control targets within midgut and salivary glands to confirm restriction of TBFV infection.

Resistance to Viral Challenge in the Days Immediately Following Vaccination.

DTIC Science & Technology

Powassan or yellow fever, by the intraperitoneal route into guinea pigs failed to induce visible signs of illness; however, with Japanese encephalitis... Powassan , and Banzi viruses, high titered complement-fixing antibodies developed. Since no disease and death could be used as a criterion of successful...infection of guinea pigs inoculated with Japanese encephalitis virus, or of hamsters inoculated with Powassan , an alternative method of determining

Vector Competence of New Zealand Mosquitoes for Selected Arboviruses

PubMed Central

Kramer, Laura D.; Chin, Pam; Cane, Rachel P.; Kauffman, Elizabeth B.; Mackereth, Graham

2011-01-01

New Zealand (NZ) historically has been free of arboviral activity with the exception of Whataroa virus (Togaviridae: Alphavirus), which is established in bird populations and is transmitted by local mosquitoes. This naive situation is threatened by global warming, invasive mosquitoes, and tourism. To determine the threat of selected medically important arboviruses to NZ, vector competence assays were conducted using field collected endemic and introduced mosquito species. Four alphaviruses (Togaviridae): Barmah Forest virus, Chikungunya virus, Ross River virus, and Sindbis virus, and five flaviviruses (Flaviviridae): Dengue virus 2, Japanese encephalitis virus, Murray Valley encephalitis virus, West Nile virus, and Yellow fever virus were evaluated. Results indicate some NZ mosquito species are highly competent vectors of selected arboviruses, particularly alphaviruses, and may pose a threat were one of these arboviruses introduced at a time when the vector was prevalent and the climatic conditions favorable for virus transmission. PMID:21734146

Potential Sympatric Vectors and Mammalian Hosts of Venezuelan Equine Encephalitis Virus in Southern Mexico.

PubMed

Sotomayor-Bonilla, Jesús; Abella-Medrano, Carlos Antonio; Chaves, Andrea; Álvarez-Mendizábal, Paulina; Rico-Chávez, Óscar; Ibáñez-Bernal, Sergio; Rostal, Melinda K; Ojeda-Flores, Rafael; Barbachano-Guerrero, Arturo; Gutiérrez-Espeleta, Gustavo; Aguirre, A Alonso; Daszak, Peter; Suzán, Gerardo

2017-07-01

Arboviruses are important zoonotic agents with complex transmission cycles and are not well understood because they may involve many vectors and hosts. We studied sympatric wild mammals and hematophagous mosquitoes having the potential to act as hosts and vectors in two areas of southern Mexico. Mosquitoes, bats, and rodents were captured in Calakmul (Campeche) and Montes Azules (Chiapas), between November 2010 and August 2011. Spleen samples from 146 bats and 14 rodents were tested for molecular evidence of Venezuelan equine encephalitis virus (VEEV), eastern equine encephalitis virus (EEEV), western equine encephalitis virus (WEEV), and West Nile virus (WNV) using PCR protocols. Bat ( Artibeus lituratus , Carollia sowelli , Glossophaga soricina , and Sturnira parvidens) and rodent ( Sigmodon hispidus and Oryzomys alfaroi ) species were positive for VEEV. No individuals were positive for WNV, EEEV, or WEEV. A total of 1,298 mosquitoes were collected at the same sites, and five of the mosquito species collected were known VEEV vectors (Aedes fulvus, Mansonia indubitans, Psorophora ferox, Psorophora cilipes, and Psorophora confinnis). This survey simultaneously presents the first molecular evidence, to our knowledge, of VEEV in bats and rodents from southern Mexico and the identification of potential sympatric vectors. Studies investigating sympatric nonhuman hosts, vectors, and arboviruses must be expanded to determine arboviral dynamics in complex systems in which outbreaks of emerging and reemerging zoonoses are continuously occurring.

The first detection of the tick-borne encephalitis virus (TBEV) RNA in Dermacentor reticulatus ticks collected from the lowland European bison (Bison bonasus bonasus L.).

PubMed

Biernat, Beata; Karbowiak, Grzegorz; Stańczak, Joanna; Masny, Aleksander; Werszko, Joanna

2016-01-01

Tick borne encephalitis virus (TBEV) (Flaviviridae, Flavivirus) is the causative agent of tick-borne encephalitis (TBE), a potentially fatal neurological infection. The disease is endemic in a large region in Eurasia, where is transmitted mainly by hard ticks: Ixodes ricinus and I. persulcatus. It is known that also Dermacentor reticulatus is involved in a circulation of TBEV, but the knowledge of its importance in the TBE epidemiology is still insufficient. The Białowieża Primeval Forest is located in eastern Poland and it is a well-known endemic focus of tick-borne encephalitis. The aim of this study was to identify the prevalence of tick-borne encephalitis virus (TBEV) in Dermacentor reticulatus ticks collected from European bison (Bison bonasus bonasus), an important host of hard ticks in the Białowieża Primeval Forest. In the years 2008-2009, a total of 114 adult D. reticulatus ticks were collected from 7 European bison and examined individually for the presence of TBEV RNA using nested RT-PCR assay. Positive results were noted in 18.42% of ticks. This is the first record of TBEV infection in ticks collected from European bison.

Herpes Simplex Virus-1 Encephalitis in Adults: Pathophysiology, Diagnosis, and Management.

PubMed

Bradshaw, Michael J; Venkatesan, Arun

2016-07-01

Herpetic infections have plagued humanity for thousands of years, but only recently have advances in antiviral medications and supportive treatments equipped physicians to combat the most severe manifestations of disease. Prompt recognition and treatment can be life-saving in the care of patients with herpes simplex-1 virus encephalitis, the most commonly identified cause of sporadic encephalitis worldwide. Clinicians should be able to recognize the clinical signs and symptoms of the infection and familiarize themselves with a rational diagnostic approach and therapeutic modalities, as early recognition and treatment are key to improving outcomes. Clinicians should also be vigilant for the development of acute complications, including cerebral edema and status epilepticus, as well as chronic complications, including the development of autoimmune encephalitis associated with antibodies to the N-methyl-D-aspartate receptor and other neuronal cell surface and synaptic epitopes. Herein, we review the pathophysiology, differential diagnosis, and clinical and radiological features of herpes simplex virus-1 encephalitis in adults, including a discussion of the most common complications and their treatment. While great progress has been made in the treatment of this life-threatening infection, a majority of patients will not return to their previous neurologic baseline, indicating the need for further research efforts aimed at improving the long-term sequelae.

Serological and molecular epidemiology of Japanese encephalitis virus infections in swine herds in China, 2006-2012.

PubMed

Chai, Chunxia; Wang, Qiao; Cao, Sanjie; Zhao, Qin; Wen, Yiping; Huang, Xiaobo; Wen, Xintian; Yan, Qiguai; Ma, Xiaoping; Wu, Rui

2018-01-31

Japanese encephalitis virus (JEV) is a mosquito-borne, zoonotic flavivirus causing viral encephalitis in humans and reproductive disorder in swine. JEV is prevalent throughout China in human; however, spatiotemporal analysis of JEV in Chinese swine herds has not been reported previously. Herein, we present serological and molecular epidemiological results and estimates of prevalence of JEV infections among swine herds in various regions of China. The results suggest that JEV infections are widespread and genotype I and III strains co-exist in the same regions. Therefore, there is an urgent need to monitor JEV infection status among swine herds in China.

Serological and molecular epidemiology of Japanese encephalitis virus infections in swine herds in China, 2006–2012

PubMed Central

Chai, Chunxia; Wang, Qiao; Cao, Sanjie; Zhao, Qin; Wen, Yiping; Huang, Xiaobo; Wen, Xintian; Yan, Qiguai; Ma, Xiaoping

2018-01-01

Japanese encephalitis virus (JEV) is a mosquito-borne, zoonotic flavivirus causing viral encephalitis in humans and reproductive disorder in swine. JEV is prevalent throughout China in human; however, spatiotemporal analysis of JEV in Chinese swine herds has not been reported previously. Herein, we present serological and molecular epidemiological results and estimates of prevalence of JEV infections among swine herds in various regions of China. The results suggest that JEV infections are widespread and genotype I and III strains co-exist in the same regions. Therefore, there is an urgent need to monitor JEV infection status among swine herds in China. PMID:28693301

Countermeasure development for Rift Valley fever: deletion, modification or targeting of major virulence factor NSs.

PubMed

Lihoradova, Olga; Ikegami, Tetsuro

2014-01-01

Rift Valley fever (RVF) is a mosquito-borne zoonotic disease characterized by a high rate of abortion in ruminants, and febrile illness, hemorrhagic fever, retinitis and encephalitis in humans. RVF is caused by the RVF virus (RVFV), belonging to the genus Phlebovirus of the family Bunyaviridae . RVFV encodes a major virulence factor, NSs , which is dispensable for viral replication, yet required for evasion of host innate immune responses. RVFV NSs inhibits host gene upregulation at the transcriptional level, while promoting viral translation in the cytoplasm. In this article, we summarize the virology and pathology of RVF, and countermeasure development for RVF, with emphasis on NSs function and applications.

Countermeasure development for Rift Valley fever: deletion, modification or targeting of major virulence factor NSs

PubMed Central

Lihoradova, Olga; Ikegami, Tetsuro

2014-01-01

Rift Valley fever (RVF) is a mosquito-borne zoonotic disease characterized by a high rate of abortion in ruminants, and febrile illness, hemorrhagic fever, retinitis and encephalitis in humans. RVF is caused by the RVF virus (RVFV), belonging to the genus Phlebovirus of the family Bunyaviridae. RVFV encodes a major virulence factor, NSs, which is dispensable for viral replication, yet required for evasion of host innate immune responses. RVFV NSs inhibits host gene upregulation at the transcriptional level, while promoting viral translation in the cytoplasm. In this article, we summarize the virology and pathology of RVF, and countermeasure development for RVF, with emphasis on NSs function and applications. PMID:24910709

TC-83 vaccine protects against airborne or subcutaneous challenge with heterologous mouse-virulent strains of Venezuelan equine encephalitis virus.

PubMed

Phillpotts, R J; Wright, A J

1999-02-26

Vaccination with TC-83 virus produced solid protection against subcutaneous challenge with Venezuelan equine encephalitis (VEEV) viruses from homologous and heterologous serogroups, but breakthrough infection and disease occurred after airborne challenge. Breakthrough occurred more often with time after vaccination, and was more frequent with epizootic, homologous serogroup 1A/B viruses than with enzootic, heterologous serogroup viruses. A decrease in VEEV-specific IgA levels in the respiratory tract of vaccinated mice may explain the increased frequency of breakthrough with time after vaccination. However increased breakthrough with the highly virulent homologous serogroup 1A/B viruses (compared to less virulent viruses from heterologous serogroups) may be a consequence of their greater ability to invade the brain via the olfactory neuroepithelium and olfactory nerve.

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

Gardner, S; Jaing, C

The goal of this project is to develop forensic genotyping assays for select agent viruses, addressing a significant capability gap for the viral bioforensics and law enforcement community. We used a multipronged approach combining bioinformatics analysis, PCR-enriched samples, microarrays and TaqMan assays to develop high resolution and cost effective genotyping methods for strain level forensic discrimination of viruses. We have leveraged substantial experience and efficiency gained through year 1 on software development, SNP discovery, TaqMan signature design and phylogenetic signature mapping to scale up the development of forensics signatures in year 2. In this report, we have summarized the Taqmanmore » signature development for South American hemorrhagic fever viruses, tick-borne encephalitis viruses and henipaviruses, Old World Arenaviruses, filoviruses, Crimean-Congo hemorrhagic fever virus, Rift Valley fever virus and Japanese encephalitis virus.« less

St. Louis Encephalitis

MedlinePlus

... and Treatment Diagnosis Links & References Fact Sheet Other diseases transmitted by mosquitoes Chikungunya virus Dengue Eastern Equine Encephalitis ... Emerging and Zoonotic Infectious Diseases (NCEZID) Division of Vector-Borne Diseases (DVBD) Email Recommend Tweet YouTube Instagram Listen Watch ...

75 FR 54888 - Determination of Regulatory Review Period for Purposes of Patent Extension; IXIARO

Federal Register 2010, 2011, 2012, 2013, 2014

2010-09-09

... marketing the human biologic product IXIARO (Japanese Encephalitis Virus, Vaccine Inactivated, Adsorbed). IXIARO is indicated for active immunization for the prevention of disease caused by Japanese encephalitis...

Development of a Genetically Engineered Venezuelan Equine Encephalitis Virus Vaccine

DTIC Science & Technology

1991-04-15

antibody neutralization titers of sera from the TC-5A immunized horses ranged from 64 to > 128; however, the sera did not neutralize the equine virulent VEE...human adenovirus 5 DNA. Virology 52:456-467. Groot, H. 1972. The health and economic impact of Venezuelan equine encephalitis (VEE). p. 7-16. In... equine encephalitis (VEE). p. 7-16. In Venezuelan Encephalitis, Sci. Pub. 243, Pan American Health Organization, Washington, D.C. Hunt, A.R., Johnson, A.J

Distinction between serological responses following tick-borne encephalitis virus (TBEV) infection vs vaccination, Sweden 2017.

PubMed

Albinsson, Bo; Vene, Sirkka; Rombo, Lars; Blomberg, Jonas; Lundkvist, Åke; Rönnberg, Bengt

2018-01-01

Tick-borne encephalitis virus (TBEV) is an important European vaccine-preventable pathogen. Discrimination of vaccine-induced antibodies from those elicited by infection is important. We studied anti-TBEV IgM/IgG responses, including avidity and neutralisation, by multiplex serology in 50 TBEV patients and 50 TBEV vaccinees. Infection induced antibodies reactive to both whole virus (WV) and non-structural protein 1 (NS1) in 48 clinical cases, whereas 47 TBEV vaccinees had WV, but not NS1 antibodies, enabling efficient discrimination of infection/vaccination.

Fatal human eosinophilic meningo-encephalitis caused by CNS co-infection with Halicephalobus gingivalis and West Nile virus.

PubMed

Anwar, M A; Gokozan, H N; Ball, M K; Otero, J; McGwire, B S

2015-10-01

The saprophytic nematode Halicephalobus is a rare cause of fatal human meningo-encephalitis, and West Nile virus is neurotropic flavivirus implicated in a variety of clinical neurologic syndromes. Here we report a case of rapidly progressive CNS encephalopathy and death. Serologic, immuno-histochemical, histopathologic and nucleic acid studies demonstrate the presence of active Halicephalobus and West Nile virus in the CNS tissue. This is the first reported case of co-infection with these neurotropic pathogens. Copyright © 2015. Published by Elsevier Ireland Ltd.

Infectious Causes and Infectious Mimics of Acute Encephalitis: a Prospective Study from Thailand

PubMed Central

Skulsujirapa, Benjawan; Wacharapluesadee, Supaporn; Petcharat, Sininat; Hemachudha, Thiravat; Wasontiwong, Abhinbhen Saraya; Putcharoen, Opass

2017-01-01

Abstract Background Previous reports of infectious encephalitis in Thailand showed viruses as major pathogens similar to worldwide data. Major viruses in studies varied among Japanese encephalitis, Enteroviruses and Herpesviruses. Infectious etiologies vary by regions, seasons and preventive strategies done. Dynamic change of pathogen is believed to occur continually. Local data in each region is important to develop an algorithm of investigations for the cost-effectiveness. Methods This is a prospective study of patients with encephalitis between January 2014 to March 2017 at a tertiary hospital in Bangkok. Microbiological and serological studies were done according to an algorithm based on initial cerebrospinal fluid analysis. Initial tests were for bacteria, fungus, mycobacterium and commonly prevalent viruses. Further tests for infectious etiology were done by stepwise approach if initial tests yielded negative. Results Fifty-two patients were enrolled. Twenty-seven (51.9%) patients had no etiology identified. Three patients (5.8%) had bacterial etiology, 10 (19.2%) had viral etiology, and 12 (23%) had immune-mediated encephalitis. Among viral etiologies, VZV was identified in 4 cases, HSV in 3 cases, CMV in 2 cases and measles in 1 case. Baseline characteristic of HIV infection or skin rash was associated with viral infection (p 0.031, p 0.006). Patients with VZV encephalitis might not have active skin lesion. The presence of prodrome, duration of prodrome, neurological onset to peak and physical examination of focal neurodeficit, meningeal irritation signs, and reflex were similar across all etiologies. White blood cell [mean 7.0 (range 0–30) cells/µL] and protein [mean 32.5 (range 11–70.4) mg/dL] from the cerebrospinal fluid of noninfectious etiologies tended to be lower than the levels of infectious causes (p 0.009, p 0.020). All patients survived at 7 days after admission. Conclusion A quarter of patients presenting with acute encephalitis in this study had autoimmune and paraneoplastic encephalitis. Infections caused by herpesviruses was the most prevalent viral etiology. Autoimmune and paraneoplastic encephalitis should be kept in the differential diagnosis in patients with acute encephalitis. Disclosures S. Wacharapluesadee, USAID: Investigator, Research grant. O. Putcharoen, USAID: Grant Investigator, Research grant.

Immunogenicity of combination DNA vaccines for Rift Valley fever virus, tick-borne encephalitis virus, Hantaan virus, and Crimean Congo hemorrhagic fever virus.

PubMed

Spik, Kristin; Shurtleff, Amy; McElroy, Anita K; Guttieri, Mary C; Hooper, Jay W; SchmalJohn, Connie

2006-05-22

DNA vaccines for Rift Valley fever virus (RVFV), Crimean Congo hemorrhagic fever virus (CCHFV), tick-borne encephalitis virus (TBEV), and Hantaan virus (HTNV), were tested in mice alone or in various combinations. The bunyavirus vaccines (RVFV, CCHFV, and HTNV) expressed Gn and Gc genes, and the flavivirus vaccine (TBEV) expressed the preM and E genes. All vaccines were delivered by gene gun. The TBEV DNA vaccine and the RVFV DNA vaccine elicited similar levels of antibodies and protected mice from challenge when delivered alone or in combination with other DNAs. Although in general, the HTNV and CCHFV DNA vaccines were not very immunogenic in mice, there were no major differences in performance when given alone or in combination with the other vaccines.

Cross-protection between West Nile and Japanese encephalitis viruses in red-winged blackbirds (Agelaius phoeniceus).

PubMed

Nemeth, Nicole M; Bosco-Lauth, Angela M; Bowen, Richard A

2009-09-01

Similar to West Nile virus (WNV), Japanese encephalitis virus (JEV) has a history of intercontinental spread, and birds are important for the maintenance and transmission of both of these closely related viruses. We examined viremic and serologic responses of blackbirds (Agelaius phoeniceus), with and without immunity to WNV, following experimental inoculation with two strains of JEV. Japanese encephalitis (JE) viremia was detected in only one of 16 (6.3%) WNV-immune birds, while all 16 nonimmune birds had detectable JE viremia. Two weeks after JEV inoculation, all birds without pre-existing WNV immunity had clearly distinguishable anti-JEV antibodies, while in all birds with pre-existing WNV immunity, antibodies to WNV and JEV were either indistinguishable or the anti-WNV antibody titers were significantly higher. As WNV is endemic throughout much of North America, WNV immunity among birds may dampen transmission while complicating the serologic diagnosis of JEV, should this pathogen be introduced to North America.

Powassan virus infection: case series and literature review from a single institution.

PubMed

Raval, Mihir; Singhal, Mayank; Guerrero, Dubert; Alonto, Augusto

2012-10-30

Powassan virus is a flavivirus related to eastern hemisphere's tick-borne encephalitis viruses. It can cause a rare but potentially life-threatening disease including encephalitis. We report four cases of POWV infection in Minnesota and North Dakota with known exposure to tick bites in 2011. Our first case was an 18-year-old male who dramatically presented with seizure and headache with positive serum analysis for Powassan virus immunoglobulin M. The second case was a 60 year old gentleman with intraparenchymal hemorrhage and was diagnosed via cerebrospinal fluid analysis. Thirdly, a 61 year old male developed altered mental status and encephalitis. Our fourth patient was a 69 year old male who had headache and non-focal weakness who was diagnosed with serum analysis. Symptoms of Powassan virus infection ranged from headaches to seizures and severe neurological symptoms. This study serves to highlight the increased detection of Powassan virus infection in the central north United States. This report focuses on the increasing incidence that can lead to increasing efforts for raising awareness regarding this infection. There is a need for clinician vigilance and public attention due to its increasing detection, westward progression and varied clinical presentations.

Occurrence of antibodies anti -Toxoplasma gondii, Neospora caninum and Leptospira interrogans in a captive deer herd in Southern Brazil.

PubMed

Zimpel, Cristina Kraemer; Grazziotin, Ana Laura; de Barros Filho, Ivan Roque; Guimaraes, Ana Marcia de Sa; dos Santos, Leonilda Correia; de Moraes, Wanderlei; Cubas, Zalmir Silvino; de Oliveira, Marcos Jose; Pituco, Edviges Maristela; Lara, Maria do Carmo Custódio de Souza Hunold; Villalobos, Eliana Monteforte Cassaro; Silva, Lília Marcia Paulin; Cunha, Elenice Maria Sequetin; Castro, Vanessa; Biondo, Alexander Welker

2015-01-01

A large number of Brazilian zoos keep many endangered species of deer, however, very few disease surveillance studies have been conducted among captive cervids. Blood samples from 32 Brazilian deer (Blastocerus dichotomus, Mazama nana and Mazama americana) kept in captivity at Bela Vista Biological Sanctuary (Foz do Iguaçu, Brazil) were investigated for 10 ruminant pathogens, with the aims of monitoring deer health status and evaluating any potential zoonotic risk. Deer serum samples were tested for Brucella abortus, Leptospira (23 serovars), Toxoplasma gondii, Neospora caninum, bovine viral diarrhea virus, infectious bovine rhinotracheitis virus, foot-and-mouth disease virus, western equine encephalitis virus, eastern equine encephalitis virus and Venezuelan equine encephalitis virus. Antibodies against T. gondii (15.6%), N. caninum (6.2%) and L. interrogans serogroup Serjoe (3.1%) were detected. The serological results for all other infectious agents were negative. The deer were considered to be clinically healthy and asymptomatic regarding any disease. Compared with studies on free-ranging deer, the prevalences of the same agents tested among the captive deer kept at the Sanctuary were lower, thus indicating good sanitary conditions and high-quality management practices at the zoo.

Opsoclonus myoclonus syndrome: an unusual presentation for West Nile virus encephalitis

PubMed Central

Afzal, Aasim; Ashraf, Sahar

2014-01-01

A record number of West Nile virus (WNV) cases and fatalities seen in 2012 have brought to light the numerous manifestations of neuroinvasive disease. We report a case of opsoclonus myoclonus syndrome attributed to WNV and its clinical course after treatment with a combination of steroids and intravenous immunoglobulin. Our objective is to highlight opsoclonus myoclonus syndrome as a potential manifestation of WNV encephalitis. PMID:24688189

Acute retinal necrosis results in low vision in a young patient with a history of herpes simplex virus encephalitis.

PubMed

Shahi, Sanjeet K

2017-05-01

Acute retinal necrosis (ARN), secondary to herpes simplex encephalitis, is a rare syndrome that can present in healthy individuals, as well as immuno-compromised patients. Most cases are caused by a secondary infection from the herpes virus family, with varicella zoster virus being the leading cause of this syndrome. Potential symptoms include blurry vision, floaters, ocular pain and photophobia. Ocular findings may consist of severe uveitis, retinal vasculitis, retinal necrosis, papillitis and retinal detachment. Clinical manifestations of this disease may include increased intraocular pressure, optic disc oedema, optic neuropathy and sheathed retinal arterioles. A complete work up is essential to rule out cytomegalovirus retinitis, herpes simplex encephalitis, herpes virus, syphilis, posterior uveitis and other conditions. Depending on the severity of the disease, the treatment options consist of anticoagulation therapy, cycloplegia, intravenous acyclovir, systemic steroids, prophylactic laser photocoagulation and pars plana vitrectomy with silicon oil for retinal detachment. An extensive history and clinical examination is crucial in making the correct diagnosis. Also, it is very important to be aware of low vision needs and refer the patients, if expressing any sort of functional issues with completing daily living skills, especially reading. In this article, we report one case of unilateral ARN 20 years after herpetic encephalitis. © 2016 Optometry Australia.

Following Acute Encephalitis, Semliki Forest Virus is Undetectable in the Brain by Infectivity Assays but Functional Virus RNA Capable of Generating Infectious Virus Persists for Life.

PubMed

Fragkoudis, Rennos; Dixon-Ballany, Catherine M; Zagrajek, Adrian K; Kedzierski, Lukasz; Fazakerley, John K

2018-05-18

Alphaviruses are mosquito-transmitted RNA viruses which generally cause acute disease including mild febrile illness, rash, arthralgia, myalgia and more severely, encephalitis. In the mouse, peripheral infection with Semliki Forest virus (SFV) results in encephalitis. With non-virulent strains, infectious virus is detectable in the brain, by standard infectivity assays, for around ten days. As we have shown previously, in severe combined immunodeficient (SCID) mice, infectious virus is detectable for months in the brain. Here we show that in MHC-II -/- mice, with no functional CD4 T-cells, infectious virus is also detectable in the brain for long periods. In contrast, in the brains of CD8 -/- mice, virus RNA persists but infectious virus is not detectable. In SCID mice infected with SFV, repeated intraperitoneal administration of anti-SFV immune serum rapidly reduced the titer of infectious virus in the brain to undetectable, however virus RNA persisted. Repeated intraperitoneal passive transfer of immune serum resulted in maintenance of brain virus RNA, with no detectable infectious virus, for several weeks. When passive antibody transfer was stopped, antibody levels declined and infectious virus was again detectable in the brain. In aged immunocompetent mice, previously infected with SFV, immunosuppression of antibody responses many months after initial infection also resulted in renewed ability to detect infectious virus in the brain. In summary, antiviral antibodies control and determine whether infectious virus is detectable in the brain but immune responses cannot clear this infection from the brain. Functional virus RNA capable of generating infectious virus persists and if antibody levels decline, infectious virus is again detectable.

Emerging Cases of Powassan Virus Encephalitis in New England: Clinical Presentation, Imaging, and Review of the Literature.

PubMed

Piantadosi, Anne; Rubin, Daniel B; McQuillen, Daniel P; Hsu, Liangge; Lederer, Philip A; Ashbaugh, Cameron D; Duffalo, Chad; Duncan, Robert; Thon, Jesse; Bhattacharyya, Shamik; Basgoz, Nesli; Feske, Steven K; Lyons, Jennifer L

2016-03-15

Powassan virus (POWV) is a rarely diagnosed cause of encephalitis in the United States. In the Northeast, it is transmitted by Ixodes scapularis, the same vector that transmits Lyme disease. The prevalence of POWV among animal hosts and vectors has been increasing. We present 8 cases of POWV encephalitis from Massachusetts and New Hampshire in 2013-2015. We abstracted clinical and epidemiological information for patients with POWV encephalitis diagnosed at 2 hospitals in Massachusetts from 2013 to 2015. We compared their brain imaging with those in published findings from Powassan and other viral encephalitides. The patients ranged in age from 21 to 82 years, were, for the most part, previously healthy, and presented with syndromes of fever, headache, and altered consciousness. Infections occurred from May to September and were often associated with known tick exposures. In all patients, cerebrospinal fluid analyses showed pleocytosis with elevated protein. In 7 of 8 patients, brain magnetic resonance imaging demonstrated deep foci of increased T2/fluid-attenuation inversion recovery signal intensity. We describe 8 cases of POWV encephalitis in Massachusetts and New Hampshire in 2013-2015. Prior to this, there had been only 2 cases of POWV encephalitis identified in Massachusetts. These cases may represent emergence of this virus in a region where its vector, I. scapularis, is known to be prevalent or may represent the emerging diagnosis of an underappreciated pathogen. We recommend testing for POWV in patients who present with encephalitis in the spring to fall in New England. © The Author 2015. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

Diagnostic Approach to Viral Acute Encephalitis Syndrome (AES) in Paediatric Age Group: A Study from New Delhi.

PubMed

Goel, Shipra; Chakravarti, Anita; Mantan, Mukta; Kumar, Surinder; Ashraf, Md Anzar

2017-09-01

Acute Encephalitis Syndrome has heralded the emergence of multiple virulent pathogens, which may result in severe morbidity and mortality. In India, encephalitis is not notified and there has been a dearth of analysis for trends in encephalitis death rates and causation. A downward trend has been observed in encephalitis deaths, due to 'known' causes, which can be largely explained by improvement in diagnostic, treatment, and prevention methods. There is still a very high proportion of encephalitis deaths in developing countries, where the aetiological diagnosis of the pathogen is not established and thus, lies the importance of monitoring encephalitis morbidity and mortality with a view to improve pathogen diagnosis and identify emerging infectious diseases. To formulate a diagnostic approach to viral acute encephalitis syndrome in paediatric age group. A cross-sectional study including 50 paediatric patients, clinically diagnosed with acute encephalitis syndrome using WHO criteria was conducted. The CSF of all the patients was evaluated to diagnose the aetiology for viral pathogens. ELISA was used for diagnosing Japanese encephalitis and dengue encephalitis; and multiplex real time PCR was used for detecting HSV-1, HSV-2, Varicella zoster virus, Mumps virus, Enterovirus and Parechovirus. Confirmed diagnosis was established in 11 (22%) of 50 cases. A confirmed or probable viral agent of encephalitis was found in 7 (14%), bacterial agent was found in 2 (4%), non-infectious aetiology was found in 2 (4%). Fatal outcome was independently associated with patient age. Despite extensive testing, the aetiologies of more than three fourth of the cases remains elusive. Nevertheless the result from the present study may be useful for future design of early diagnosis and treatment of the disease. New strategies for pathogen identification and continued analysis of clinical features and case histories should help us improve our ability to diagnose, treat and prevent encephalitis.

Nucleotide and deduced amino acid sequence of the envelope gene of the Vasilchenko strain of TBE virus; comparison with other flaviviruses.

PubMed

Gritsun, T S; Frolova, T V; Pogodina, V V; Lashkevich, V A; Venugopal, K; Gould, E A

1993-02-01

A strain of tick-borne encephalitis virus known as Vasilchenko (Vs) exhibits relatively low virulence characteristics in monkeys, Syrian hamsters and humans. The gene encoding the envelope glycoprotein of this virus was cloned and sequenced. Alignment of the sequence with those of other known tick-borne flaviviruses and identification of the recognised amino acid genetic marker EHLPTA confirmed its identity as a member of the TBE complex. However, Vs virus was distinguishable from eastern and western tick-borne serotypes by the presence of the sequence AQQ at amino acid positions 232-234 and also by the presence of other specific amino acid substitutions which may be genetic markers for these viruses and could determine their pathogenetic characteristics. When compared with other tick-borne flaviviruses, Vs virus had 12 unique amino acid substitutions including an additional potential glycosylation site at position (315-317). The Vs virus strain shared closest nucleotide and amino acid homology (84.5% and 95.5% respectively) with western and far eastern strains of tick-borne encephalitis virus. Comparison with the far eastern serotype of tick-borne encephalitis virus, by cross-immunoelectrophoresis of Vs virions and PAGE analysis of the extracted virion proteins, revealed differences in surface charge and virus stability that may account for the different virulence characteristics of Vs virus. These results support and enlarge upon previous data obtained from molecular and serological analysis.

Analytical validation of viral CNS Flow Chip kit for detection of acute meningitis and encephalitis.

PubMed

Pérez-Ruiz, Mercedes; Pedrosa-Corral, Irene; Sanbonmatsu-Gámez, Sara; Gómez-Camarasa, Cristina; Navarro-Marí, José María

2018-06-12

A new molecular assay (Viral CNS Flow Chip kit, Master Diagnóstica, Spain) has been developed for the detection of eight viruses causing acute meningitis and encephalitis, i.e. herpes simplex viruses 1-2, varicella zoster virus, human enterovirus, human parechovirus, Toscana virus, human cytomegalovirus and Epstein Barr virus. The new assay is a multiplex one-step RT-PCR followed by automatic flow-through hybridization, colorimetric detection and image analysis. The limit of detection was 50 copies/reaction, and 10 copies/reaction for human enterovirus and the other seven viruses, respectively. The analytical validation was performed with nucleic acids extracted from 268 cerebrospinal fluid samples and the results were compared with routine molecular assays. An excellent coefficient of agreement was observed between V-CNS and routine assays [kappa index: 0.948 (95%CI: 0.928-0.968)]. The overall sensitivity and specificity was 95.9% (95%CI: 91.2-98.3%) and 99.9% (95%CI: 99.6-100%), respectively. Viral CNS Flow Chip kit is an efficient multiplex platform for the detection of the main viruses involved in acute meningitis and encephalitis. The inclusion of a TOSV genome target may improve the laboratory diagnosis of viral neurological infections in endemic areas. Copyright © 2018 Elsevier B.V. All rights reserved.

Persistent West Nile Virus Transmission and the Apparent Displacement St. Louis Encephalitis Virus in Southeastern California, 2003−2006

PubMed Central

REISEN, WILLIAM K.; LOTHROP, HUGH D.; WHEELER, SARAH S.; KENNSINGTON, MARC; GUTIERREZ, ARTURO; FANG, YING; GARCIA, SANDRA; LOTHROP, BRANKA

2008-01-01

West Nile virus (family Flaviviridae, genus Flavivirus, WNV) invaded the Colorado Desert biome of southern California during summer 2003 and seemed to displace previously endemic St. Louis encephalitis virus (family Flaviviridae, genus Flavivirus, SLEV, an antigenically similar Flavivirus in the Japanese encephalitis virus serocomplex). Western equine encephalomyelitis virus (family Togaviridae, genus Alphavirus, WEEV), an antigenically distinct Alphavirus, was detected during 2005 and 2006, indicating that conditions were suitable for encephalitis virus introduction and detection. Cross-protective “avian herd immunity” due to WNV infection possibly may have prevented SLEV reintroduction and/or amplification to detectable levels. During 2003−2006, WNV was consistently active at wetlands and agricultural habitats surrounding the Salton Sea where Culex tarsalis Coquillett served as the primary enzootic maintenance and amplification vector. Based on published laboratory infection studies and the current seroprevalence estimates, house sparrows, house finches, and several Ardeidae may have been important avian amplifying hosts in this region. Transmission efficiency may have been dampened by high infection rates in incompetent avian hosts, including Gamble's quail, mourning doves, common ground doves, and domestic pigeons. Early season WNV amplification and dispersal from North Shore in the southeastern portion of the Coachella Valley resulted in sporadic WNV incursions into the urbanized Upper Valley near Palm Springs, where Culex pipiens quinquefasciatus Say was the primary enzootic and bridge vector. Although relatively few human cases were detected during the 2003−2006 period, all were concentrated in the Upper Valley and were associated with high human population density and WNV infection in peridomestic populations of Cx. p. quinquefasciatus. Intensive early mosquito control during 2006 seemed to interrupt and delay transmission, perhaps setting the stage for the future reintroduction of SLEV. PMID:18533445

Three-dimensional morphometric analysis of microglial changes in a mouse model of virus encephalitis: age and environmental influences.

PubMed

de Sousa, Aline A; Dos Reis, Renata R; de Lima, Camila M; de Oliveira, Marcus A; Fernandes, Taiany N; Gomes, Giovanni F; Diniz, Daniel G; Magalhães, Nara M; Diniz, Cristovam G; Sosthenes, Marcia C K; Bento-Torres, João; Diniz, José Antonio P; Vasconcelos, Pedro F da C; Diniz, Cristovam Wanderley P

2015-08-01

Many RNA virus CNS infections cause neurological disease. Because Piry virus has a limited human pathogenicity and exercise reduces activation of microglia in aged mice, possible influences of environment and aging on microglial morphology and behavior in mice sublethal encephalitis were investigated. Female albino Swiss mice were raised either in standard (S) or in enriched (EE) cages from age 2 to 6 months (young - Y), or from 2 to 16 months (aged - A). After behavioral tests, mice nostrils were instilled with Piry-virus-infected or with normal brain homogenates. Brain sections were immunolabeled for virus antigens or microglia at 8 days post-infection (dpi), when behavioral changes became apparent, and at 20 and 40 dpi, after additional behavioral testing. Young infected mice from standard (SYPy) and enriched (EYPy) groups showed similar transient impairment in burrowing activity and olfactory discrimination, whereas aged infected mice from both environments (EAPy, SAPy) showed permanent reduction in both tasks. The beneficial effects of an enriched environment were smaller in aged than in young mice. Six-hundred and forty microglial cells, 80 from each group were reconstructed. An unbiased, stereological sampling approach and multivariate statistical analysis were used to search for microglial morphological families. This procedure allowed distinguishing between microglial morphology of infected and control subjects. More severe virus-associated microglial changes were observed in young than in aged mice, and EYPy seem to recover microglial homeostatic morphology earlier than SYPy . Because Piry-virus encephalitis outcomes were more severe in aged mice, it is suggested that the reduced inflammatory response in those individuals may aggravate encephalitis outcomes. © 2015 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Laser Capture Microdissection Assessment of Virus Compartmentalization in the Central Nervous Systems of Macaques Infected with Neurovirulent Simian Immunodeficiency Virus

PubMed Central

Matsuda, Kenta; Brown, Charles R.; Foley, Brian; Goeken, Robert; Whitted, Sonya; Dang, Que; Wu, Fan; Plishka, Ronald; Buckler-White, Alicia

2013-01-01

Nonhuman primate-simian immunodeficiency virus (SIV) models are powerful tools for studying the pathogenesis of human immunodeficiency virus type 1 (HIV-1) in the brain. Our laboratory recently isolated a neuropathogenic viral swarm, SIVsmH804E, a derivative of SIVsmE543-3, which was the result of sequential intravenous passages of viruses isolated from the brains of rhesus macaques with SIV encephalitis. Animals infected with SIVsmH804E or its precursor (SIVsmH783Br) developed SIV meningitis and/or encephalitis at high frequencies. Since we observed macaques with a combination of meningitis and encephalitis, as well as animals in which meningitis or encephalitis was the dominant component, we hypothesized that distinct mechanisms could be driving the two pathological states. Therefore, we assessed viral populations in the meninges and the brain parenchyma by laser capture microdissection. Viral RNAs were isolated from representative areas of the meninges, brain parenchyma, terminal plasma, and cerebrospinal fluid (CSF) and from the inoculum, and the SIV envelope fragment was amplified by PCR. Phylogenetic analysis of envelope sequences from the conventional progressors revealed compartmentalization of viral populations between the meninges and the parenchyma. In one of these animals, viral populations in meninges were closely related to those from CSF and shared signature truncations in the cytoplasmic domain of gp41, consistent with a common origin. Apart from magnetic resonance imaging (MRI) and positron-emission tomography (PET) imaging, CSF is the most accessible assess to the central nervous system for HIV-1-infected patients. However, our results suggest that the virus in the CSF may not always be representative of viral populations in the brain and that caution should be applied in extrapolating between the properties of viruses in these two compartments. PMID:23720733

Human and Equine Infection with Alphaviruses and Flaviviruses in Panamá during 2010: A Cross-Sectional Study of Household Contacts during an Encephalitis Outbreak.

PubMed

Carrera, Jean-Paul; Bagamian, Karoun H; Travassos da Rosa, Amelia P; Wang, Eryu; Beltran, Davis; Gundaker, Nathan D; Armien, Blas; Arroyo, Gianfranco; Sosa, Néstor; Pascale, Juan Miguel; Valderrama, Anayansi; Tesh, Robert B; Vittor, Amy Y; Weaver, Scott C

2018-06-01

Members of the genera Alphavirus (family Togaviridae ) and Flavivirus (family Flaviridae ) are important zoonotic human and equine etiologic agents of neurologic diseases in the New World. In 2010, an outbreak of Madariaga virus (MADV; formerly eastern equine encephalitis virus) and Venezuelan equine encephalitis virus (VEEV) infections was reported in eastern Panamá. We further characterized the epidemiology of the outbreak by studying household contacts of confirmed human cases and of equine cases with neurological disease signs. Serum samples were screened using a hemagglutination inhibition test, and human results were confirmed using plaque reduction neutralization tests. A generalized linear model was used to evaluate the human MADV and VEEV seroprevalence ratios by age (in tercile) and gender. Overall, antibody prevalence for human MADV infection was 19.4%, VEEV 33.3%, and Mayaro virus 1.4%. In comparison with individuals aged 2-20 years, people from older age groups (21-41 and > 41 years) were five times more likely to have antibodies against VEEV, whereas the MADV prevalence ratio was independent of age. The overall seroprevalence of MADV in equids was 26.3%, VEEV 29.4%, West Nile virus (WNV) 2.6%, and St. Louis encephalitis virus (SLEV) was 63.0%. Taken together, our results suggest that multiple arboviruses are circulating in human and equine populations in Panamá. Our findings of a lack of increase in the seroprevalence ratio with age support the hypothesis of recent MADV exposure to people living in the affected region.

Critical role of microRNA-155 in herpes simplex encephalitis.

PubMed

Bhela, Siddheshvar; Mulik, Sachin; Reddy, Pradeep B J; Richardson, Raphael L; Gimenez, Fernanda; Rajasagi, Naveen K; Veiga-Parga, Tamara; Osmand, Alexander P; Rouse, Barry T

2014-03-15

HSV infection of adult humans occasionally results in life-threatening herpes simplex encephalitis (HSE) for reasons that remain to be defined. An animal system that could prove useful to model HSE could be microRNA-155 knockout (miR-155KO) mice. Thus, we observe that mice with a deficiency of miR-155 are highly susceptible to HSE with a majority of animals (75-80%) experiencing development of HSE after ocular infection with HSV-1. The lesions appeared to primarily represent the destructive consequences of viral replication, and animals could be protected from HSE by acyclovir treatment provided 4 d after ocular infection. The miR-155KO animals were also more susceptible to development of zosteriform lesions, a reflection of viral replication and dissemination within the nervous system. One explanation for the heightened susceptibility to HSE and zosteriform lesions could be because miR-155KO animals develop diminished CD8 T cell responses when the numbers, functionality, and homing capacity of effector CD8 T cell responses were compared. Indeed, adoptive transfer of HSV-immune CD8 T cells to infected miR-155KO mice at 24 h postinfection provided protection from HSE. Deficiencies in CD8 T cell numbers and function also explained the observation that miR-155KO animals were less able than control animals to maintain HSV latency. To our knowledge, our observations may be the first to link miR-155 expression with increased susceptibility of the nervous system to virus infection.

Cerebrospinal fluid cyto-/chemokine profile during acute herpes simplex virus induced anti-N-methyl-d-aspartate receptor encephalitis and in chronic neurological sequelae.

PubMed

Kothur, Kavitha; Gill, Deepak; Wong, Melanie; Mohammad, Shekeeb S; Bandodkar, Sushil; Arbunckle, Susan; Wienholt, Louise; Dale, Russell C

2017-08-01

To examine the cytokine/chemokine profile of cerebrospinal fluid (CSF) during acute herpes simplex virus-induced N-methyl-d-aspartate receptor (NMDAR) autoimmunity and in chronic/relapsing post-herpes simplex virus encephalitis (HSE) neurological syndromes. We measured longitudinal serial CSF cyto-/chemokines (n=34) and a glial marker (calcium-binding astroglial protein, S100B) in one patient during acute HSE and subsequent anti-NMDAR encephalitis, and compared the results with those from two patients with anti-NMDAR encephalitis without preceding HSE. We also compared cyto-/chemokines in cross-sectional CSF samples from three children with previous HSE who had ongoing chronic or relapsing neurological symptoms (2yr 9 mo-16y after HSE) with those in a group of children having non-inflammatory neurological conditions (n=20). Acute HSE showed elevation of a broad range of all T-helper-subset-related cyto-/chemokines and S100B whereas the post-HSE anti-NMDAR encephalitis phase showed persistent elevation of two of five T-helper-1 (chemokine [C-X-C motif] ligand 9 [CXCL9], CXCL10), three of five predominantly B-cell (CXCL13, CCL19, a proliferation-inducing ligand [APRIL])-mediated cyto-/chemokines, and interferon-α. The post-HSE anti-NMDAR encephalitis inflammatory response was more pronounced than anti-NMDAR encephalitis. All three chronic post-HSE cases showed persistent elevation of CXCL9, CXCL10, and interferon-α, and there was histopathological evidence of chronic lymphocytic inflammation in one biopsied case 7 years after HSE. Two of three chronic cases showed a modest response to immune therapy. HSE-induced anti-NMDAR encephalitis is a complex and pronounced inflammatory syndrome. There is persistent CSF upregulation of cyto-/chemokines in chronic or relapsing post-HSE neurological symptoms, which may be modifiable with immune therapy. The elevated cyto-/chemokines may be targets of monoclonal therapies. © 2017 Mac Keith Press.

Nipah Virus Infection Outbreak with Nosocomial and Corpse-to-Human Transmission, Bangladesh

PubMed Central

Hossain, M. Jahangir; Gurley, Emily S.; Ameen, Kazi M.H.; Parveen, Shahana; Islam, M. Saiful; Faruque, Labib I.; Podder, Goutam; Banu, Sultana S.; Lo, Michael K.; Rollin, Pierre E.; Rota, Paul A.; Daszak, Peter; Rahman, Mahmudur; Luby, Stephen P.

2013-01-01

Active Nipah virus encephalitis surveillance identified an encephalitis cluster and sporadic cases in Faridpur, Bangladesh, in January 2010. We identified 16 case-patients; 14 of these patients died. For 1 case-patient, the only known exposure was hugging a deceased patient with a probable case, while another case-patient’s exposure involved preparing the same corpse for burial by removing oral secretions and anogenital excreta with a cloth and bare hands. Among 7 persons with confirmed sporadic cases, 6 died, including a physician who had physically examined encephalitis patients without gloves or a mask. Nipah virus–infected patients were more likely than community-based controls to report drinking raw date palm sap and to have had physical contact with an encephalitis patient (29% vs. 4%, matched odds ratio undefined). Efforts to prevent transmission should focus on reducing caregivers’ exposure to infected patients’ bodily secretions during care and traditional burial practices. PMID:23347678

A decade of Japanese encephalitis surveillance in Sarawak, Malaysia: 1997-2006.

PubMed

Wong, See C; Ooi, Mong H; Abdullah, Abdul R; Wong, See Y; Krishnan, Shekhar; Tio, Phaik H; Pek, Peng C; Lai, Boon F; Mohan, Anand; Muhi, Jamail; Kiyu, Andrew; Arif, Mohamad T; Cardosa, Mary J

2008-01-01

Japanese encephalitis virus (JEV) is an important encephalitis virus in Asia, but there are few data on Malaysia. A hospital-based surveillance system for Japanese encephalitis (JE) has been in operation in Sarawak, Malaysia, for the last 10 years. JEV is endemic in Sarawak, with cases occurring throughout the year and a seasonal peak in the last quarter (one-way anova, P < 0.0001). Ninety-two per cent of 133 cases were children aged 12 years or younger; the introduction of JE vaccination in July 2001 reduced the number of JE cases (84 in the four seasons prior to vs. 49 in the six seasons after, McNemar's test, P = 0.0001). After implementation of the programme, the mean age of infected children increased from 6.3 to 8.0 years (Student's t-test, P = 0.0037), suggesting the need for a catch-up programme.

Japanese encephalitis in a racing thoroughbred gelding in Hong Kong.

PubMed

Lam, K H K; Ellis, T M; Williams, D T; Lunt, R A; Daniels, P W; Watkins, K L; Riggs, C M

2005-08-06

A horse in Hong Kong that had been vaccinated against Japanese encephalitis suffered a pyrexic episode that culminated in a hyperexcitable state and self-inflicted trauma. Japanese encephalitis was diagnosed on the basis of clinical, pathological and serological observations, and confirmed by the detection of genomic sequences of the virus in spinal cord tissue. Phylogenetic analyses of E gene and NS5-3'UTR sequences revealed divergent clustering of these segments with previously described genotypes, suggesting the possibility that the horse might have been infected with a recombinant between genotype I and genotype II viruses. Horses are considered to be dead-end hosts for the disease, but the occurrence of an infected horse in a population may have implications for the health status of the national herd. The effect that this case had on the horse industry in Hong Kong is discussed with specific reference to the movement of horses and the vaccination programme for Japanese encephalitis.

Cognitive and Learning Strategies for Longstanding Temporal Lobe Lesions in a Child Who Suffered from "Herpes Simplex" Virus Encephalitis: A Case Study over 10 Years

ERIC Educational Resources Information Center

van Schoor, A. N.; Naude, H.; van Rensburg, M.; Pretorius, E.; Boon, J. M.

2005-01-01

This article presents a case study indicating that "Herpes simplex" virus (HSV) encephalitis may cause permanent learning disabilities due to damage to the temporal lobes as it discusses the results of a case study extending over 10 years to determine the long-term effects on both the anatomy of the brain and the intellectual functioning of the…

Cognitive and Learning Strategies for Longstanding Temporal Lobe Lesions in a Child Who Suffered from "Herpes Simplex" Virus Encephalitis: A Case Study over 10 Years

ERIC Educational Resources Information Center

van Schoor, A. N.; Naude, H.; van Rensburg, M.; Pretorius, E.; Boon, J. M.

2004-01-01

This article presents a case study indicating that "Herpes simplex" virus (HSV) encephalitis may cause permanent learning disabilities due to damage to the temporal lobes, as it discusses the results of a case study extending over 10 years to determine the long-term effects on both the anatomy of the brain and the intellectual functioning of the…

Clinically severe Epstein-Barr virus encephalitis with mild cerebrospinal fluid abnormalities in an immunocompetent adolescent: a case report.

PubMed

Engelmann, Ilka; Nasser, Hala; Belmiloudi, Soufien; Le Guern, Rémi; Dewilde, Anny; Vallée, Louis; Hober, Didier

2013-06-01

A 15-year-old boy developed Epstein-Barr virus (EBV) encephalitis, a rare complication of infectious mononucleosis. The severe clinical picture and the marked neuroimaging changes were in contrast with mild cerebrospinal fluid abnormalities: leukocyte count was normal and protein level was only slightly elevated. EBV DNA was detected in cerebrospinal fluid by polymerase chain reaction. Copyright © 2013 Elsevier Inc. All rights reserved.

Management of adult infectious encephalitis in metropolitan France.

PubMed

Goulenok, T; Buzelé, R; Duval, X; Bruneel, F; Stahl, J P; Fantin, B

2017-05-01

Infectious encephalitis is a severe disease leading to a high mortality and morbidity. The most frequent causes include Herpes simplex virus, Varicella Zoster virus, Listeria monocytogenes, and Mycobacterium tuberculosis. Urgent treatment is required (anti-infective therapy and nonspecific supportive care). The aim of this study was to define treatment strategy, empirical and after microbiological documentation at 48hours, through a systematic literature review. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Postepizootic Persistence of Venezuelan Equine Encephalitis Virus, Venezuela

PubMed Central

Navarro, Juan-Carlos; Medina, Gladys; Vasquez, Clovis; Coffey, Lark L.; Wang, Eryu; Suárez, Alexander; Biord, Hernán; Salas, Marlene

2005-01-01

Five years after the apparent end of the major 1995 Venezuelan equine encephalitis (VEE) epizootic/epidemic, focal outbreaks of equine encephalitis occurred in Carabobo and Barinas States of western Venezuela. Virus isolates from horses in each location were nearly identical in sequence to 1995 isolates, which suggests natural persistence of subtype IC VEE virus (VEEV) strains in a genetically stable mode. Serologic evidence indicated that additional outbreaks occurred in Barinas State in 2003. Field studies identified known Culex (Melanoconion) spp. vectors and reservoir hosts of enzootic VEEV but a dearth of typical epidemic vectors. Cattle serosurveys indicated the recent circulation of enzootic VEEV strains, and possibly of epizootic strains. Persistence of VEEV subtype IC strains and infection of horses at the end of the rainy season suggest the possibility of an alternative, cryptic transmission cycle involving survival through the dry season of infected vectors or persistently infected vertebrates. PMID:16485478

Illnesses on the Rise From Mosquito, Tick, and Flea Bites

MedlinePlus

... gets sick has a vector-borne disease, like dengue, Zika, Lyme, or plague. Between 2004 and 2016, ... Mosquito-borne diseases California serogroup viruses Chikungunya virus Dengue viruses Eastern equine encephalitis virus Malaria plasmodium St. ...

Comparative genome analysis of Alkhumra hemorrhagic fever virus with Kyasanur forest disease and tick-borne encephalitis viruses by the in silico approach.

PubMed

Palanisamy, Navaneethan; Akaberi, Dario; Lennerstrand, Johan; Lundkvist, Åke

2018-05-10

Alkhumra hemorrhagic fever virus (AHFV), a relatively new member of the Flaviviruses, was discovered in Saudi Arabia 23 years ago. AHFV is classified in the tick-borne encephalitis virus serocomplex, along with the Kyasanur forest disease virus (KFDV) and tick-borne encephalitis virus (TBEV). Currently, very little is known about the pathologies of AHFV. In this study, using the available genome information of AHFV, KFDV and TBEV, we have predicted and compared the following aspects of these viruses: evolution, nucleotide and protein compositions, recombination, codon frequency, substitution rate, N- and O-glycosylation sites, signal peptide and cleavage site, transmembrane region, secondary structure of 5' and 3' UTRs and RNA-RNA interactions. Additionally, we have modeled the 3D protease and RNA-dependent RNA polymerase structures for AHFV, KFDV and TBEV. Recombination analysis showed no evidence of recombination in the AHFV genome with that of either KFDV or TBEV, although single break point analysis showed that nucleotide position 7399 (in the NS4B) is a breakpoint location. AHFV, KFDV and TBEV are very similar in terms of codon frequency, the number of transmembrane regions, properties of the polyprotein, RNA-RNA interaction sequences, NS3 protease and NS5 polymerase structures and 5' UTR structure. Using genome sequences, we showed the similarities between these closely- related viruses on several different areas.

Chikungunya virus-associated encephalitis: A cohort study on La Réunion Island, 2005-2009.

PubMed

Gérardin, Patrick; Couderc, Thérèse; Bintner, Marc; Tournebize, Patrice; Renouil, Michel; Lémant, Jérome; Boisson, Véronique; Borgherini, Gianandrea; Staikowsky, Frédérik; Schramm, Frédéric; Lecuit, Marc; Michault, Alain

2016-01-05

To estimate the cumulative incidence rate (CIR) of Chikungunya virus (CHIKV)-associated CNS disease during the La Réunion outbreak, and assess the disease burden and patient outcome after 3 years. CHIKV-associated CNS disease was characterized retrospectively in a cohort of patients with positive CHIKV reverse transcriptase PCR or anti-CHIKV immunoglobulin M antibodies in the CSF and fulfilling International Encephalitis Consortium criteria for encephalitis or encephalopathy. Neurologic sequelae were assessed after 3 years. Between September 2005 and June 2006, 57 patients were diagnosed with CHIKV-associated CNS disease, including 24 with CHIKV-associated encephalitis, the latter corresponding to a CIR of 8.6 per 100,000 persons. Patients with encephalitis were observed at both extremes of age categories. CIR per 100,000 persons were 187 and 37 in patients below 1 year and over 65 years, respectively, both far superior to those of cumulated causes of encephalitis in the United States in these age categories. The case-fatality rate of CHIKV-associated encephalitis was 16.6% and the proportion of children discharged with persistent disabilities estimated between 30% and 45%. Beyond the neonatal period, the clinical presentation and outcomes were less severe in infants than in adults. In the context of a large outbreak, CHIKV is a significant cause of CNS disease. As with other etiologies, CHIKV-associated encephalitis case distribution by age follows a U-shaped parabolic curve. © 2015 American Academy of Neurology.

Chemokine Receptor Ccr7 Restricts Fatal West Nile Virus Encephalitis.

PubMed

Bardina, Susana V; Brown, Julia A; Michlmayr, Daniela; Hoffman, Kevin W; Sum, Janet; Pletnev, Alexander G; Lira, Sergio A; Lim, Jean K

2017-05-15

West Nile virus (WNV) is a mosquito-transmitted flavivirus that can cause debilitating encephalitis. To delineate the mechanisms behind this pathology, we studied Ccr7-deficient mice, which afforded us the capacity to study infection in mice with disrupted peripheral cellular trafficking events. The loss of Ccr7 resulted in an immediate pan-leukocytosis that remained elevated throughout the infection. This leukocytosis resulted in a significant enhancement of leukocyte accumulation within the central nervous system (CNS). Despite an excess of virus-specific T cells in the CNS, Ccr7-deficient mice had significantly higher CNS viral loads and mortality rates than wild-type animals. Mechanistically, the elevated trafficking of infected myeloid cells into the brain in Ccr7-deficient mice resulted in increased levels of WNV in the CNS, thereby effectively contributing to neuroinflammation and lowering viral clearance. Combined, our experiments suggest that during WNV infection, Ccr7 is a gatekeeper for nonspecific viral transference to the brain. IMPORTANCE In this study, we show that Ccr7 is required for the sufficient migration of dendritic cells and T cells into the draining lymph node immediately following infection and for the restriction of leukocyte migration into the brain. Further, the severe loss of dendritic cells in the draining lymph node had no impact on viral replication in this organ, suggesting that WNV may migrate from the skin into the lymph node through another mechanism. Most importantly, we found that the loss of Ccr7 results in a significant leukocytosis, leading to hypercellularity within the CNS, where monocytes/macrophages contribute to CNS viremia, neuroinflammation, and increased mortality. Together, our data point to Ccr7 as a critical host defense restriction factor limiting neuroinflammation during acute viral infection. Copyright © 2017 American Society for Microbiology.

[Emerging viral diseases in Europe].

PubMed

Löbermann, M; Gürtler, L G; Eichler-Löbermann, B; Reisinger, E C

2012-04-01

Emergence of viral agents in Europe is influenced by various factors. Climatic changes influencing possible vectors, insufficient vaccination, and travel of man and goods are among the most important reasons to explain these changes. Fever and arthralgia are the leading symptoms in infection with Dengue, Sindbis, or Chikungunya virus. In contrast, tick-born encephalitis (TBE), Toscana, or West Nile virus infections mainly lead to meningo-encephalitis. In Europe, hemorrhagic fever is caused by Crimean Congo and Hanta virus. Protective vaccines are available for emerging viral agents like TBE, influenza and measles. © Georg Thieme Verlag KG Stuttgart · New York.

Emergence of zoonotic arboviruses by animal trade and migration

PubMed Central

2010-01-01

Arboviruses are transmitted in nature exclusively or to a major extend by arthropods. They belong to the most important viruses invading new areas in the world and their occurrence is strongly influenced by climatic changes due to the life cycle of the transmitting vectors. Several arboviruses have emerged in new regions of the world during the last years, like West Nile virus (WNV) in the Americas, Usutu virus (USUV) in Central Europe, or Rift Valley fever virus (RVFV) in the Arabian Peninsula. In most instances the ways of introduction of arboviruses into new regions are not known. Infections acquired during stays in the tropics and subtropics are diagnosed with increasing frequency in travellers returning from tropical countries, but interestingly no attention is paid on accompanying pet animals or the hematophagous ectoparasites that may still be attached to them. Here we outline the known ecology of the mosquito-borne equine encephalitis viruses (WEEV, EEEV, and VEEV), WNV, USUV, RVFV, and Japanese Encephalitis virus, as well as Tick-Borne Encephalitis virus and its North American counterpart Powassan virus, and will discuss the most likely mode that these viruses could expand their respective geographical range. All these viruses have a different epidemiology as different vector species, reservoir hosts and virus types have adapted to promiscuous and robust or rather very fine-balanced transmission cycles. Consequently, these viruses will behave differently with regard to the requirements needed to establish new endemic foci outside their original geographical ranges. Hence, emphasis is given on animal trade and suitable ecologic conditions, including competent vectors and vertebrate hosts. PMID:20377873

The first isolations of eastern encephalitis, group C, and Guama group arboviruses from the Peruvian Amazon region of western South America.

PubMed

Scherer, W F; Madalengoitia, J; Flores, W; Acosta, M

1975-01-01

Two strains of eastern encephalitis (EE) virus were isolated in the Amazon region of Peru near Pucallpa, Loreto Department, using sentinel hamsters. EE virus antibodies were found in healthy horses at both Pucallpa and Iquitos in the same Department. Fourteen group C and four Guama group arboviruses were recovered from sentenel hamsters and mosquitoes near Iquitos. The group C agents were Caraparu-Ossa, Marituba, and Oriboca-Itaqui viruses, and the Guama group agents were Bimiti virus. Besides providing a detailed account of these investigations, this article includes a current list of known arboviruses of the American tropics that can be detected with sentinel hamsters.

Detection of West Nile virus and tick-borne encephalitis virus in birds in Slovakia, using a universal primer set.

PubMed

Csank, Tomáš; Bhide, Katarína; Bencúrová, Elena; Dolinská, Saskia; Drzewnioková, Petra; Major, Peter; Korytár, Ľuboš; Bocková, Eva; Bhide, Mangesh; Pistl, Juraj

2016-06-01

West Nile virus (WNV) is a mosquito-borne neurotropic pathogen that presents a major public health concern. Information on WNV prevalence and circulation in Slovakia is insufficient. Oral and cloacal swabs and bird brain samples were tested for flavivirus RNA by RT-PCR using newly designed generic primers. The species designation was confirmed by sequencing. WNV was detected in swab and brain samples, whereas one brain sample was positive for tick-borne encephalitis virus (TBEV). The WNV sequences clustered with lineages 1 and 2. These results confirm the circulation of WNV in birds in Slovakia and emphasize the risk of infection of humans and horses.

Diagnosis and treatment of viral encephalitis

PubMed Central

Chaudhuri, A; Kennedy, P

2002-01-01

Acute encephalitis constitutes a medical emergency. In most cases, the presence of focal neurological signs and focal seizures will distinguish encephalitis from encephalopathy. Acute disseminated encephalomyelitis is a non-infective inflammatory encephalitis that may require to be treated with steroids. Acute infective encephalitis is usually viral. Herpes simplex encephalitis (HSE) is the commonest sporadic acute viral encephalitis in the Western world. Magnetic resonance imaging of brain is the investigation of choice in HSE and the diagnosis may be confirmed by the polymerase chain reaction test for the virus in the cerebrospinal fluid. In this article, we review the diagnosis, investigations, and management of acute encephalitis. With few exceptions (for example, aciclovir for HSE), no specific therapy is available for most forms of viral encephalitis. Mortality and morbidity may be high and long term sequelae are known among survivors. The emergence of unusual forms of zoonotic encephalitis has posed an important public health problem. Vaccination and vector control measures are useful preventive strategies in certain arboviral and zoonotic encephalitis. However, we need better antiviral therapy to meet the challenge of acute viral encephalitis more effectively. PMID:12415078

A recombinant chimeric La Crosse virus expressing the surface glycoproteins of Jamestown Canyon virus is immunogenic and protective against challenge with either parental virus in mice or monkeys.

PubMed

Bennett, R S; Gresko, A K; Nelson, J T; Murphy, B R; Whitehead, S S

2012-01-01

La Crosse virus (LACV) and Jamestown Canyon virus (JCV), family Bunyaviridae, are mosquito-borne viruses that are endemic in North America and recognized as etiologic agents of encephalitis in humans. Both viruses belong to the California encephalitis virus serogroup, which causes 70 to 100 cases of encephalitis a year. As a first step in creating live attenuated viral vaccine candidates for this serogroup, we have generated a recombinant LACV expressing the attachment/fusion glycoproteins of JCV. The JCV/LACV chimeric virus contains full-length S and L segments derived from LACV. For the M segment, the open reading frame (ORF) of LACV is replaced with that derived from JCV and is flanked by the untranslated regions of LACV. The resulting chimeric virus retained the same robust growth kinetics in tissue culture as observed for either parent virus, and the virus remains highly infectious and immunogenic in mice. Although both LACV and JCV are highly neurovirulent in 21 day-old mice, with 50% lethal dose (LD₅₀) values of 0.1 and 0.5 log₁₀ PFU, respectively, chimeric JCV/LACV is highly attenuated and does not cause disease even after intracerebral inoculation of 10³ PFU. Parenteral vaccination of mice with 10¹ or 10³ PFU of JCV/LACV protected against lethal challenge with LACV, JCV, and Tahyna virus (TAHV). The chimeric virus was infectious and immunogenic in rhesus monkeys and induced neutralizing antibodies to JCV, LACV, and TAHV. When vaccinated monkeys were challenged with JCV, they were protected against the development of viremia. Generation of highly attenuated yet immunogenic chimeric bunyaviruses could be an efficient general method for development of vaccines effective against these pathogenic viruses.

Novel Treatment with Neuroprotective and Antiviral Properties against a Neuroinvasive Human Respiratory Virus

PubMed Central

Brison, Elodie; Jacomy, Hélène

2014-01-01

ABSTRACT Human coronaviruses (HCoVs) are recognized respiratory pathogens with neuroinvasive and neurotropic properties in mice and humans. HCoV strain OC43 (HCoV-OC43) can infect and persist in human neural cells and activate neuroinflammatory and neurodegenerative mechanisms, suggesting that it could be involved in neurological disease of unknown etiology in humans. Moreover, we have shown that HCoV-OC43 is neurovirulent in susceptible mice, causing encephalitis, and that a viral mutant with a single point mutation in the viral surface spike (S) protein induces a paralytic disease that involves glutamate excitotoxicity in susceptible mice. Herein, we show that glutamate recycling via the glial transporter 1 protein transporter and glutamine synthetase are central to the dysregulation of glutamate homeostasis and development of motor dysfunctions and paralytic disease in HCoV-OC43-infected mice. Moreover, memantine, an N-methyl-d-aspartate receptor antagonist widely used in the treatment of neurological diseases in humans, improved clinical scores related to paralytic disease and motor disabilities by partially restoring the physiological neurofilament phosphorylation state in virus-infected mice. Interestingly, memantine attenuated mortality rates and body weight loss and reduced HCoV-OC43 replication in the central nervous system in a dose-dependent manner. This novel action of memantine on viral replication strongly suggests that it could be used as an antiviral agent to directly limit viral replication while improving neurological symptoms in various neurological diseases with a viral involvement. IMPORTANCE PMID:24227863

Correlation of TBE Incidence with Red Deer and Roe Deer Abundance in Slovenia

PubMed Central

Knap, Nataša; Avšič-Županc, Tatjana

2013-01-01

Tick-borne encephalitis (TBE) is a virus infection which sometimes causes human disease. The TBE virus is found in ticks and certain vertebrate tick hosts in restricted endemic localities termed TBE foci. The formation of natural foci is a combination of several factors: the vectors, a suitable and numerous enough number of hosts and in a habitat with suitable vegetation and climate. The present study investigated the influence of deer on the incidence of tick-borne encephalitis. We were able to obtain data from deer culls. Using this data, the abundance of deer was estimated and temporal and spatial analysis was performed. The abundance of deer has increased in the past decades, as well as the incidence of tick-borne encephalitis. Temporal analysis confirmed a correlation between red deer abundance and tick-borne encephalitis occurrence. Additionally, spatial analysis established, that in areas with high incidence of tick-borne encephalitis red deer density is higher, compared to areas with no or few human cases of tick-borne encephalitis. However, such correlation could not be confirmed between roe deer density and the incidence of tick-borne encephalitis. This is presumably due to roe deer density being above a certain threshold so that availability of tick reproduction hosts has no apparent effect on ticks' host finding and consequently may not be possible to correlate with incidence of human TBE. PMID:23776668

THE USE OF MICE IN TESTS OF IMMUNITY AGAINST YELLOW FEVER

PubMed Central

Sawyer, W. A.; Lloyd, Wray

1931-01-01

1. A method of testing sera for protective power against yellow fever is described and designated as the intraperitoneal protection test in mice. 2. The test consists essentially of the inoculation of mice intra-peritoneally with yellow fever virus, fixed for mice, together with the serum to be tested, and the simultaneous injection of starch solution into the brain to localize the virus. If the serum lacks protective power the mice die of yellow fever encephalitis. 3. The test is highly sensitive. Consequently it is useful in epidemiological studies to determine whether individuals have ever had yellow fever and in tests to find whether vaccinated persons or animals have in reality been immunized. 4. When mice were given large intraperitoneal injections of yellow fever virus fixed for mice, the virus could be recovered from the blood for 4 days although encephalitis did not occur. If the brain was mildly injured at the time of the intraperitoneal injection, the symptoms of yellow fever encephalitis appeared 6 days later, but the virus was then absent from the blood. 5. Strains of white mice vary greatly in their susceptibility to yellow fever. PMID:19869938

Serosurveillance for Japanese encephalitis and West Nile viruses in resident birds in Hawai'i.

PubMed

Nemeth, Nicole M; Bosco-Lauth, Angela M; Sciulli, Rebecca H; Gose, Remedios B; Nagata, Mark T; Bowen, Richard A

2010-04-01

Japanese encephalitis virus (JEV) and West Nile virus (WNV) are emerging zoonotic arboviruses that have recently undergone intercontinental expansion. Both JEV and WNV are naturally transmitted between mosquito vectors and vertebrate reservoir hosts, including birds. A potential route of JEV introduction from Asia to western North America is via the Hawaiian archipelago, while the spread of WNV from mainland North America to Hawai'i is also considered an impending threat. We surveyed resident, non-native bird sera for antibodies to JEV and WNV on two Hawaiian Islands from 2004-2005. Three of 1,835 birds (0.16%) had evidence of antiflavivirus antibodies, demonstrating neutralizing activity to JEV and St. Louis encephalitis virus (SLEV). These detections could represent a limited transmission focus of either, or both, JEV and SLEV, or cross-reactive antibodies due to primary infection with an alternate flavivirus. Frequent air traffic from both Asia and North America to Hawai'i, along with the presence of probable competent vectors and amplifying vertebrate hosts in Hawai'i, increases the likelihood of introduction and maintenance of novel flaviviruses. Therefore, it is important to monitor for the presence of these viruses.

Experimental West Nile Virus Infection in Rabbits: An Alternative Model for Studying Induction of Disease and Virus Control

PubMed Central

Suen, Willy W.; Uddin, Muhammad J.; Wang, Wenqi; Brown, Vienna; Adney, Danielle R.; Broad, Nicole; Prow, Natalie A.; Bowen, Richard A.; Hall, Roy A.; Bielefeldt-Ohmann, Helle

2015-01-01

The economic impact of non-lethal human and equine West Nile virus (WNV) disease is substantial, since it is the most common presentation of the infection. Experimental infection with virulent WNV strains in the mouse and hamster models frequently results in severe neural infection and moderate to high mortality, both of which are not representative features of most human and equine infections. We have established a rabbit model for investigating pathogenesis and immune response of non-lethal WNV infection. Two species of rabbits, New Zealand White (Oryctolagus cuniculus) and North American cottontail (Sylvilagus sp.), were experimentally infected with virulent WNV and Murray Valley encephalitis virus strains. Infected rabbits exhibited a consistently resistant phenotype, with evidence of low viremia, minimal-absent neural infection, mild-moderate neuropathology, and the lack of mortality, even though productive virus replication occurred in the draining lymph node. The kinetics of anti-WNV neutralizing antibody response was comparable to that commonly seen in infected horses and humans. This may be explained by the early IFNα/β and/or γ response evident in the draining popliteal lymph node. Given this similarity to the human and equine disease, immunocompetent rabbits are, therefore, a valuable animal model for investigating various aspects of non-lethal WNV infections. PMID:26184326

Herpes simplex virus-induced anti-N-methyl-d-aspartate receptor encephalitis: a systematic literature review with analysis of 43 cases.

PubMed

Nosadini, Margherita; Mohammad, Shekeeb S; Corazza, Francesco; Ruga, Ezia Maria; Kothur, Kavitha; Perilongo, Giorgio; Frigo, Anna Chiara; Toldo, Irene; Dale, Russell C; Sartori, Stefano

2017-08-01

To conduct a systematic literature review on patients with biphasic disease with herpes simplex virus (HSV) encephalitis followed by anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. We conducted a case report and systematic literature review (up to 10 December 2016), focused on differences between herpes simplex encephalitis (HSE) and anti-NMDAR encephalitis phases, age-related characteristics of HSV-induced anti-NMDAR encephalitis, and therapy. For statistical analyses, McNemar's test, Fisher's test, and Wilcoxon rank sum test were used (two-tailed significance level set at 5%). Forty-three patients with biphasic disease were identified (31 children). Latency between HSE and anti-NMDAR encephalitis was significantly shorter in children than adults (median 24 vs 40.5d; p=0.006). Compared with HSE, anti-NMDAR encephalitis was characterized by significantly higher frequency of movement disorder (2.5% vs 75% respectively; p<0.001), and significantly lower rate of seizures (70% vs 30% respectively; p=0.001). Compared with adults, during anti-NMDAR encephalitis children had significantly more movement disorders (86.7% children vs 40% adults; p=0.006), fewer psychiatric symptoms (41.9% children vs 90.0% adults; p=0.025), and a slightly higher median modified Rankin Scale score (5 in children vs 4 in adults; p=0.015). During anti-NMDAR encephalitis, 84.6 per cent of patients received aciclovir (for ≤7d in 22.7%; long-term antivirals in 18.0% only), and 92.7 per cent immune therapy, but none had recurrence of HSE clinically or using cerebrospinal fluid HSV polymerase chain reaction (median follow-up 7mo). Our review suggests that movement disorder may help differentiate clinically an episode of HSV-induced anti-NMDAR encephalitis from HSE relapse. Compared with adults, children have shorter latency between HSE and anti-NMDAR encephalitis and, during anti-NMDAR encephalitis, more movement disorder, fewer psychiatric symptoms, and slightly more severe disease. According to our results, immune therapy given for HSV-induced anti-NMDAR encephalitis does not predispose patients to HSE recurrence. © 2017 Mac Keith Press.

Susceptibility of Peruvian Mosquitoes to Eastern Equine Encephalitis virus

DTIC Science & Technology

2008-07-01

the Amazon Basin, near Iquitos, Peru , and used in experimental studies to evaluate their susceptibility to strains of eastern equine encephalitis virus...the repeated isolation of strains of EEEV from Cx. pedroi captured in the Amazon Basin region of Peru , suggests that Cx. pedroi may be the primary...in the Amazon Basin region in Peru , mosquitoes were cap- tured and identiÞed and tested for arboviruses (Pecor et al. 2000, Jones et al. 2004, Turell

Chikungunya infection presenting as mild encephalitis with a reversible lesion in the splenium: a case report.

PubMed

Nagpal, Kadam; Agarwal, Puneet; Kumar, Amit; Reddi, Rajashekhar

2017-06-01

Chikungunya fever is an Aedes mosquito-transmitted infection caused by chikungunya virus, an RNA virus in the family Togaviridae. The disease is characteristically manifested as fever, arthralgia, and/or rash. Various neurological manifestations like meningoencephalitis, myelitis, and myeloneuropathy have been mentioned in various reports. We present a rare case of chikungunya fever presenting with mild encephalitis with a reversible lesion of the splenium (MERS), which showed complete clinical and radiological recovery.

Powassan virus infection: case series and literature review from a single institution

PubMed Central

2012-01-01

Background Powassan virus is a flavivirus related to eastern hemisphere’s tick-borne encephalitis viruses. It can cause a rare but potentially life-threatening disease including encephalitis. Case presentation We report four cases of POWV infection in Minnesota and North Dakota with known exposure to tick bites in 2011. Our first case was an 18-year-old male who dramatically presented with seizure and headache with positive serum analysis for Powassan virus immunoglobulin M. The second case was a 60 year old gentleman with intraparenchymal hemorrhage and was diagnosed via cerebrospinal fluid analysis. Thirdly, a 61 year old male developed altered mental status and encephalitis. Our fourth patient was a 69 year old male who had headache and non-focal weakness who was diagnosed with serum analysis. Conclusion Symptoms of Powassan virus infection ranged from headaches to seizures and severe neurological symptoms. This study serves to highlight the increased detection of Powassan virus infection in the central north United States. This report focuses on the increasing incidence that can lead to increasing efforts for raising awareness regarding this infection. There is a need for clinician vigilance and public attention due to its increasing detection, westward progression and varied clinical presentations. PMID:23111001

Acute West Nile Virus Meningoencephalitis Diagnosed Via Metagenomic Deep Sequencing of Cerebrospinal Fluid in a Renal Transplant Patient.

PubMed

Wilson, M R; Zimmermann, L L; Crawford, E D; Sample, H A; Soni, P R; Baker, A N; Khan, L M; DeRisi, J L

2017-03-01

Solid organ transplant patients are vulnerable to suffering neurologic complications from a wide array of viral infections and can be sentinels in the population who are first to get serious complications from emerging infections like the recent waves of arboviruses, including West Nile virus, Chikungunya virus, Zika virus, and Dengue virus. The diverse and rapidly changing landscape of possible causes of viral encephalitis poses great challenges for traditional candidate-based infectious disease diagnostics that already fail to identify a causative pathogen in approximately 50% of encephalitis cases. We present the case of a 14-year-old girl on immunosuppression for a renal transplant who presented with acute meningoencephalitis. Traditional diagnostics failed to identify an etiology. RNA extracted from her cerebrospinal fluid was subjected to unbiased metagenomic deep sequencing, enhanced with the use of a Cas9-based technique for host depletion. This analysis identified West Nile virus (WNV). Convalescent serum serologies subsequently confirmed WNV seroconversion. These results support a clear clinical role for metagenomic deep sequencing in the setting of suspected viral encephalitis, especially in the context of the high-risk transplant patient population. © 2016 The Authors. American Journal of Transplantation published by Wiley Periodicals, Inc. on behalf of American Society of Transplant Surgeons.

The zoonotic flaviviruses of southern, south-eastern and eastern Asia, and Australasia: the potential for emergent viruses.

PubMed

Mackenzie, J S; Williams, D T

2009-08-01

The genus Flaviviridae comprises about 70 members, of which about 30 are found in southern, south-eastern and eastern Asia and Australasia. These include major pathogens such as Japanese encephalitis (JE), West Nile (WN), Murray Valley encephalitis (MVE), tick-borne encephalitis, Kyasanur Forest disease virus, and the dengue viruses. Other members are known to be associated with mild febrile disease in humans, or with no known disease. In addition, novel flaviviruses continue to be discovered, as demonstrated recently by New Mapoon virus in Australia, Sitiawan virus in Malaysia, and ThCAr virus in Thailand. About 19 of these viruses are mosquito-borne, six are tick-borne, and four have no known vector and represent isolates from rodents or bats. Evidence from phylogenetic studies suggest that JE, MVE and Alfuy viruses probably emerged in the Malaya-Indonesian region from an African progenitor virus, possibly a virus related to Usutu virus. WN virus, however, is believed to have emerged in Africa, and then dispersed through avian migration. Evidence suggests that there are at least seven genetic lineages of WN virus, of which lineage 1b spread to Australasia as Kunjin virus, lineages 1a and 5 spread to India, and lineage 6 spread to Malaysia. Indeed, flaviviruses have a propensity to spread and emerge in new geographic areas, and they represent a potential source for new disease emergence. Many of the factors associated with disease emergence are present in the region, such as changes in land use and deforestation, increasing population movement, urbanization, and increasing trade. Furthermore, because of their ecology and dependence on climate, there is a strong likelihood that global warming may significantly increase the potential for disease emergence and/or spread.

Recombinant Measles AIK-C Vaccine Strain Expressing the prM-E Antigen of Japanese Encephalitis Virus.

PubMed

Higuchi, Akira; Toriniwa, Hiroko; Komiya, Tomoyoshi; Nakayama, Tetsuo

2016-01-01

An inactivated Japanese encephalitis virus (JEV) vaccine, which induces neutralizing antibodies, has been used for many years in Japan. In the present study, the JEV prM-E protein gene was cloned, inserted at the P/M junction of measles AIK-C cDNA, and an infectious virus was recovered. The JEV E protein was expressed in B95a cells infected with the recombinant virus. Cotton rats were inoculated with recombinant virus. Measles PA antibodies were detected three weeks after immunization. Neutralizing antibodies against JEV developed one week after inoculation, and EIA antibodies were detected three weeks after immunization. The measles AIK-C-based recombinant virus simultaneously induced measles and JEV immune responses, and may be a candidate for infant vaccines. Therefore, the present strategy of recombinant viruses based on a measles vaccine vector would be applicable to the platform for vaccine development.

Herpes simplex type 2 encephalitis and methotrexate medication: a fortuitous or causative association in a patient with spondyloarthritis?

PubMed

Lupo, Julien; Dos Santos, Ophélie; Germi, Raphaele; Baccard-Longère, Monique; Stahl, Jean-Paul; Epaulard, Olivier; Morand, Patrice

2017-01-01

It is unclear whether immunosuppression is a risk factor for herpes encephalitis. Herein, we describe a rare case of herpes simplex virus type 2 encephalitis in a patient treated with low-dose methotrexate for HLA-B27-associated spondyloarthritis. The patient was successfully treated with acyclovir but presented sequelae of encephalitis. Here we discuss the possible role of low-dose methotrexate therapy as a risk factor of neurological herpes reactivation and severe disease. The host-related and viral risk factors are also addressed.

Dengue encephalitis

PubMed Central

Borawake, Kapil; Prayag, Parikshit; Wagh, Atul; Dole, Swati

2011-01-01

We report a case of dengue fever with features of encephalitis. The diagnosis of dengue was confirmed by the serum antibodies to dengue and the presence of a dengue antigen in the cerebrospinal fluid. This patient had characteristic magnetic resonance imaging brain findings, mainly involving the bilateral thalami, with hemorrhage. Dengue is not primarily a neurotropic virus and encephalopathy is a common finding in Dengue. Hence various other etiological possibilities were considered before concluding this as a case of Dengue encephalitis. This case explains the importance of considering the diagnosis of dengue encephalitis in appropriate situations. PMID:22013316

Japanese encephalitis virus NS1' protein depends on pseudoknot secondary structure and is cleaved by caspase during virus infection and cell apoptosis.

PubMed

Sun, Jin; Yu, Yongxin; Deubel, Vincent

2012-09-01

Japanese encephalitis virus (JEV) is a flavivirus with a complex life cycle involving mosquito vectors that mainly target birds and pigs, and causes severe encephalitis in children in Asia. Neurotropic flaviviruses of the JEV serogroup have a particular characteristic of expressing a unique nonstructural NS1' protein, which is a prolongation of NS1 at the C terminus by 52 amino acids derived from a pseudoknot-driven-1 translation frameshift. Protein NS1' is associated with virus neuro-invasiveness. In this study, the need of the pseudoknot structure for NS1' synthesis was confirmed. By using a specific antibody against the prolonged peptide, NS1' was found to be absent from the JEV SA14-14-2 vaccine strain, resulting from a single nucleotide silent mutation in the pseudoknot. A partial cleavage of NS1' at a specific site of its C-terminal appendix recognized by caspases and inhibited by caspase inhibitors suggests a unique feature of intracellular NS1'. Copyright © 2012 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.

[Role of Toscana virus in meningo-encephalitis in Tunisia].

PubMed

Bahri, O; Fazaa, O; Ben Alaya-Bouafif, N; Bouloy, M; Triki, H; Bouattour, A

2011-12-01

To detect the presence of Toscana virus (TOSV) circulation in Tunisia and to study its role in viral meningo-encephalitis. A total of 315 (167 sera and 178 cerobrospinal fluid [CSF]) samples was investigated. These samples are colleted from Tunisian patients with neurological diseases during the period between January 2003 and December 2009. All samples were tested negative for enterovirus, Herpes Simplex virus and West Nile virus. Detection for IgM and IgG specific to TOSV was done by ELISA tests. Specific IgM for TOSV were detected in 10 % of patients with neurological diseases (31 cases). These recent infections were distributed throughout the study period and predominated during summer and automn. Patients were originated, in the majority from the coastal region. IgG were isolated in 22 cases (7 %) corresponding to previous infection. This is the first report of TOSV circulating in Tunisia and its frequent implication in neurological diseases. These results incited to include TOSV as one of the viral etiologies to target in the diagnosis of viral meningitis and encephalitis in the country. Copyright © 2010 Elsevier Masson SAS. All rights reserved.

Production of single-round infectious chimeric flaviviruses with DNA-based Japanese encephalitis virus replicon.

PubMed

Suzuki, Ryosuke; Ishikawa, Tomohiro; Konishi, Eiji; Matsuda, Mami; Watashi, Koichi; Aizaki, Hideki; Takasaki, Tomohiko; Wakita, Takaji

2014-01-01

A method for rapid production of single-round infectious particles (SRIPs) of flavivirus would be useful for viral mutagenesis studies. Here, we established a DNA-based production system for SRIPs of flavivirus. We constructed a Japanese encephalitis virus (JEV) subgenomic replicon plasmid, which lacked the C-prM-E (capsid-pre-membrane-envelope) coding region, under the control of the cytomegalovirus promoter. When the JEV replicon plasmid was transiently co-transfected with a JEV C-prM-E expression plasmid into 293T cells, SRIPs were produced, indicating successful trans-complementation with JEV structural proteins. Equivalent production levels were observed when C and prM-E proteins were provided separately. Furthermore, dengue types 1-4, West Nile, yellow fever or tick-borne encephalitis virus prM-E proteins could be utilized for production of chimaeric flavivirus SRIPs, although the production was less efficient for dengue and yellow fever viruses. These results indicated that our plasmid-based system is suitable for investigating the life cycles of flaviviruses, diagnostic applications and development of safer vaccine candidates.

Tick-Borne Encephalitis Virus Nonstructural Protein NS5 Induces RANTES Expression Dependent on the RNA-Dependent RNA Polymerase Activity.

PubMed

Zheng, Zifeng; Yang, Jieyu; Jiang, Xuan; Liu, Yalan; Zhang, Xiaowei; Li, Mei; Zhang, Mudan; Fu, Ming; Hu, Kai; Wang, Hanzhong; Luo, Min-Hua; Gong, Peng; Hu, Qinxue

2018-05-14

Tick-borne encephalitis virus (TBEV) is one of the flaviviruses that targets the CNS and causes encephalitis in humans. The mechanism of TBEV that causes CNS destruction remains unclear. It has been reported that RANTES-mediated migration of human blood monocytes and T lymphocytes is specifically induced in the brain of mice infected with TBEV, which causes ensuing neuroinflammation and may contribute to brain destruction. However, the viral components responsible for RANTES induction and the underlying mechanisms remain to be fully addressed. In this study, we demonstrate that the NS5, but not other viral proteins of TBEV, induces RANTES production in human glioblastoma cell lines and primary astrocytes. TBEV NS5 appears to activate the IFN regulatory factor 3 (IRF-3) signaling pathway in a manner dependent on RIG-I/MDA5, which leads to the nuclear translocation of IRF-3 to bind with RANTES promoter. Further studies reveal that the activity of RNA-dependent RNA polymerase (RdRP) but not the RNA cap methyltransferase is critical for TBEV NS5-induced RANTES expression, and this is likely due to RdRP-mediated synthesis of dsRNA. Additional data indicate that the residues at K359, D361, and D664 of TBEV NS5 are critical for RdRP activity and RANTES induction. Of note, NS5s from other flaviviruses, including Japanese encephalitis virus, West Nile virus, Zika virus, and dengue virus, can also induce RANTES expression, suggesting the significance of NS5-induced RANTES expression in flavivirus pathogenesis. Our findings provide a foundation for further understanding how flaviviruses cause neuroinflammation and a potential viral target for intervention. Copyright © 2018 by The American Association of Immunologists, Inc.

Eastern Equine Encephalitis in Latin America

PubMed Central

Carrera, Jean-Paul; Forrester, Naomi; Wang, Eryu; Vittor, Amy Y.; Haddow, Andrew D.; López-Vergès, Sandra; Abadía, Ivan; Castaño, Elizabeth; Sosa, Nestor; Báez, Carmen; Estripeaut, Dora; Díaz, Yamilka; Beltrán, Davis; Cisneros, Julio; Cedeño, Hector G.; da Rosa, Amelia P. Travassos; Hernandez, Humberto; Martínez-Torres, Alex O.; Tesh, Robert B.; Weaver, Scott C.

2013-01-01

BACKGROUND The eastern equine encephalitis (EEE) and Venezuelan equine encephalitis (VEE) viruses are pathogens that infect humans and horses in the Americas. Outbreaks of neurologic disease in humans and horses were reported in Panama from May through early August 2010. METHODS We performed antibody assays and tests to detect viral RNA and isolate the viruses in serum samples from hospitalized patients. Additional cases were identified with enhanced surveillance. RESULTS A total of 19 patients were hospitalized for encephalitis. Among them, 7 had confirmed EEE, 3 had VEE, and 1 was infected with both viruses; 3 patients died, 1 of whom had confirmed VEE. The clinical findings for patients with EEE included brain lesions, seizures that evolved to status epilepticus, and neurologic sequelae. An additional 99 suspected or probable cases of alphavirus infection were detected during active surveillance. In total, 13 cases were confirmed as EEE, along with 11 cases of VEE and 1 case of dual infection. A total of 50 cases in horses were confirmed as EEE and 8 as VEE; mixed etiologic factors were associated with 11 cases in horses. Phylogenetic analyses of isolates from 2 cases of equine infection with the EEE virus and 1 case of human infection with the VEE virus indicated that the viruses were of enzootic lineages previously identified in Panama rather than new introductions. CONCLUSIONS Cases of EEE in humans in Latin America may be the result of ecologic changes that increased human contact with enzootic transmission cycles, genetic changes in EEE viral strains that resulted in increased human virulence, or an altered host range. (Funded by the National Institutes of Health and the Secretaría Nacional de Ciencia, Tecnología e Innovación, Panama.) PMID:23964935

Absent anti-N-methyl-D-aspartate receptor NR1a antibodies in herpes simplex virus encephalitis and varicella zoster virus infections.

PubMed

Berger, Benjamin; Pytlik, Maximilian; Hottenrott, Tilman; Stich, Oliver

2017-02-01

A 2012 report and subsequent case series described anti-N-methyl-D-aspartate receptor (NMDAR) antibodies in patients during the acute phase and relapse of herpes simplex virus 1 (HSV1) encephalitis (HSV1E). However, the prevalence of this phenomenon is unknown and systematic studies on other viral infections of the nervous system are missing. We retrospectively analyzed serial cerebrospinal fluid (CSF) and serum samples of consecutive patients treated for neurological HSV1, HSV2 and varicella zoster virus (VZV) infections in our tertiary care university hospital between 2003 and 2013 for the presence of antibodies directed against the NR1a subunit of the NMDAR using indirect immunofluorescence. In total, 88 patients with the following infections were identified through an electronic database search: HSV1 (24 with encephalitis), HSV2 (6 with meningitis, 3 with encephalitis and 1 with myelitis), or VZV (3 with meningitis, 33 with encephalitis, 17 with radiculitis and 1 with myelitis). Two patients with HSV1E and HSV2E, respectively, experienced a clinical relapse. Clinical follow-up was for up to 85 months, and repetitive serum and CSF analyses for up to 43 months. However, at no time did any of the 88 patients exhibit anti-NMDAR NR1a antibodies. In this study, we did not detect anti-NMDAR NR1a antibodies in serial CSF and serum samples of HSV1E patients or patients with other viral infections (HSV2 and VZV). However, the presence of antibodies directed against other epitopes of the NMDAR and other neuronal cell surface antigens cannot be excluded, necessitating further studies.

West Nile virus disease and other arboviral diseases--United States, 2010.

PubMed

2011-08-05

Arthropod-borne viruses (arboviruses) are transmitted to humans primarily through the bites of infected mosquitoes and ticks. Since West Nile virus (WNV) was first detected in the Western Hemisphere in 1999, it has become the leading cause of neuroinvasive arboviral disease in the United States. However, several other arboviruses continue to cause sporadic cases and seasonal outbreaks of neuroinvasive disease (i.e., meningitis, encephalitis, or acute flaccid paralysis). This report summarizes surveillance data reported to CDC in 2010 for WNV and other nationally notifiable arboviruses (excluding dengue, which is reported separately). In 2010, 40 states and the District of Columbia (DC) reported 1,021 cases of WNV disease. Of these, 629 (62%) were classified as WNV neuroinvasive disease, for a national incidence of 0.20 per 100,000 population. States with the highest incidence were Arizona (1.60), New Mexico (1.03), Nebraska (0.55), and Colorado (0.51). After WNV, the next most commonly reported cause of neuroinvasive arboviral disease was California serogroup viruses (CALV), with 68 cases, followed by eastern equine encephalitis virus (EEEV), 10 cases, St. Louis encephalitis virus (SLEV), eight cases, and Powassan virus (POWV), eight cases. WNV and other arboviruses continue to cause focal outbreaks and severe illness in substantial numbers of persons in the United States. Maintaining surveillance remains important to guide arboviral disease prevention activities.

Journal of Special Operations Medicine. Volume 11, Edition 1, Winter 2011

DTIC Science & Technology

2011-01-01

encephalitis, Japanese encephalitis (in Asia) or encephalitis from other herpes viruses. Meningitis, especially if caused by tubercu- losis, may have a...recovering from economic depression. He avoided pre-war hype. Following the attack of Japanese forces against U.S. forces at Pearl Harbor, he...radio, and in literature and cinema . The focal point of understanding presented by the au- thor offers contemporary readers insight into wartime

Estimating the Burden of Japanese Encephalitis Virus and Other Encephalitides in Countries of the Mekong Region

PubMed Central

Tarantola, Arnaud; Goutard, Flavie; Newton, Paul; de Lamballerie, Xavier; Lortholary, Olivier; Cappelle, Julien; Buchy, Philippe

2014-01-01

Diverse aetiologies of viral and bacterial encephalitis are widely recognized as significant yet neglected public health issues in the Mekong region. A robust analysis of the corresponding health burden is lacking. We retrieved 75 articles on encephalitis in the region published in English or in French from 1965 through 2011. Review of available data demonstrated that they are sparse and often derived from hospital-based studies with significant recruitment bias. Almost half (35 of 75) of articles were on Japanese encephalitis virus (JEV) alone or associated with dengue. In the Western Pacific region the WHO reported 30,000–50,000 annual JEV cases (15,000 deaths) between 1966 and 1996 and 4,633 cases (200 deaths) in 2008, a decline likely related to the introduction of JEV vaccination in China, Vietnam, or Thailand since the 1980s. Data on dengue, scrub typhus and rabies encephalitis, among other aetiologies, are also reviewed and discussed. Countries of the Mekong region are undergoing profound demographic, economic and ecological change. As the epidemiological aspects of Japanese encephalitis (JE) are transformed by vaccination in some countries, highly integrated expert collaborative research and objective data are needed to identify and prioritize the human health, animal health and economic burden due to JE and other pathogens associated with encephalitides. PMID:24498443

Transient widespread cortical and splenial lesions in acute encephalitis/encephalopathy associated with primary Epstein-Barr virus infection.

PubMed

Zhang, Shuo; Feng, Juan; Shi, Yifang

2016-01-01

Infection with Epstein-Barr virus (EBV) is very common and usually occurs in childhood or early adulthood. Encephalitis/encephalopathy is an uncommon but serious neurological complication of EBV. A case of EBV-associated encephalitis/encephalopathy with involvement of reversible widespread cortical and splenial lesions is presented herein. An 8-year-old Chinese girl who presented with fever and headache, followed by seizures and drowsiness, was admitted to the hospital. Magnetic resonance imaging revealed high signal intensities on diffusion-weighted imaging in widespread cortical and splenial lesions. The clinical and laboratory examination results together with the unusual radiology findings suggested acute encephalitis/encephalopathy due to primary EBV infection. After methylprednisolone pulse therapy together with ganciclovir, the patient made a full recovery without any brain lesions. The hallmark clinical-radiological features of this patient included severe encephalitis/encephalopathy at onset, the prompt and complete recovery, and rapidly reversible widespread involvement of the cortex and splenium. Patients with EBV encephalitis/encephalopathy who have multiple lesions, even with the widespread involvement of cortex and splenium of the corpus callosum, may have a favorable outcome with complete disappearance of all brain lesions. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Emerging viral diseases of Southeast Asia and the Western Pacific.

PubMed Central

Mackenzie, J. S.; Chua, K. B.; Daniels, P. W.; Eaton, B. T.; Field, H. E.; Hall, R. A.; Halpin, K.; Johansen, C. A.; Kirkland, P. D.; Lam, S. K.; McMinn, P.; Nisbet, D. J.; Paru, R.; Pyke, A. T.; Ritchie, S. A.; Siba, P.; Smith, D. W.; Smith, G. A.; van den Hurk, A. F.; Wang, L. F.; Williams, D. T.

2001-01-01

Over the past 6 years, a number of zoonotic and vectorborne viral diseases have emerged in Southeast Asia and the Western Pacific. Vectorborne disease agents discussed in this article include Japanese encephalitis, Barmah Forest, Ross River, and Chikungunya viruses. However, most emerging viruses have been zoonotic, with fruit bats, including flying fox species as the probable wildlife hosts, and these will be discussed as well. The first of these disease agents to emerge was Hendra virus, formerly called equine morbillivirus. This was followed by outbreaks caused by a rabies-related virus, Australian bat lyssavirus, and a virus associated with porcine stillbirths and malformations, Menangle virus. Nipah virus caused an outbreak of fatal pneumonia in pigs and encephalitis in humans in the Malay Peninsula. Most recently, Tioman virus has been isolated from flying foxes, but it has not yet been associated with animal or human disease. Of nonzoonotic viruses, the most important regionally have been enterovirus 71 and HIV. PMID:11485641

Infectious and autoantibody-associated encephalitis: clinical features and long-term outcome.

PubMed

Pillai, Sekhar C; Hacohen, Yael; Tantsis, Esther; Prelog, Kristina; Merheb, Vera; Kesson, Alison; Barnes, Elizabeth; Gill, Deepak; Webster, Richard; Menezes, Manoj; Ardern-Holmes, Simone; Gupta, Sachin; Procopis, Peter; Troedson, Christopher; Antony, Jayne; Ouvrier, Robert A; Polfrit, Yann; Davies, Nicholas W S; Waters, Patrick; Lang, Bethan; Lim, Ming J; Brilot, Fabienne; Vincent, Angela; Dale, Russell C

2015-04-01

Pediatric encephalitis has a wide range of etiologies, clinical presentations, and outcomes. This study seeks to classify and characterize infectious, immune-mediated/autoantibody-associated and unknown forms of encephalitis, including relative frequencies, clinical and radiologic phenotypes, and long-term outcome. By using consensus definitions and a retrospective single-center cohort of 164 Australian children, we performed clinical and radiologic phenotyping blinded to etiology and outcomes, and we tested archived acute sera for autoantibodies to N-methyl-D-aspartate receptor, voltage-gated potassium channel complex, and other neuronal antigens. Through telephone interviews, we defined outcomes by using the Liverpool Outcome Score (for encephalitis). An infectious encephalitis occurred in 30%, infection-associated encephalopathy in 8%, immune-mediated/autoantibody-associated encephalitis in 34%, and unknown encephalitis in 28%. In descending order of frequency, the larger subgroups were acute disseminated encephalomyelitis (21%), enterovirus (12%), Mycoplasma pneumoniae (7%), N-methyl-D-aspartate receptor antibody (6%), herpes simplex virus (5%), and voltage-gated potassium channel complex antibody (4%). Movement disorders, psychiatric symptoms, agitation, speech dysfunction, cerebrospinal fluid oligoclonal bands, MRI limbic encephalitis, and clinical relapse were more common in patients with autoantibodies. An abnormal outcome occurred in 49% of patients after a median follow-up of 5.8 years. Herpes simplex virus and unknown forms had the worst outcomes. According to our multivariate analysis, an abnormal outcome was more common in patients with status epilepticus, magnetic resonance diffusion restriction, and ICU admission. We have defined clinical and radiologic phenotypes of infectious and immune-mediated/autoantibody-associated encephalitis. In this resource-rich cohort, immune-mediated/autoantibody-associated etiologies are common, and the recognition and treatment of these entities should be a clinical priority. Copyright © 2015 by the American Academy of Pediatrics.

Use of Clinical and Neuroimaging Characteristics to Distinguish Temporal Lobe Herpes Simplex Encephalitis From Its Mimics

PubMed Central

Chow, Felicia C.; Glaser, Carol A.; Sheriff, Heather; Xia, Dongxiang; Messenger, Sharon; Whitley, Richard; Venkatesan, Arun

2015-01-01

Background. We describe the spectrum of etiologies associated with temporal lobe (TL) encephalitis and identify clinical and radiologic features that distinguish herpes simplex encephalitis (HSE) from its mimics. Methods. We reviewed all adult cases of encephalitis with TL abnormalities on magnetic resonance imaging (MRI) from the California Encephalitis Project. We evaluated the association between specific clinical and MRI characteristics and HSE compared with other causes of TL encephalitis and used multivariate logistic modeling to identify radiologic predictors of HSE. Results. Of 251 cases of TL encephalitis, 43% had an infectious etiology compared with 16% with a noninfectious etiology. Of infectious etiologies, herpes simplex virus was the most commonly identified agent (n = 60), followed by tuberculosis (n = 8) and varicella zoster virus (n = 7). Of noninfectious etiologies, more than half (n = 21) were due to autoimmune disease. Patients with HSE were older (56.8 vs 50.2 years; P = .012), more likely to be white (53% vs 35%; P = .013), more likely to present acutely (88% vs 64%; P = .001) and with a fever (80% vs 49%; P < .001), and less likely to present with a rash (2% vs 15%; P = .010). In a multivariate model, bilateral TL involvement (odds ratio [OR], 0.38; 95% confidence interval [CI], .18–.79; P = .010) and lesions outside the TL, insula, or cingulate (OR, 0.37; 95% CI, .18–.74; P = .005) were associated with lower odds of HSE. Conclusions. In addition to HSE, other infectious and noninfectious etiologies should be considered in the differential diagnosis for TL encephalitis, depending on the presentation. Specific clinical and imaging features may aid in distinguishing HSE from non-HSE causes of TL encephalitis. PMID:25637586

Autoimmune encephalitis and its relation to infection.

PubMed

Venkatesan, Arun; Benavides, David R

2015-03-01

Encephalitis, an inflammatory condition of the brain that results in substantial morbidity and mortality, has numerous causes. Over the past decade, it has become increasingly recognized that autoimmune conditions contribute significantly to the spectrum of encephalitis causes. Clinical suspicion and early diagnosis of autoimmune etiologies are of particular importance due to the need for early institution of immune suppressive therapies to improve outcome. Emerging clinical observations suggest that the most commonly recognized cause of antibody-mediated autoimmune encephalitis, anti-N-methyl-D-aspartate (NMDA) receptor encephalitis, may in some cases be triggered by herpes virus infection. Other conditions such as Rasmussen's encephalitis (RE) and febrile infection-related epilepsy syndrome (FIRES) have also been posited to be autoimmune conditions triggered by infectious agents. This review focuses on emerging concepts in central nervous system autoimmunity and addresses clinical and mechanistic findings linking autoimmune encephalitis and infections. Particular consideration will be given to anti-NMDA receptor encephalitis and its relation to herpes simplex encephalitis.

Images in Health Surveillance: Tickborne Disease Vectors and Lyme Disease Clinical Diagnosis

DTIC Science & Technology

2012-05-01

Powassan virus encephalitis, babesiosis, and Colorado tick fever. Tick bites are also a mode of transmission for tularemia and Q fever. 15. SUBJECT...anaplasmosis, Powassan virus encephalitis, babesiosis, and Colorado tick fever. Tick bites are also a mode of trans- mission for tularemia and Q...east- ern and central U.S. and in limited areas on the Pacifi c Coast (Figure 5).4 It is the major vector of RMSF and can also trans- mit tularemia

Ultrastructural study of Rift Valley fever virus in the mouse model

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

Reed, Christopher; Steele, Keith E.; Honko, Anna

Detailed ultrastructural studies of Rift Valley fever virus (RVFV) in the mouse model are needed to develop and characterize a small animal model of RVF for the evaluation of potential vaccines and therapeutics. In this study, the ultrastructural features of RVFV infection in the mouse model were analyzed. The main changes in the liver included the presence of viral particles in hepatocytes and hepatic stem cells accompanied by hepatocyte apoptosis. However, viral particles were observed rarely in the liver; in contrast, particles were extremely abundant in the CNS. Despite extensive lymphocytolysis, direct evidence of viral replication was not observed inmore » the lymphoid tissue. These results correlate with the acute-onset hepatitis and delayed-onset encephalitis that are dominant features of severe human RVF, but suggest that host immune-mediated mechanisms contribute significantly to pathology. The results of this study expand our knowledge of RVFV-host interactions and further characterize the mouse model of RVF.« less

Nonstructural Protein L* Species Specificity Supports a Mouse Origin for Vilyuisk Human Encephalitis Virus.

PubMed

Drappier, Melissa; Opperdoes, Fred R; Michiels, Thomas

2017-07-15

Vilyuisk human encephalitis virus (VHEV) is a picornavirus related to Theiler's murine encephalomyelitis virus (TMEV). VHEV was isolated from human material passaged in mice. Whether this VHEV is of human or mouse origin is therefore unclear. We took advantage of the species-specific activity of the nonstructural L* protein of theiloviruses to track the origin of TMEV isolates. TMEV L* inhibits RNase L, the effector enzyme of the interferon pathway. By using coimmunoprecipitation and functional RNase L assays, the species specificity of RNase L antagonism was tested for L* from mouse (DA) and rat (RTV-1) TMEV strains as well as for VHEV. Coimmunoprecipitation and functional assay data confirmed the species specificity of L* activity and showed that L* from rat strain RTV-1 inhibited rat but not mouse or human RNase L. Next, we showed that the VHEV L* protein was phylogenetically related to L* of mouse viruses and that it failed to inhibit human RNase L but readily antagonized mouse RNase L, unambiguously showing the mouse origin of VHEV. IMPORTANCE Defining the natural host of a virus can be a thorny issue, especially when the virus was isolated only once or when the isolation story is complex. The species Theilovirus includes Theiler's murine encephalomyelitis virus (TMEV), infecting mice and rats, and Saffold virus (SAFV), infecting humans. One TMEV strain, Vilyuisk human encephalitis virus (VHEV), however, was isolated from mice that were inoculated with cerebrospinal fluid of a patient presenting with chronic encephalitis. It is therefore unclear whether VHEV was derived from the human sample or from the inoculated mouse. The L* protein encoded by TMEV inhibits RNase L, a cellular enzyme involved in innate immunity, in a species-specific manner. Using binding and functional assays, we show that this species specificity even allows discrimination between TMEV strains of mouse and of rat origins. The VHEV L* protein clearly inhibited mouse but not human RNase L, indicating that this virus originates from mice. Copyright © 2017 American Society for Microbiology.

Evaluation of Animal and Plant Pathogens as Terrorism and Warfare Agents, Vectors and Pests

DTIC Science & Technology

2001-09-01

fever virus Bluetongue virus African horse sickness virus Nipah swine encephalitis virus Lumpy skin disease virus Camel pox virus Bacteria Bacillus...anthracis Bulkholderia (Pseudomonas) mallei Brucella spp. Mycoplasmas Contagious bovine (pleuropneum.) (M. mycoides var. mycoides type SC) (CBPP...virus Newcastle disease virus Rinderpest virus Pest des petits ruminants virus Bluetongue virus Teschen disease virus (Porcine enterovirus type 1) Rift

[Meningitis and encephalitis in Poland in 2010].

PubMed

Parda, Natalia; Polkowska, Aleksandra

2012-01-01

Annually 2 000-3 000 cases of meningitis and encephalitis are notified to the Polish surveillance system. The leading etiologic agents of the bacterial infections are: N. meningitidis, S. pneumoniae, H. influenzae type B and L. monocytogenes. The most common causes of bacterial infections in children are: E. coli, S. agalactiae and H. influenzae type B. The viral infections are mainly caused by the following pathogens: Echovirus, Coxsackie virus group A and B. The agents responsible for the viral infections are also: arboviruses, Herpes simplex virus and mumps virus. The objectives of the present article are to analyze the epidemiology of meningitis and encephalitis in Poland in 2010 and to present the information on the vaccines used to prevent the discussed infections. The analysis was based on the data retrieved from the questionnaires used for the surveillance purposes, aggregated data on meningitis and encephalitis published in "Infectious diseases and poisonings in Poland in 2010", aggregated data on the vaccination coverage published in "Vaccinations in Poland in 2010", "Case definitions for the infectious diseases used for the surveillance purposes in 2009-2011" and Polish Immunization Programme for 2010. In 2010, Poland reported 3 063 neuroinfections--nearly 22% more than in 2009. The incidence rate was 8.03 cases per 100 000 population. From the analysis of data transpired that of the notified cases, 1 619 were of viral etiology, 846--were bacterial and 598 of other or unknown origin. Given the bacterial infections of determined etiology, the leading pathogenic agent was S. pneumoniae (180 cases), following by N. meningitidis (146 cases) and Haemophilus influenzae typu B (11 cases). Among confirmed cases of the viral infections, the predominant were tick-borne encephalitis cases (294). Compared to the data from 2009, the epidemiologic situation of the meningitis and encephalitis in Poland in 2010 has not changed significantly.

Unusual Necrotizing Encephalitis in Raccoons and Skunks Concurrently Infected With Canine Distemper Virus and Sarcocystis sp.

PubMed

Kubiski, S V; Sisó, S; Church, M E; Cartoceti, A N; Barr, B; Pesavento, P A

2016-05-01

Canine distemper virus commonly infects free-ranging, terrestrial mesopredators throughout the United States. Due to the immunosuppressive effects of the virus, concurrent opportunistic infections are also common. Among these, secondary systemic protozoal infections have been described in a number of species. We report an unusual presentation of necrotizing encephalitis associated withSarcocystissp in four raccoons and one skunk concurrently infected with canine distemper virus. Lesions were characterized by variably sized necrotizing cavitations composed of abundant mineral admixed with inflammatory cells and protozoa.Sarcocystissp was confirmed via immunohistochemistry using a monoclonal antibody toSarcocystis neurona The pathologic changes are similar to lesions in human AIDS patients infected withToxoplasma gondii. © The Author(s) 2015.

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

The West Nile Virus-Like Flavivirus Koutango Is Highly Virulent in Mice due to Delayed Viral Clearance and the Induction of a Poor Neutralizing Antibody Response

PubMed Central

Setoh, Yin X.; Biron, Rebecca M.; Sester, David P.; Kim, Kwang Sik; Hobson-Peters, Jody; Hall, Roy A.; Bielefeldt-Ohmann, Helle

2014-01-01

ABSTRACT The mosquito-borne West Nile virus (WNV) is responsible for outbreaks of viral encephalitis in humans, horses, and birds, with particularly virulent strains causing recent outbreaks of disease in eastern Europe, the Middle East, North America, and Australia. Previous studies have phylogenetically separated WNV strains into two main genetic lineages (I and II) containing virulent strains associated with neurological disease. Several WNV-like strains clustering outside these lineages have been identified and form an additional five proposed lineages. However, little is known about whether these strains have the potential to induce disease. In a comparative analysis with the highly virulent lineage I American strain (WNVNY99), the low-pathogenicity lineage II strain (B956), a benign Australian strain, Kunjin (WNVKUN), the African WNV-like Koutango virus (WNVKOU), and a WNV-like isolate from Sarawak, Malaysia (WNVSarawak), were assessed for neuroinvasive properties in a murine model and for their replication kinetics in vitro. While WNVNY99 replicated to the highest levels in vitro, in vivo mouse challenge revealed that WNVKOU was more virulent, with a shorter time to onset of neurological disease and higher morbidity. Histological analysis of WNVKOU- and WNVNY99-infected brain and spinal cords demonstrated more prominent meningoencephalitis and the presence of viral antigen in WNVKOU-infected mice. Enhanced virulence of WNVKOU also was associated with poor viral clearance in the periphery (sera and spleen), a skewed innate immune response, and poor neutralizing antibody development. These data demonstrate, for the first time, potent neuroinvasive and neurovirulent properties of a WNV-like virus outside lineages I and II. IMPORTANCE In this study, we characterized the in vitro and in vivo properties of previously uncharacterized West Nile virus strains and West Nile-like viruses. We identified a West Nile-like virus, Koutango virus (WNVKOU), that was more virulent than a known virulent lineage I virus, WNVNY99. The enhanced virulence of WNVKOU was associated with poor viral clearance and the induction of a poor neutralizing antibody response. These findings provide new insights into the pathogenesis of West Nile virus. PMID:24942584

[Activating effect of cyclophosphane at late stages of persistence of the tick-borne encephalitis virus].

PubMed

Frolova, T V; Pogodina, V V; Larina, G I; Frolova, M P; Karmysheva, V Ia

1982-01-01

Conditions of activation of persistent infection caused by subcutaneous inoculation of Syrian hamsters with the B-383 and Vasilchenko strains of tick-borne encephalitis virus (TBE) were studied. After 2 administrations of cyclophosphane (CP) on day 170 of infection clinically manifest disease developed in some animals with increasingly severe pathomorphological lesions in the CNS. Several variants of activated TBE virus were isolated from brains and spleens of CP-treated hamsters. The activation of persistent infection was observed in the presence of marked decreased of humoral immunity level, weight of the thymus, and values of spontaneous rosette-formation.

QUALITY ASSURANCE FOR METHODS TO DETECT HUMAN ENTERIC VIRUSES IN DRINKING WATER

EPA Science Inventory

Surface or groundwaters impacted by untreated or inadequately treated domestic wastes may contain human pathogenic viruses that cause hepatitis, gastroenteritis, meningitis, encephalitis, myocarditis, diabetes, conjunctivitis and temporary or permanent paralysis. These viruses c...

[Activating effect of adrenaline, prednisolone and vincristine in the late periods of tick-borne encephalitis virus persistence].

PubMed

Frolova, T V; Pogodina, V V

1984-01-01

The activating effect of adrenalin (A), prednisolone (P), and vincristine (V) on persistent infection caused by subcutaneous inoculation of Syrian hamsters with the Vasilchenko and B-383 strains of tick-borne encephalitis virus (TBE) was studied. The drugs were administered once, twice, or three times 250-270 days after virus inoculation. Complement-fixing antigen was found in the organs of the infected animals given no A, P, or V; in the organ explants synthesis of hemagglutinin was observed but no infectious virus could be isolated. After treatment of the infected hamsters with A, P, or V organ explants yielded TBE virus strains which showed either high or low virulence for white mice. The activated TBE virus strains were obtained from explants of hamster brains and spleens but not liver. V produced the most marked activating effect, A the least.

Ebola virus glycoprotein Fc fusion protein confers protection against lethal challenge in vaccinated mice

PubMed Central

Konduru, Krishnamurthy; Bradfute, Steven B.; Jacques, Jerome; Manangeeswaran, Mohanraj; Nakamura, Siham; Morshed, Sufi; Wood, Steven C.; Bavari, Sina

2011-01-01

Ebola virus is a Filoviridae that causes hemorrhagic fever in humans and induces high morbidity and mortality rates. Filoviruses are classified as "Category A bioterrorism agents", and currently there are no licensed therapeutics or vaccines to treat and prevent infection. The Filovirus glycoprotein (GP) is sufficient to protect individuals against infection, and several vaccines based on GP are under development including recombinant adenovirus, parainfluenza virus, Venezuelan equine encephalitis virus, vesicular stomatitis virus (VSV) and virus-like particles. Here we describe the development of a GP Fc fusion protein as a vaccine candidate. We expressed the extracellular domain of the Zaire Ebola virus (ZEBOV) GP fused to the Fc fragment of human IgG1 (ZEBOVGP-Fc) in mammalian cells and showed that GP undergoes the complex furin cleavage and processing observed in the native membrane-bound GP. Mice immunized with ZEBOVGP-Fc developed T-cell immunity against ZEBOV GP and neutralizing antibodies against replication-competent VSV-G deleted recombinant VSV containing ZEBOV GP. The ZEBOVGP-Fc vaccinated mice were protected against challenge with a lethal dose of ZEBOV. These results show that vaccination with the ZEBOVGP-Fc fusion protein alone without the need of a viral vector or assembly into virus-like particles is sufficient to induce protective immunity against ZEBOV in mice. Our data suggested that Filovirus GP Fc fusion proteins could be developed as a simple, safe, efficacious, and cost effective vaccine against Filovirus infection for human use. PMID:21329775

Comparative Neuropathogenesis and Neurovirulence of Attenuated Flaviviruses in Nonhuman Primates▿ †

PubMed Central

Maximova, Olga A.; Ward, Jerrold M.; Asher, David M.; St. Claire, Marisa; Finneyfrock, Brad W.; Speicher, James M.; Murphy, Brian R.; Pletnev, Alexander G.

2008-01-01

Based on previous preclinical evaluation in mice and monkeys, the chimeric TBEV/DEN4Δ30 virus, carrying the prM and E protein genes from a highly virulent Far Eastern strain of tick-borne encephalitis virus (TBEV) on the backbone of a nonneuroinvasive dengue type 4 virus (DEN4), has been identified as a promising live attenuated virus vaccine candidate against disease caused by TBEV. However, prior to use of this vaccine candidate in humans, its neurovirulence in nonhuman primates needed to be evaluated. In the present study, we compared the neuropathogeneses of the chimeric TBEV/DEN4Δ30 virus; Langat virus (LGTV), a former live TBEV vaccine; and yellow fever 17D virus vaccine (YF 17D) in rhesus monkeys inoculated intracerebrally. TBEV/DEN4Δ30 and YF 17D demonstrated remarkably similar spatiotemporal profiles of virus replication and virus-associated histopathology in the central nervous system (CNS) that were high in cerebral hemispheres but progressively decreased toward the spinal cord. In contrast, the neurovirulence of LGTV exhibited the reverse profile, progressing from the site of inoculation toward the cerebellum and spinal cord. Analysis of the spatiotemporal distribution of viral antigens in the CNS of monkeys revealed a prominent neurotropism associated with all three attenuated viruses. Nevertheless, TBEV/DEN4Δ30 virus exhibited higher neurovirulence in monkeys than either LGTV or YF 17D, suggesting insufficient attenuation. These results provide insight into the neuropathogenesis associated with attenuated flaviviruses that may guide the design of safe vaccines. PMID:18353947

Electron microscopic diagnosis of human flavivirus encephalitis: use of confocal microscopy as an aid.

PubMed

Chu, C T; Howell, D N; Morgenlander, J C; Hulette, C M; McLendon, R E; Miller, S E

1999-10-01

The distinction between intracranial viral infections and inflammatory conditions requiring immunosuppression is important. Although specific laboratory reagents are readily available for some viruses, diagnosis of arbovirus infection is more difficult. Transmission electron microscopy (TEM) theoretically allows identification of viral particles independent of reagent availability, but it has limited sensitivity. We report two cases of human flavivirus encephalitis diagnosed by TEM. Laser scanning confocal microscopy (LSCM) was used in one case to survey unembedded tissue slices for focal abnormalities, from which fragments smaller than 1 mm2 were excised for epoxy embedding. This facilitated TEM identification of intracytoplasmic, budding, 35-40 nm spherical virus particles, confirmed by serology as St. Louis encephalitis. In contrast to mosquitoes and newborn mice, in which high viral loads are associated with minimal tissue responses, these biopsies showed florid angiodestructive inflammation and microgliosis, with rare virions in necrotic perivascular cells and astrocytes. To our knowledge, this represents the first ultrastructural study of St. Louis encephalitis in humans, indicating the potential value of LSCM-aided TEM.

Infectious Causes of Encephalitis and Meningoencephalitis in Thailand, 2003–2005

PubMed Central

Campbell, Angela P.; Supawat, Krongkaew; Liamsuwan, Sahas; Chotpitayasunondh, Tawee; Laptikulthum, Somsak; Viriyavejakul, Akravudh; Tantirittisak, Tasanee; Tunlayadechanont, Supoch; Visudtibhan, Anannit; Vasiknanonte, Punnee; Janjindamai, Supachai; Boonluksiri, Pairoj; Rajborirug, Kiatsak; Watanaveeradej, Veerachai; Khetsuriani, Nino; Dowell, Scott F.

2015-01-01

Acute encephalitis is a severe neurologic syndrome. Determining etiology from among ≈100 possible agents is difficult. To identify infectious etiologies of encephalitis in Thailand, we conducted surveillance in 7 hospitals during July 2003–August 2005 and selected patients with acute onset of brain dysfunction with fever or hypothermia and with abnormalities seen on neuroimages or electroencephalograms or with cerebrospinal fluid pleocytosis. Blood and cerebrospinal fluid were tested for >30 pathogens. Among 149 case-patients, median age was 12 (range 0–83) years, 84 (56%) were male, and 15 (10%) died. Etiology was confirmed or probable for 54 (36%) and possible or unknown for 95 (64%). Among confirmed or probable etiologies, the leading pathogens were Japanese encephalitis virus, enteroviruses, and Orientia tsutsugamushi. No samples were positive for chikungunya, Nipah, or West Nile viruses; Bartonella henselae; or malaria parasites. Although a broad range of infectious agents was identified, the etiology of most cases remains unknown. PMID:25627940

Prevalence of tick-borne encephalitis virus (TBEV) in samples of raw milk taken randomly from cows, goats and sheep in eastern Poland.

PubMed

Cisak, Ewa; Wójcik-Fatla, Angelina; Zając, Violetta; Sroka, Jacek; Buczek, Alicja; Dutkiewicz, Jacek

2010-01-01

A total of 119 unpasteurized milk samples taken from 63 cows, 29 goats and 27 sheep bred on 8 farms situated on the territory of the Lublin province (eastern Poland), an area of risk of tick-borne encephalitis (TBE), were examined for the presence of RNA of tick-borne encephalitis virus (TBEV) by the nested RT-PCR method. Milk samples were also tested for the presence of anti-TBEV antibodies by ELISA test. By RT-PCR, the greatest prevalence of TBE virus was found in the milk of sheep (22.2%), followed by milk of goats (20.7%) and cows (11.1%). By ELISA, the greatest prevalence of anti- TBEV antibodies was found also in the milk of sheep (14.8%), followed by milk of cows (3.2%) and goats (0%). The results suggest a potential risk of infection with TBEV by drinking raw milk on endemic areas of TBE, and indicate a need for milk pasteurization before consumption.

Dengue, Japanese encephalitis and Chikungunya virus antibody prevalence among captive monkey (Macaca nemestrina) colonies of Northern Thailand.

PubMed

Nakgoi, Khajornpong; Nitatpattana, Narong; Wajjwalku, Worawidh; Pongsopawijit, Pornsawan; Kaewchot, Supakarn; Yoksan, Sutee; Siripolwat, Voravit; Souris, Marc; Gonzalez, Jean-Paul

2014-01-01

The potential of macaque Macaca nemestrina leonina in Thailand to be infected by endemic arboviruses was assessed. The prevalence of antibodies of three arboviruses actively circulating in Thailand was determined by Plaque Reduction Neutralization assay procedures using samples from captive colonies in Northern Thailand. Out of 38 macaques, 9 (24%) presented reacting antibodies against dengue virus, 5 (13%) against Japanese encephalitis virus, and 4 (10%) against Chikungunya virus. Our results indicate that the northern pig-tailed macaque in Thailand can be infected by these arboviruses, inferring therefore that their virus specific vectors have bitten them. Given that, northern pig-tailed macaque represents an abundant population, living in close range to human or in peridomestic setting, they could play a role as potential reservoir host for arboviruses circulating in Thailand. © 2013 Wiley Periodicals, Inc.

Herpes simplex virus-1 evasion of CD8+ T cell accumulation contributes to viral encephalitis.

PubMed

Koyanagi, Naoto; Imai, Takahiko; Shindo, Keiko; Sato, Ayuko; Fujii, Wataru; Ichinohe, Takeshi; Takemura, Naoki; Kakuta, Shigeru; Uematsu, Satoshi; Kiyono, Hiroshi; Maruzuru, Yuhei; Arii, Jun; Kato, Akihisa; Kawaguchi, Yasushi

2017-10-02

Herpes simplex virus-1 (HSV-1) is the most common cause of sporadic viral encephalitis, which can be lethal or result in severe neurological defects even with antiviral therapy. While HSV-1 causes encephalitis in spite of HSV-1-specific humoral and cellular immunity, the mechanism by which HSV-1 evades the immune system in the central nervous system (CNS) remains unknown. Here we describe a strategy by which HSV-1 avoids immune targeting in the CNS. The HSV-1 UL13 kinase promotes evasion of HSV-1-specific CD8+ T cell accumulation in infection sites by downregulating expression of the CD8+ T cell attractant chemokine CXCL9 in the CNS of infected mice, leading to increased HSV-1 mortality due to encephalitis. Direct injection of CXCL9 into the CNS infection site enhanced HSV-1-specific CD8+ T cell accumulation, leading to marked improvements in the survival of infected mice. This previously uncharacterized strategy for HSV-1 evasion of CD8+ T cell accumulation in the CNS has important implications for understanding the pathogenesis and clinical treatment of HSV-1 encephalitis.

Distemper virus encephalitis exerts detrimental effects on hippocampal neurogenesis.

PubMed

von Rüden, E-L; Avemary, J; Zellinger, C; Algermissen, D; Bock, P; Beineke, A; Baumgärtner, W; Stein, V M; Tipold, A; Potschka, H

2012-08-01

Despite knowledge about the impact of brain inflammation on hippocampal neurogenesis, data on the influence of virus encephalitis on dentate granule cell neurogenesis are so far limited. Canine distemper is considered an interesting model of virus encephalitis, which can be associated with a chronic progressing disease course and can cause symptomatic seizures. To determine the impact of canine distemper virus (CDV) infection on hippocampal neurogenesis, we compared post-mortem tissue from dogs with infection with and without seizures, from epileptic dogs with non-viral aetiology and from dogs without central nervous system diseases. The majority of animals with infection and with epilepsy of non-viral aetiology exhibited neuronal progenitor numbers below the age average in controls. Virus infection with and without seizures significantly decreased the mean number of neuronal progenitor cells by 43% and 76% as compared to age-matched controls. Ki-67 labelling demonstrated that hippocampal cell proliferation was neither affected by infection nor by epilepsy of non-viral aetiology. Analysis of CDV infection in cells expressing caspase-3, doublecortin or Ki-67 indicated that infection of neuronal progenitor cells is extremely rare and suggests that infection might damage non-differentiated progenitor cells, hamper neuronal differentiation and promote glial differentiation. A high inter-individual variance in the number of lectin-reactive microglial cells was evident in dogs with distemper infection. Statistical analyses did not reveal a correlation between the number of lectin-reactive microglia cells and neuronal progenitor cells. Our data demonstrate that virus encephalitis with and without seizures can exert detrimental effects on hippocampal neurogenesis, which might contribute to long-term consequences of the disease. The lack of a significant impact of distemper virus on Ki-67-labelled cells indicates that the infection affected neuronal differentiation and survival of newborn cells rather than hippocampal cell proliferation. © 2011 The Authors. Neuropathology and Applied Neurobiology © 2011 British Neuropathological Society.

An in vitro recombination-based reverse genetic system for rapid mutagenesis of structural genes of the Japanese encephalitis virus.

PubMed

Du, Ruikun; Wang, Manli; Hu, Zhihong; Wang, Hualin; Deng, Fei

2015-10-01

Japanese encephalitis virus (JEV) is one of the most common pathogens of severe viral encephalitis, which is a severe threat to human health. Despite instability of the JEV genome in bacteria, many strategies have been developed to establish molecular clone systems of JEV, providing convenient tools for studying the virus life cycle and virus-host interactions. In this study, we adapted an In-Fusion enzyme-based in vitro recombination method to construct a reverse genetic system of JEV, thereby providing a rapid approach to introduce mutations into the structural genes. A truncated genome without the structural genes was constructed as the backbone, and the complementary segment containing the structural genes was recombined in vitro, which was then transfected directly into virus-permissive cells. The progeny of the infectious virus was successfully detected in the supernatant of the transfected cells, and showed an identical phenotype to its parental virus. To provide a proof-of-principle, the 12 conserved cysteine residues in the envelope (E) protein of JEV were respectively mutated using this approach, and all mutations resulted in a complete failure to generate infectious virus. However, a leucine-tophenylanine mutation at amino acid 107 of the E protein did not interfere with the production of the infectious virus. These results suggested that all 12 cysteines in the E protein are essential for the JEV life cycle. In summary, a novel reverse genetic system of JEV was established for rapidly introducing mutations into structural genes, which will serve as a useful tool for functional studies.

Serologic survey of domestic animals for zoonotic arbovirus infections in the Lacandón Forest region of Chiapas, Mexico.

PubMed

Ulloa, Armando; Langevin, Stanley A; Mendez-Sanchez, J D; Arredondo-Jimenez, Juan I; Raetz, Janae L; Powers, Ann M; Villarreal-Treviño, C; Gubler, Duane J; Komar, Nicholas

2003-01-01

A serologic survey in domestic animals (birds and mammals) was conducted in four communities located in the Lacandón Forest region of northeastern Chiapas, Mexico, during June 29 to July 1, 2001, with the objective to identify zoonotic arboviruses circulating in this area. We collected 202 serum samples from healthy domestic chickens, geese, ducks, turkeys, horses and cattle. The samples were tested by plaque-reduction neutralization test for antibodies to selected mosquito-borne flaviviruses (family Flaviviridae), including St. Louis encephalitis (SLE), Rocio (ROC), Ilheus (ILH), Bussuquara (BSQ), and West Nile (WN) viruses, and selected alphaviruses (family Togaviridae), including Western equine encephalitis (WEE), Eastern equine encephalomyelitis (EEE), and Venezuelan equine encephalitis (VEE) viruses. Neutralizing antibodies to SLE virus were detected in two (8%) of 26 turkeys, 15 (23%) of 66 cattle, and three (60%) of five horses. Antibodies to VEE virus were detected in 29 (45%) of 65 cattle. Because some of these animals were as young as 2 months old, we demonstrated recent activity of these two viruses. Sub-typing of the VEE antibody responses indicated that the etiologic agents of these infections belonged to the IE variety of VEE, which has been reported from other regions of Chiapas. WN virus-neutralizing antibodies were detected in a single cattle specimen (PRNT(90) = 1:80) that also circulated SLE virus-neutralizing antibodies (PRNT(90) = 1:20), suggesting that WN virus may have been introduced into the region. We also detected weak neutralizing activity to BSQ virus in four cattle and a chicken specimen, suggesting the presence of this or a closely related virus in Mexico. There was no evidence for transmission of the other viruses (ROC, ILH, EEE, WEE) in the study area.

Case of Primary Central Nervous System Lymphoma Arising at Site of Remote Herpes Encephalitis.

PubMed

Li, Victor; Levine, Adrian B; Gooderham, Peter A; Yip, Stephen; Chew, Jason

2018-05-01

Primary central nervous system lymphoma (PCNSL) is a rare malignancy that usually arises in the context of severe immunosuppression but has incompletely understood etiology, limiting effective treatments. We present the case of an 81-year-old immunocompetent man who developed a PCNSL in the right temporal lobe, at the site of a remote episode of herpes simplex virus (HSV) encephalitis 8 years prior. There are numerous viruses with known oncogenic associations; however, to our knowledge, this is the first reported case of PCNSL with an antecedent HSV infection. We discuss this case in the context of our current understandings of the pathogenesis of HSV encephalitis and PCNSL and postulate mechanisms through which the 2 could be associated. Copyright © 2018 Elsevier Inc. All rights reserved.

Integrated cluster- and case-based surveillance for detecting stage III zoonotic pathogens: an example of Nipah virus surveillance in Bangladesh.

PubMed

Naser, A M; Hossain, M J; Sazzad, H M S; Homaira, N; Gurley, E S; Podder, G; Afroj, S; Banu, S; Rollin, P E; Daszak, P; Ahmed, B-N; Rahman, M; Luby, S P

2015-07-01

This paper explores the utility of cluster- and case-based surveillance established in government hospitals in Bangladesh to detect Nipah virus, a stage III zoonotic pathogen. Physicians listed meningo-encephalitis cases in the 10 surveillance hospitals and identified a cluster when ⩾2 cases who lived within 30 min walking distance of one another developed symptoms within 3 weeks of each other. Physicians collected blood samples from the clustered cases. As part of case-based surveillance, blood was collected from all listed meningo-encephalitis cases in three hospitals during the Nipah season (January-March). An investigation team visited clustered cases' communities to collect epidemiological information and blood from the living cases. We tested serum using Nipah-specific IgM ELISA. Up to September 2011, in 5887 listed cases, we identified 62 clusters comprising 176 encephalitis cases. We collected blood from 127 of these cases. In 10 clusters, we identified a total of 62 Nipah cases: 18 laboratory-confirmed and 34 probable. We identified person-to-person transmission of Nipah virus in four clusters. From case-based surveillance, we identified 23 (4%) Nipah cases. Faced with thousands of encephalitis cases, integrated cluster surveillance allows targeted deployment of investigative resources to detect outbreaks by stage III zoonotic pathogens in resource-limited settings.

Treatment of Venezuelan Equine Encephalitis Virus Infection with (-)-Carbodine

PubMed Central

Bowen, Richard A.; Rao, Jagadeeshwar R.; Day, Craig; Shafer, Kristiina; Smee, Donald F.; Morrey, John D.; Chu, Chung K.

2008-01-01

Venezuelan equine encephalitis virus (VEEV) may cause encephalitis in humans, for which no FDA-approved antiviral treatment is available. Carbocyclic cytosine (carbodine) has broad-spectrum activity but toxicity has limited its utility. It was anticipated that one of the enantiomers of carbodine would show enhanced activity and reduced toxicity. The activity of the D-(-) enantiomer of carbodine [(-)-carbodine] was evaluated by infectious cell culture assay and was found to have a 50% effective concentration (EC50) of 0.2 μg/ml against the TC-83 vaccine strain of VEEV in Vero cells, while the L-(+) enantiomer had no activity. Virus titer inhibition correlated with intracellular cytidine triphosphate reduction after treatment with (-)-carbodine, as determined by HPLC analysis. Pre-treatment with 200 mg/kg/d resulted in significant improvement in survival, virus load in the brain, weight change, and mean day to death in a mouse model of TC-83 VEEV disease. A single dose of (-)-Carbodine resulted in a slight extension of mean time to death in mice infected with wild-type VEEV. Post-virus exposure treatment with (-)-carbodine was effective in significantly improving disease parameters in mice infected with TC-83 VEEV when treatment was initiated as late as 4 days post-virus installation (dpi). It is remarkable that (-)-carbodine is effective when initiated after the establishment of brain infection. PMID:18675850

Molecular detection of viral causes of encephalitis and meningitis in New York State.

PubMed

Dupuis, Michelle; Hull, Rene; Wang, Heng; Nattanmai, Seela; Glasheen, Bernadette; Fusco, Heather; Dzigua, Lela; Markey, Katie; Tavakoli, Norma P

2011-12-01

The etiology of encephalitis and meningitis, serious diseases of the central nervous system (CNS), in most cases remains unknown. The importance of establishing a diagnosis however, becomes even more important as advances are made in effective therapy. Molecular methods of detection, in particular, PCR, are being used routinely and have established a place in the arsenal of tools for diagnosis of CNS infections. In this study a viral etiological agent was detected by PCR in 340 of the total 2,357 specimens from patients who exhibited symptoms of encephalitis or meningitis. The detection rate increased from 8.9% during the first year of the study to 14.8% during the second year of the study with improved methodology and an expanded panel of viral agents. Methods were enhanced by developing real-time PCR assays (some multiplexed), using increased automation, superior nucleic acid extraction, and reverse transcription (RT) methods, and incorporation of an internal extraction control. Additionally, adenovirus and human herpes virus 6 (HHV-6) were added to the original panel of 10 viruses that included enteroviruses, herpesviruses, and arboviruses. The most common viruses detected were enteroviruses (129; 5.5%), Epstein-Barr virus (EBV) (85; 3.6%), herpes simplex viruses (HSVs) 1 and 2 (67; 2.8%), and varicella zoster virus (VZV) (44; 1.9%). Copyright © 2011 Wiley Periodicals, Inc.

[Clinical experience and next-generation sequencing analysis of encephalitis caused by pseudorabies virus].

PubMed

Zhao, W L; Wu, Y H; Li, H F; Li, S Y; Fan, S Y; Wu, H L; Li, Y J; Lü, Y L; Han, J; Zhang, W C; Zhao, Y; Li, G L; Qiao, X D; Ren, H T; Zhu, Y C; Peng, B; Cui, L Y; Guan, H Z

2018-04-17

Objective: To detect potential pathogens including pseudorabies virus in patients with encephalitis of unknown etiology in China and describe novel encephalitic entities. Methods: Patients with clinically suspected infectious encephalitis were enrolled in a multicenter study to identify the pathogens in PUMCH Encephalitis Program.Next-generation sequencing(NGS) of cerebrospinal fluid (CSF) was used in patients with encephalitis of unknown etiology enrolled from 2016 to 2017.The patients diagnosed as PRV encephalitis were studied to describe this novel entity. Results: The four patients(3 male, 1 male, 38-54 years old) had occupational exposure to raw park when working in the production or marketing of pork and at least one got injured during pork-cutting.Two of them were confirmed with NGS of CSF, and anti-PRV antibodies were positive in 3 patients whose serum was available for serological analysis.They all presented with an acute onset of fever, convulsion, loss of consciousness and respiratory failure within 1 to 4 days and rapidly deteriorated even on extensive treatment.All the patients needed ICU admission and 3 needed mechanical ventilation.Two patients also had bilateral retinitis.Neuroimaging revealed symmetric gray matter lesions including limbic system, basal ganglia and midbrain without obvious hemorrhage.Lumbar puncture revealed elevated intracranial pressure and lymphocytic pleocytosis [(6-64)×10(6)/L] of CSF.The patients failed to response to the treatment of acyclovir combined with intravenous immunoglobulin and steroids.Modified Rankin Score was 3, 5, 5 and 6 (died) for the 4 patients respectively on last follow-up. Conclusions: PRV could be a cause of severe encephalitis.The patients with suspected pseudorabies encephalitis (PRE) need to be tested for PRV DNA timely.Severe encephalitis with bilateral involvement of limbic system, basal ganglion, thalamus and midbrain in patient with occupational exposure indicate this emerging infectious encephalitis.

Systematic analysis of viral genes responsible for differential virulence between American and Australian West Nile virus strains.

PubMed

Setoh, Yin Xiang; Prow, Natalie A; Rawle, Daniel J; Tan, Cindy Si En; Edmonds, Judith H; Hall, Roy A; Khromykh, Alexander A

2015-06-01

A variant Australian West Nile virus (WNV) strain, WNVNSW2011, emerged in 2011 causing an unprecedented outbreak of encephalitis in horses in south-eastern Australia. However, no human cases associated with this strain have yet been reported. Studies using mouse models for WNV pathogenesis showed that WNVNSW2011 was less virulent than the human-pathogenic American strain of WNV, New York 99 (WNVNY99). To identify viral genes and mutations responsible for the difference in virulence between WNVNSW2011 and WNVNY99 strains, we constructed chimeric viruses with substitution of large genomic regions coding for the structural genes, non-structural genes and untranslated regions, as well as seven individual non-structural gene chimeras, using a modified circular polymerase extension cloning method. Our results showed that the complete non-structural region of WNVNSW2011, when substituted with that of WNVNY99, significantly enhanced viral replication and the ability to suppress type I IFN response in cells, resulting in higher virulence in mice. Analysis of the individual non-structural gene chimeras showed a predominant contribution of WNVNY99 NS3 to increased virus replication and evasion of IFN response in cells, and to virulence in mice. Other WNVNY99 non-structural proteins (NS2A, NS4B and NS5) were shown to contribute to the modulation of IFN response. Thus a combination of non-structural proteins, likely NS2A, NS3, NS4B and NS5, is primarily responsible for the difference in virulence between WNVNSW2011 and WNVNY99 strains, and accumulative mutations within these proteins would likely be required for the Australian WNVNSW2011 strain to become significantly more virulent. © 2015 The Authors.

Small ruminant lentiviruses: Strain variation, viral tropism, and host genetics influence pathogenesis

USDA-ARS?s Scientific Manuscript database

Small Ruminant Lentiviruses (SRLV), which include the Maedi-Visna virus, also known as ovine progressive pneumonia virus (OPPV), and caprine arthritis and encephalitis virus (CAEV), are of global economic importance to sheep and goat producers, respectively. These viruses belong to the genus Lentivi...

Transmembrane Domains of NS2B Contribute to both Viral RNA Replication and Particle Formation in Japanese Encephalitis Virus.

PubMed

Li, Xiao-Dan; Deng, Cheng-Lin; Ye, Han-Qing; Zhang, Hong-Lei; Zhang, Qiu-Yan; Chen, Dong-Dong; Zhang, Pan-Tao; Shi, Pei-Yong; Yuan, Zhi-Ming; Zhang, Bo

2016-06-15

Flavivirus nonstructural protein 2B (NS2B) is a transmembrane protein that functions as a cofactor for viral NS3 protease. The cytoplasmic region (amino acids 51 to 95) alone of NS2B is sufficient for NS3 protease activity, whereas the role of transmembrane domains (TMDs) remains obscure. Here, we demonstrate for the first time that flavivirus NS2B plays a critical role in virion assembly. Using Japanese encephalitis virus (JEV) as a model, we performed a systematic mutagenesis at the flavivirus conserved residues within the TMDs of NS2B. As expected, some mutations severely attenuated (L38A and R101A) or completely destroyed (G12L) viral RNA synthesis. Interestingly, two mutations (G37L and P112A) reduced viral RNA synthesis and blocked virion assembly. None of the mutations affected NS2B-NS3 protease activity. Because mutations G37L and P112A affected virion assembly, we selected revertant viruses for these two mutants. For mutant G37L, replacement with G37F, G37H, G37T, or G37S restored virion assembly. For mutant P112A, insertion of K at position K127 (leading to K127KK) of NS2B rescued virion assembly. A biomolecular fluorescent complementation (BiFC) analysis demonstrated that (i) mutation P112A selectively weakened NS2B-NS2A interaction and (ii) the adaptive mutation K127KK restored NS2B-NS2A interaction. Collectively, our results demonstrate that, in addition to being a cofactor for NS3 protease, flavivirus NS2B also functions in viral RNA replication, as well as virion assembly. Many flaviviruses are important human pathogens. Understanding the molecular mechanisms of the viral infection cycle is essential for vaccine and antiviral development. In this study, we demonstrate that the TMDs of JEV NS2B participate in both viral RNA replication and virion assembly. A viral genetic study and a BiFC assay demonstrated that interaction between NS2B and NS2A may participate in modulating viral assembly in the flavivirus life cycle. Compensatory-mutation analysis confirmed that there was a correlation between viral assembly and NS2B-NS2A interaction. TMDs of NS2B may serve as novel antiviral targets to prevent flavivirus infection, and the structure determination of NS2B will help us to understand the functional mechanism of NS2B in viral RNA replication and assembly. The results have uncovered a new function of flavivirus NS2B in virion assembly, possibly through interaction with the NS2A protein. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Attenuation of Recombinant Yellow Fever 17D Viruses Expressing Foreign Protein Epitopes at the Surface

PubMed Central

Bonaldo, Myrna C.; Garratt, Richard C.; Marchevsky, Renato S.; Coutinho, Evandro S. F.; Jabor, Alfredo V.; Almeida, Luís F. C.; Yamamura, Anna M. Y.; Duarte, Adriana S.; Oliveira, Prisciliana J.; Lizeu, Jackeline O. P.; Camacho, Luiz A. B.; Freire, Marcos S.; Galler, Ricardo

2005-01-01

The yellow fever (YF) 17D vaccine is a live attenuated virus. Three-dimensional (3D) homology modeling of the E protein structure from YF 17D virus and its comparison with that from tick-borne encephalitis virus revealed that it is possible to accommodate inserts of different sizes and amino acid compositions in the flavivirus E protein fg loop. This is consistent with the 3D structures of both the dimeric and trimeric forms in which the fg loop lies exposed to solvents. We demonstrate here that YF 17D viruses bearing foreign humoral (17D/8) and T-cell (17D/13) epitopes, which vary in sequence and length, displayed growth restriction. It is hypothesized that interference with the dimer-trimer transition and with the formation of a ring of such trimers in order to allow fusion compromises the capability of the E protein to induce fusion of viral and endosomal membranes, and a slower rate of fusion may delay the extent of virus production. This would account for the lower levels of replication in cultured cells and of viremia in monkeys, as well as for the more attenuated phenotype of the recombinant viruses in monkeys. Testing of both recombinant viruses (17D/8 and 17D/13) for monkey neurovirulence also suggests that insertion at the 17D E protein fg loop does not compromise the attenuated phenotype of YF 17D virus, further confirming the potential use of this site for the development of new live attenuated 17D virus-based vaccines. PMID:15956601

Purification and crystallization of dengue and West Nile virus NS2B–NS3 complexes

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

D’Arcy, Allan, E-mail: allan.darcy@novartis.com; Chaillet, Maxime; Schiering, Nikolaus

Crystals of dengue serotype 2 and West Nile virus NS2B–NS3 protease complexes have been obtained and the crystals of both diffract to useful resolution. Sample homogeneity was essential for obtaining X-ray-quality crystals of the dengue protease. Controlled proteolysis produced a crystallizable fragment of the apo West Nile virus NS2B–NS3 and crystals were also obtained in the presence of a peptidic inhibitor. Both dengue and West Nile virus infections are an increasing risk to humans, not only in tropical and subtropical areas, but also in North America and parts of Europe. These viral infections are generally transmitted by mosquitoes, but maymore » also be tick-borne. Infection usually results in mild flu-like symptoms, but can also cause encephalitis and fatalities. Approximately 2799 severe West Nile virus cases were reported this year in the United States, resulting in 102 fatalities. With this alarming increase in the number of West Nile virus infections in western countries and the fact that dengue virus already affects millions of people per year in tropical and subtropical climates, there is a real need for effective medicines. A possible therapeutic target to combat these viruses is the protease, which is essential for virus replication. In order to provide structural information to help to guide a lead identification and optimization program, crystallizations of the NS2B–NS3 protease complexes from both dengue and West Nile viruses have been initiated. Crystals that diffract to high resolution, suitable for three-dimensional structure determinations, have been obtained.« less

Brain Macrophages in Simian Immunodeficiency Virus-Infected, Antiretroviral-Suppressed Macaques: a Functional Latent Reservoir.

PubMed

Avalos, Claudia R; Abreu, Celina M; Queen, Suzanne E; Li, Ming; Price, Sarah; Shirk, Erin N; Engle, Elizabeth L; Forsyth, Ellen; Bullock, Brandon T; Mac Gabhann, Feilim; Wietgrefe, Stephen W; Haase, Ashley T; Zink, M Christine; Mankowski, Joseph L; Clements, Janice E; Gama, Lucio

2017-08-15

A human immunodeficiency virus (HIV) infection cure requires an understanding of the cellular and anatomical sites harboring virus that contribute to viral rebound upon treatment interruption. Despite antiretroviral therapy (ART), HIV-associated neurocognitive disorders (HAND) are reported in HIV-infected individuals on ART. Biomarkers for macrophage activation and neuronal damage in cerebrospinal fluid (CSF) of HIV-infected individuals demonstrate continued effects of HIV in brain and suggest that the central nervous system (CNS) may serve as a viral reservoir. Using a simian immunodeficiency virus (SIV)/macaque model for HIV encephalitis and AIDS, we evaluated whether infected cells persist in brain despite ART. Eight SIV-infected pig-tailed macaques were virally suppressed with ART, and plasma and CSF viremia levels were analyzed longitudinally. To assess whether virus persisted in brain macrophages (BrMΦ) in these macaques, we used a macrophage quantitative viral outgrowth assay (MΦ-QVOA), PCR, and in situ hybridization (ISH) to measure the frequency of infected cells and the levels of viral RNA and DNA in brain. Viral RNA in brain tissue of suppressed macaques was undetectable, although viral DNA was detected in all animals. The MΦ-QVOA demonstrated that the majority of suppressed animals contained latently infected BrMΦ. We also showed that virus produced in the MΦ-QVOAs was replication competent, suggesting that latently infected BrMΦ are capable of reestablishing productive infection upon treatment interruption. This report provides the first confirmation of the presence of replication-competent SIV in BrMΦ of ART-suppressed macaques and suggests that the highly debated issue of viral latency in macrophages, at least in brain, has been addressed in SIV-infected macaques treated with ART. IMPORTANCE Resting CD4 + T cells are currently the only cells that fit the definition of a latent reservoir. However, recent evidence suggests that HIV/SIV-infected macrophages persist despite ART. Markers of macrophage activation and neuronal damage are observed in the CSF of HIV-infected individuals and of SIV-infected macaques on suppressive ART regimens, suggesting that the CNS has continued virus infection and latent infection. A controversy exists as to whether brain macrophages represent a latent source of replication-competent virus capable of reestablishing infection upon treatment interruption. In this study, we demonstrated the presence of the latent macrophage reservoir in brains of SIV-infected ART-treated macaques and analyzed the reservoir using our established outgrowth assay to quantitate macrophages harboring replication-competent SIV genomes. Our results support the idea of the existence of other latent reservoirs in addition to resting CD4 + T cells and underscore the importance of macrophages in developing strategies to eradicate HIV. Copyright © 2017 Avalos et al.

Comparison of immune responses of brown-headed cowbird and related blackbirds to West Nile and other mosquito-borne encephalitis viruses

USGS Publications Warehouse

Reisen, W.K.; Hahn, D.C.

2007-01-01

The rapid geographic spread of West Nile virus (family Flaviviridae, genus Flavivirus, WNV) across the United States has stimulated interest in comparative host infection studies to delineate competent avian hosts critical for viral amplification. We compared the host competence of four taxonomically related blackbird species (Icteridae) after experimental infection with WNV and with two endemic, mosquito-borne encephalitis viruses, western equine encephalomyelitis virus (family Togaviridae, genus Alphavirus, WEEV), and St, Louis encephalitis virus (family Flaviviridae, genus Flavivirus, SLEV). We predicted differences in disease resistance among the blackbird species based on differences in life history, because they differ in geographic range and life history traits that include mating and breeding systems. Differences were observed among the response of these hosts to all three viruses, Red-winged Blackbirds were more susceptible to SLEV than Brewer's Blackbirds, whereas Brewer's Blackbirds were more susceptible to WEEV than Red-winged Blackbirds. In response to WNV infection, cowbirds showed the lowest mean viremias, cleared their infections faster, and showed lower antibody levels than concurrently infected species. Brown-headed Cowbirds also exhibited significantly lower viremia responses after infection with SLEV and WEEV as well as coinfection with WEEV and WNV than concurrently infected icterids. We concluded that cowbirds may be more resistant to infection to both native and introduced viruses because they experience heightened exposure to a variety of pathogens of parenting birds during the course of their parasitic life style.

Flavivirus-induced antibody cross-reactivity

PubMed Central

Mansfield, Karen L.; Horton, Daniel L.; Johnson, Nicholas; Li, Li; Barrett, Alan D. T.; Smith, Derek J.; Galbraith, Sareen E.; Solomon, Tom

2011-01-01

Dengue viruses (DENV) cause countless human deaths each year, whilst West Nile virus (WNV) has re-emerged as an important human pathogen. There are currently no WNV or DENV vaccines licensed for human use, yet vaccines exist against other flaviviruses. To investigate flavivirus cross-reactivity, sera from a human cohort with a history of vaccination against tick-borne encephalitis virus (TBEV), Japanese encephalitis virus (JEV) and yellow fever virus (YFV) were tested for antibodies by plaque reduction neutralization test. Neutralization of louping ill virus (LIV) occurred, but no significant neutralization of Murray Valley encephalitis virus was observed. Sera from some individuals vaccinated against TBEV and JEV neutralized WNV, which was enhanced by YFV vaccination in some recipients. Similarly, some individuals neutralized DENV-2, but this was not significantly influenced by YFV vaccination. Antigenic cartography techniques were used to generate a geometric illustration of the neutralization titres of selected sera against WNV, TBEV, JEV, LIV, YFV and DENV-2. This demonstrated the individual variation in antibody responses. Most sera had detectable titres against LIV and some had titres against WNV and DENV-2. Generally, LIV titres were similar to titres against TBEV, confirming the close antigenic relationship between TBEV and LIV. JEV was also antigenically closer to TBEV than WNV, using these sera. The use of sera from individuals vaccinated against multiple pathogens is unique relative to previous applications of antigenic cartography techniques. It is evident from these data that notable differences exist between amino acid sequence identity and mapped antigenic relationships within the family Flaviviridae. PMID:21900425

Flavivirus-induced antibody cross-reactivity.

PubMed

Mansfield, Karen L; Horton, Daniel L; Johnson, Nicholas; Li, Li; Barrett, Alan D T; Smith, Derek J; Galbraith, Sareen E; Solomon, Tom; Fooks, Anthony R

2011-12-01

Dengue viruses (DENV) cause countless human deaths each year, whilst West Nile virus (WNV) has re-emerged as an important human pathogen. There are currently no WNV or DENV vaccines licensed for human use, yet vaccines exist against other flaviviruses. To investigate flavivirus cross-reactivity, sera from a human cohort with a history of vaccination against tick-borne encephalitis virus (TBEV), Japanese encephalitis virus (JEV) and yellow fever virus (YFV) were tested for antibodies by plaque reduction neutralization test. Neutralization of louping ill virus (LIV) occurred, but no significant neutralization of Murray Valley encephalitis virus was observed. Sera from some individuals vaccinated against TBEV and JEV neutralized WNV, which was enhanced by YFV vaccination in some recipients. Similarly, some individuals neutralized DENV-2, but this was not significantly influenced by YFV vaccination. Antigenic cartography techniques were used to generate a geometric illustration of the neutralization titres of selected sera against WNV, TBEV, JEV, LIV, YFV and DENV-2. This demonstrated the individual variation in antibody responses. Most sera had detectable titres against LIV and some had titres against WNV and DENV-2. Generally, LIV titres were similar to titres against TBEV, confirming the close antigenic relationship between TBEV and LIV. JEV was also antigenically closer to TBEV than WNV, using these sera. The use of sera from individuals vaccinated against multiple pathogens is unique relative to previous applications of antigenic cartography techniques. It is evident from these data that notable differences exist between amino acid sequence identity and mapped antigenic relationships within the family Flaviviridae.

Comparison of immune responses of brown-headed cowbird and related blackbirds to west Nile and other mosquito-borne encephalitis viruses.

PubMed

Reisen, William K; Hahn, D Caldwell

2007-07-01

The rapid geographic spread of West Nile virus (family Flaviviridae, genus Flavivirus, WNV) across the United States has stimulated interest in comparative host infection studies to delineate competent avian hosts critical for viral amplification. We compared the host competence of four taxonomically related blackbird species (Icteridae) after experimental infection with WNV and with two endemic, mosquito-borne encephalitis viruses, western equine encephalomyelitis virus (family Togaviridae, genus Alphavirus, WEEV), and St. Louis encephalitis virus (family Flaviviridae, genus Flavivirus, SLEV). We predicted differences in disease resistance among the blackbird species based on differences in life history, because they differ in geographic range and life history traits that include mating and breeding systems. Differences were observed among the response of these hosts to all three viruses. Red-winged Blackbirds were more susceptible to SLEV than Brewer's Blackbirds, whereas Brewer's Blackbirds were more susceptible to WEEV than Red-winged Blackbirds. In response to WNV infection, cowbirds showed the lowest mean viremias, cleared their infections faster, and showed lower antibody levels than concurrently infected species. Brown-headed Cowbirds also exhibited significantly lower viremia responses after infection with SLEV and WEEV as well as coinfection with WEEV and WNV than concurrently infected icterids. We concluded that cowbirds may be more resistant to infection to both native and introduced viruses because they experience heightened exposure to a variety of pathogens of parenting birds during the course of their parasitic life style.

Effects of virus dose and extrinsic incubation temperature on vector competence of Culex nigripalpus (Diptera: Culicidae) for St. Louis encephalitis virus.

PubMed

Richards, Stephanie L; Anderson, Sheri L; Lord, Cynthia C; Tabachnick, Walter J

2012-11-01

Culex nigripalpus Theobald is a primary vector of St. Louis encephalitis virus in the southeastern United States. Cx. nigripalpus females were fed blood containing a low (4.0 +/- 0.01 log10 plaque-forming unit equivalents (PFUeq) /ml) or high (4.7 +/- 0.1 log10 PFUeq/ml) St. Louis encephalitis virus dose and maintained at extrinsic incubation temperatures (EIT) of 25 or 28 degrees C for 12 d. Vector competence was measured via quantitative real-time reverse transcriptase polymerase chain reaction to estimate PFUeq using rates of infection, dissemination, and transmission. There were no differences in infection rates between the two EITs at either dose. The low dose had higher infection rates at both EITs. Dissemination rates were significantly higher at 28 degrees C compared with 25 degrees C at both doses. Virus transmission was observed (<7%) only at 28 degrees C for both doses. The virus titer in body tissues was greater at 28 degrees C compared with 25 degrees C at both doses. The difference between the EITs was greater at the low dose, resulting in a higher titer for the low dose than the high dose at 28 degrees C. Virus titers in leg tissues were greater in mosquitoes fed the high versus low dose, but were not influenced by EIT. Further investigations using a variety of environmental and biological factors would be useful in exploring the complexity of vector competence.

Effects of Virus Dose and Extrinsic Incubation Temperature on Vector Competence of Culex nigripalpus (Diptera: Culicidae) for St. Louis Encephalitis Virus

PubMed Central

RICHARDS, STEPHANIE L.; ANDERSON, SHERI L.; LORD, CYNTHIA C.; TABACHNICK, WALTER J.

2013-01-01

Culex nigripalpus Theobald is a primary vector of St. Louis encephalitis virus in the southeastern United States. Cx. nigripalpus females were fed blood containing a low (4.0 ± 0.01 log10 plaque-forming unit equivalents (PFUeq)/ml) or high (4.7 ± 0.1 log10 PFUeq/ml) St. Louis encephalitis virus dose and maintained at extrinsic incubation temperatures (EIT) of 25 or 28°C for 12 d. Vector competence was measured via quantitative real-time reverse transcriptase polymerase chain reaction to estimate PFUeq using rates of infection, dissemination, and transmission. There were no differences in infection rates between the two EITs at either dose. The low dose had higher infection rates at both EITs. Dissemination rates were significantly higher at 28°C compared with 25°C at both doses. Virus transmission was observed (<7%) only at 28°C for both doses. The virus titer in body tissues was greater at 28°C compared with 25°C at both doses. The difference between the EITs was greater at the low dose, resulting in a higher titer for the low dose than the high dose at 28°C. Virus titers in leg tissues were greater in mosquitoes fed the high versus low dose, but were not influenced by EIT. Further investigations using a variety of environmental and biological factors would be useful in exploring the complexity of vector competence. PMID:23270182

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

PubMed

Levina, L S; Pogodina, V V

1981-01-01

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

West nile virus and other arboviral diseases - United States, 2013.

PubMed

Lindsey, Nicole P; Lehman, Jennifer A; Staples, J Erin; Fischer, Marc

2014-06-20

Arthropod-borne viruses (arboviruses) are transmitted to humans primarily through the bites of infected mosquitoes and ticks. West Nile virus (WNV) is the leading cause of domestically acquired arboviral disease in the United States. However, several other arboviruses also cause sporadic cases and seasonal outbreaks of neuroinvasive disease (i.e., meningitis, encephalitis, and acute flaccid paralysis). This report summarizes surveillance data reported to CDC in 2013 for WNV and other nationally notifiable arboviruses, excluding dengue. Forty-seven states and the District of Columbia reported 2,469 cases of WNV disease. Of these, 1,267 (51%) were classified as WNV neuroinvasive disease, for a national incidence of 0.40 per 100,000 population. After WNV, the next most commonly reported cause of arboviral disease was La Crosse virus (LACV) (85 cases), followed by Jamestown Canyon virus (JCV), Powassan virus (POWV), and eastern equine encephalitis virus (EEEV) (eight). WNV and other arboviruses continue to cause serious illness in substantial numbers of persons annually. Maintaining surveillance remains important to help direct and promote prevention activities.

Serologic diagnosis of West Nile and St. Louis encephalitis virus infections in domestic chickens.

PubMed

Patiris, Peter J; Oceguera, Leopoldo F; Peck, George W; Chiles, Robert E; Reisen, William K; Hanson, Carl V

2008-03-01

Adult domestic chickens were infected with West Nile virus (WNV) or St. Louis encephalitis virus (SLEV) and challenged with homologous or heterologous virus at 21 or 56 days postinfection (dpi). Sera were collected at selected time points after infection and assayed by enzyme immunoassay (EIA), plaque reduction neutralization test (PRNT), and a Western blot (WB) alternative to PRNT. EIA results were sensitive and accurate (few false positives) but not specific, requiring a confirmatory test to determine virus infection history. PRNT results generally were specific until challenge, after which test results were frequently equivocal and inadequate to determine first or second infecting virus. WB results confirmed the serologic cross-reactivity between WNV and SLEV envelope protein. Non-structural protein 1 and pre-membrane protein reactivities were highly specific for WNV during SLEV infection, but less specific for SLEV during WNV infection. WB and PRNT specificities were similar for both viruses from 6 to 14 dpi, and sensitivities to WNV were virtually identical.

Structure of a Venezuelan equine encephalitis virus assembly intermediate isolated from infected cells

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

Lamb, Kristen; Lokesh, G.L.; Sherman, Michael

2010-10-25

Venezuelan equine encephalitis virus (VEEV) is a prototypical enveloped ssRNA virus of the family Togaviridae. To better understand alphavirus assembly, we analyzed newly formed nucleocapsid particles (termed pre-viral nucleocapsids) isolated from infected cells. These particles were intermediates along the virus assembly pathway, and ultimately bind membrane-associated viral glycoproteins to bud as mature infectious virus. Purified pre-viral nucleocapsids were spherical with a unimodal diameter distribution. The structure of one class of pre-viral nucleocapsids was determined with single particle reconstruction of cryo-electron microscopy images. These studies showed that pre-viral nucleocapsids assembled into an icosahedral structure with a capsid stoichiometry similar to themore » mature nucleocapsid. However, the individual capsomers were organized significantly differently within the pre-viral and mature nucleocapsids. The pre-viral nucleocapsid structure implies that nucleocapsids are highly plastic and undergo glycoprotein and/or lipid-driven rearrangements during virus self-assembly. This mechanism of self-assembly may be general for other enveloped viruses.« less

CLEC5A Regulates Japanese Encephalitis Virus-Induced Neuroinflammation and Lethality

PubMed Central

Chen, Szu-Ting; Liu, Ren-Shyan; Wu, Ming-Fang; Lin, Yi-Ling; Chen, Se-Yi; Tan, David Tat-Wei; Chou, Teh-Ying; Tsai, I-Shuen; Li, Lei; Hsieh, Shie-Liang

2012-01-01

CLEC5A/MDL-1, a member of the myeloid C-type lectin family expressed on macrophages and neutrophils, is critical for dengue virus (DV)-induced hemorrhagic fever and shock syndrome in Stat1 −/− mice and ConA-treated wild type mice. However, whether CLEC5A is involved in the pathogenesis of viral encephalitis has not yet been investigated. To investigate the role of CLEC5A to regulate JEV-induced neuroinflammation, antagonistic anti-CLEC5A mAb and CLEC5A-deficient mice were generated. We find that Japanese encephalitis virus (JEV) directly interacts with CLEC5A and induces DAP12 phosphorylation in macrophages. In addition, JEV activates macrophages to secrete proinflammatory cytokines and chemokines, which are dramatically reduced in JEV-infected Clec5a−/− macrophages. Although blockade of CLEC5A cannot inhibit JEV infection of neurons and astrocytes, anti-CLEC5A mAb inhibits JEV-induced proinflammatory cytokine release from microglia and prevents bystander damage to neuronal cells. Moreover, JEV causes blood-brain barrier (BBB) disintegrity and lethality in STAT1-deficient (Stat1 −/−) mice, whereas peripheral administration of anti-CLEC5A mAb reduces infiltration of virus-harboring leukocytes into the central nervous system (CNS), restores BBB integrity, attenuates neuroinflammation, and protects mice from JEV-induced lethality. Moreover, all surviving mice develop protective humoral and cellular immunity against JEV infection. These observations demonstrate the critical role of CLEC5A in the pathogenesis of Japanese encephalitis, and identify CLEC5A as a target for the development of new treatments to reduce virus-induced brain damage. PMID:22536153

Multi-Gene Detection and Identification of Mosquito-Borne RNA Viruses Using an Oligonucleotide Microarray

PubMed Central

Grubaugh, Nathan D.; McMenamy, Scott S.; Turell, Michael J.; Lee, John S.

2013-01-01

Background Arthropod-borne viruses are important emerging pathogens world-wide. Viruses transmitted by mosquitoes, such as dengue, yellow fever, and Japanese encephalitis viruses, infect hundreds of millions of people and animals each year. Global surveillance of these viruses in mosquito vectors using molecular based assays is critical for prevention and control of the associated diseases. Here, we report an oligonucleotide DNA microarray design, termed ArboChip5.1, for multi-gene detection and identification of mosquito-borne RNA viruses from the genera Flavivirus (family Flaviviridae), Alphavirus (Togaviridae), Orthobunyavirus (Bunyaviridae), and Phlebovirus (Bunyaviridae). Methodology/Principal Findings The assay utilizes targeted PCR amplification of three genes from each virus genus for electrochemical detection on a portable, field-tested microarray platform. Fifty-two viruses propagated in cell-culture were used to evaluate the specificity of the PCR primer sets and the ArboChip5.1 microarray capture probes. The microarray detected all of the tested viruses and differentiated between many closely related viruses such as members of the dengue, Japanese encephalitis, and Semliki Forest virus clades. Laboratory infected mosquitoes were used to simulate field samples and to determine the limits of detection. Additionally, we identified dengue virus type 3, Japanese encephalitis virus, Tembusu virus, Culex flavivirus, and a Quang Binh-like virus from mosquitoes collected in Thailand in 2011 and 2012. Conclusions/Significance We demonstrated that the described assay can be utilized in a comprehensive field surveillance program by the broad-range amplification and specific identification of arboviruses from infected mosquitoes. Furthermore, the microarray platform can be deployed in the field and viral RNA extraction to data analysis can occur in as little as 12 h. The information derived from the ArboChip5.1 microarray can help to establish public health priorities, detect disease outbreaks, and evaluate control programs. PMID:23967358

Elaboration of a clinical and paraclinical score to estimate the probability of herpes simplex virus encephalitis in patients with febrile, acute neurologic impairment.

PubMed

Gennai, S; Rallo, A; Keil, D; Seigneurin, A; Germi, R; Epaulard, O

2016-06-01

Herpes simplex virus (HSV) encephalitis is associated with a high risk of mortality and sequelae, and early diagnosis and treatment in the emergency department are necessary. However, most patients present with non-specific febrile, acute neurologic impairment; this may lead clinicians to overlook the diagnosis of HSV encephalitis. We aimed to identify which data collected in the first hours in a medical setting were associated with the diagnosis of HSV encephalitis. We conducted a multicenter retrospective case-control study in four French public hospitals from 2007 to 2013. The cases were the adult patients who received a confirmed diagnosis of HSV encephalitis. The controls were all the patients who attended the emergency department of Grenoble hospital with a febrile acute neurologic impairment, without HSV detection by polymerase chain reaction (PCR) in the cerebrospinal fluid (CSF), in 2012 and 2013. A multivariable logistic model was elaborated to estimate factors significantly associated with HSV encephalitis. Finally, an HSV probability score was derived from the logistic model. We identified 36 cases and 103 controls. Factors independently associated with HSV encephalitis were the absence of past neurological history (odds ratio [OR] 6.25 [95 % confidence interval (CI): 2.22-16.7]), the occurrence of seizure (OR 8.09 [95 % CI: 2.73-23.94]), a systolic blood pressure ≥140 mmHg (OR 5.11 [95 % CI: 1.77-14.77]), and a C-reactive protein <10 mg/L (OR 9.27 [95 % CI: 2.98-28.88]). An HSV probability score was calculated summing the value attributed to each independent factor. HSV encephalitis diagnosis may benefit from the use of this score based upon some easily accessible data. However, diagnostic evocation and probabilistic treatment must remain the rule.

Cognitive impairment after acute encephalitis: comparison of herpes simplex and other aetiologies.

PubMed Central

Hokkanen, L; Poutiainen, E; Valanne, L; Salonen, O; Iivanainen, M; Launes, J

1996-01-01

OBJECTIVE: To compare the cognitive defects after acute acyclovir treated herpes simplex encephalitis with those after other types of acute encephalitis. METHODS: Seventy seven consecutive patients between 1985 and 1995 and 29 normal controls were studied. Of the 77 patients without concomitant neurological conditions, 17 had herpes simplex, one virus encephalitis (HSVE group), 27 had some other identified aetiology (non-HSVE group), and in 33 patients the cause was unknown. Acyclovir treatment was started less than four days after the first mental symptoms in 12 of 17 patients with HSVE. A thorough neuropsychological assessment was carried out about one month after the onset. RESULTS: The HSVE group had deficits in verbal memory, verbal-semantic functions, and visuoperceptual functions more often than the non-HSVE group. The risk for cognitive defects was twofold to four-fold in the patients with HSVE compared with the non-HSVE patients. Two (12%) of the patients with HSVE and 12 (44%) of the non-HSVE patients were cognitively intact. Six patients with HSVE (46%) and 17 (89%) non-HSVE patients later returned to work. The lesions on CT or MRI were bilateral only in one patient with HSVE. The defects in the three patients with adenovirus infection were severe and resembled the amnesia after HSVE. Cognitive impairment, not previously reported, was found in encephalitis after rotavirus infection and epidemic nephropathy. CONCLUSION: The recovery in the HSVE group was better than expected based on the medical literature. On the other hand there were surprisingly severe cognitive defects in encephalitis after other viruses. With early acyclovir treatment patients with the least severe HSVE were equivalent to those with non-HSV encephalitis with good outcome whereas those with the most severe non-HSV encephalitis were equivalent to those with HSVE with poor outcome. PMID:8937342

Experimental Infection of Syrian Hamsters with Aerosolized Nipah virus.

PubMed

Escaffre, Olivier; Hill, Terence; Ikegami, Tetsuro; Juelich, Terry L; Smith, Jennifer K; Zhang, Lihong; Perez, David E; Atkins, Colm; Park, Arnold; Lawrence, William S; Sivasubramani, Satheesh K; Peel, Jennifer E; Peterson, Johnny W; Lee, Benhur; Freiberg, Alexander N

2018-06-15

Nipah virus (NiV) is a paramyxovirus (genus henipavirus) that can cause severe respiratory illness and encephalitis in humans. Transmission occurs through consumption of NiV-contaminated foods, and contact with NiV-infected animals or human body fluids. However, it is unclear whether aerosols derived from aforesaid sources or others also contribute to transmission, and current knowledge on NiV-induced pathogenicity after small particle aerosol exposure is still limited. infectivity, pathogenicity and real-time dissemination of aerosolized NiV in Syrian hamsters was evaluated using NiV-Malaysia (NiV-M) and/or its recombinant expressing firefly luciferase (rNiV-Fluc NP). both viruses had an equivalent pathogenicity in hamsters that developed respiratory and neurological symptoms of disease, similar to using intranasal route, with no direct correlations to the dose. Finally, we show that virus replication was predominantly initiated in the lower respiratory tract, and although delayed, also intensely in the oronasal cavity and possibly the brain, with gradual increase of signal in these regions until at least day 5-6 post-infection. hamsters infected with small-particle aerosolized NiV undergo similar clinical manifestations of the disease as previously described using liquid inoculum, and exhibit histopathological lesions consistent with NiV patient reports. NiV droplets could therefore play a role in transmission by close contact.

Regulation of cell survival and death during Flavivirus infections

PubMed Central

Ghosh Roy, Sounak; Sadigh, Beata; Datan, Emmanuel; Lockshin, Richard A; Zakeri, Zahra

2014-01-01

Flaviviruses, ss(+) RNA viruses, include many of mankind’s most important pathogens. Their pathogenicity derives from their ability to infect many types of cells including neurons, to replicate, and eventually to kill the cells. Flaviviruses can activate tumor necrosis factor α and both intrinsic (Bax-mediated) and extrinsic pathways to apoptosis. Thus they can use many approaches for activating these pathways. Infection can lead to necrosis if viral load is extremely high or to other types of cell death if routes to apoptosis are blocked. Dengue and Japanese Encephalitis Virus can also activate autophagy. In this case the autophagy temporarily spares the infected cell, allowing a longer period of reproduction for the virus, and the autophagy further protects the cell against other stresses such as those caused by reactive oxygen species. Several of the viral proteins have been shown to induce apoptosis or autophagy on their own, independent of the presence of other viral proteins. Given the versatility of these viruses to adapt to and manipulate the metabolism, and thus to control the survival of, the infected cells, we need to understand much better how the specific viral proteins affect the pathways to apoptosis and autophagy. Only in this manner will we be able to minimize the pathology that they cause. PMID:24921001

Alexander the Great and West Nile virus encephalitis.

PubMed

Marr, John S; Calisher, Charles H

2003-12-01

Alexander the Great died in Babylon in 323 BC. His death at age 32 followed a 2-week febrile illness. Speculated causes of death have included poisoning; assassination, and a number of infectious diseases. One incident, mentioned by Plutarch but not considered by previous investigators, may shed light on the cause of Alexander's death. The incident, which occurred as he entered Babylon, involved a flock of ravens exhibiting unusual behavior and subsequently dying at his feet. The inexplicable behavior of ravens is reminiscent of avian illness and death weeks before the first human cases of West Nile virus infection were identified in the United States. We posit that Alexander may have died of West Nile virus encephalitis.

BK virus encephalitis with thrombotic microangiopathy in an allogeneic hematopoietic stem cell transplant recipient.

PubMed

Lopes da Silva, R; Ferreira, I; Teixeira, G; Cordeiro, D; Mafra, M; Costa, I; Bravo Marques, J M; Abecasis, M

2011-04-01

BK virus (BKV) infection occurs most often in immunocompromised hosts, in the setting of renal or bone marrow transplantation. Hemorrhagic cystitis is the commonest manifestation but in recent years infections in other organ systems have been reported. We report an unusual case of biopsy-proven BKV encephalitis in a hematopoietic stem cell transplant patient who subsequently developed thrombotic microangiopathy. As far as we know, this is the first report of such an association in a transplant patient. © 2010 John Wiley & Sons A/S.

Multifunctional Nature of the Arenavirus RING Finger Protein Z

PubMed Central

Fehling, Sarah Katharina; Lennartz, Frank; Strecker, Thomas

2012-01-01

Arenaviruses are a family of enveloped negative-stranded RNA viruses that can cause severe human disease ranging from encephalitis symptoms to fulminant hemorrhagic fever. The bi‑segmented RNA genome encodes four polypeptides: the nucleoprotein NP, the surface glycoprotein GP, the polymerase L, and the RING finger protein Z. Although it is the smallest arenavirus protein with a length of 90 to 99 amino acids and a molecular weight of approx. 11 kDa, the Z protein has multiple functions in the viral life cycle including (i) regulation of viral RNA synthesis, (ii) orchestration of viral assembly and budding, (iii) interaction with host cell proteins, and (iv) interferon antagonism. In this review, we summarize our current understanding of the structural and functional role of the Z protein in the arenavirus replication cycle. PMID:23202512

Japanese encephalitis virus replicon-based vaccine expressing enterovirus-71 epitope confers dual protection from lethal challenges.

PubMed

Huang, Yi-Ting; Liao, Jia-Teh; Yen, Li-Chen; Chang, Yung-Kun; Lin, Yi-Ling; Liao, Ching-Len

2015-09-11

To construct safer recombinant flavivirus vaccine, we exploited Japanese encephalitis virus (JEV) replicon-based platform to generate single-round infectious particles (SRIPs) that expressed heterologous neutralizing epitope SP70 derived from enterovirus-71 (EV71). Such pseudo-infectious virus particles, named SRIP-SP70, although are not genuine viable viruses, closely mimic live virus infection to elicit immune responses within one round of viral life cycle. We found that, besides gaining of full protection to thwart JEV lethal challenge, female outbred ICR mice, when were immunized with SRIP-SP70 by prime-boost protocol, could not only induce SP70-specific and IgG2a predominant antibodies but also provide their newborns certain degree of protection against EV71 lethal challenge. Our results therefore exemplify that this vaccination strategy could indeed confer an immunized host a dual protective immunity against subsequent lethal challenge from JEV or EV71.

Environmental and Biological Factors Influencing Culex pipiens quinquefasciatus Say (Diptera: Culicidae) Vector Competence for Saint Louis Encephalitis Virus

PubMed Central

Richards, Stephanie L.; Lord, Cynthia C.; Pesko, Kendra; Tabachnick, Walter J.

2009-01-01

Complex interactions between environmental and biological factors influence the susceptibility of Culex pipiens quinquefasciatus to St. Louis encephalitis virus and could affect the epidemiology of virus transmission. Similar interactions could have epidemiologic implications for other vector-virus systems. We conducted an experiment to examine four such factors in combination: mosquito age, extrinsic incubation temperature (EIT), virus dose, and colony. The proportion of mosquitoes with body infections or disseminated infections varied between colonies, and was dependant on age, EIT, and dose. We also show that the probability of a body or leg infection interacted in complex ways between colonies, ages, EITs, and doses. The complex interactive effects of environmental and biological factors must be taken into account for studies of vector competence and epidemiology, especially when laboratory studies are used to generalize to natural transmission dynamics where the extent of variation is largely unknown. PMID:19635881

Nipah virus outbreak in Malaysia.

PubMed

Chua, Kaw Bing

2003-04-01

Nipah virus, a novel paramyxovirus, closely related to Hendra virus emerged in northern part of Peninsular Malaysia in 1998. The virus caused an outbreak of severe febrile encephalitis in humans with a high mortality rate, whereas, in pigs, encephalitis and respiratory diseases but with a relatively low mortality rate. The outbreak subsequently spread to various regions of the country and Singapore in the south due to the movement of infected pigs. Nipah virus caused systemic infections in humans, pigs and other mammals. Histopathological and radiological findings were characteristic of the disease. Fruitbats of Pteropid species were identified as the natural reservoir hosts. Evidence suggested that climatic and anthropogenic driven ecological changes coupled with the location of piggeries in orchard and the design of pigsties allowed the spill-over of this novel paramyxovirus from its reservoir host into the domestic pigs and ultimately to humans and other animals.

Production of Japanese encephalitis virus-like particles in insect cells.

PubMed

Yamaji, Hideki; Konishi, Eiji

2013-01-01

Virus-like particles (VLPs) are composed of one or several recombinant viral surface proteins that spontaneously assemble into particulate structures without the incorporation of virus DNA or RNA. The baculovirus-insect cell system has been used extensively for the production of recombinant virus proteins including VLPs. While the baculovirus-insect cell system directs the transient expression of recombinant proteins in a batch culture, stably transformed insect cells allow constitutive production. In our recent study, a secretory form of Japanese encephalitis (JE) VLPs was successfully produced by Trichoplusia ni BTI-TN-5B1-4 (High Five) cells engineered to coexpress the JE virus (JEV) premembrane (prM) and envelope (E) proteins. A higher yield of E protein was attained with recombinant High Five cells than with the baculovirus-insect cell system. This study demonstrated that recombinant insect cells offer a promising approach to the high-level production of VLPs for use as vaccines and diagnostic antigens.

Antibodies to H5 subtype avian influenza virus and Japanese encephalitis virus in northern pintails (Anas acuta) sampled in Japan

USGS Publications Warehouse

Ramey, Andy M.; Spackman, Erica; Yeh, Jung-Yong; Fujita, Go; Konishi, Kan; Reed, John A.; Wilcox, Benjamin R.; Brown, Justin D.; Stallknecht, David E.

2013-01-01

Blood samples from 105 northern pintails (Anas acuta) captured on Hokkaido, Japan were tested for antibodies to avian influenza virus (AIV), Japanese encephalitis virus (JEV), and West Nile virus (WNV) to assess possible involvement of this species in the spread of economically important and potentially zoonotic pathogens. Antibodies to AIV were detected in 64 of 105 samples (61%). Of the 64 positives, 95% and 81% inhibited agglutination of two different H5 AIV antigens (H5N1 and H5N9), respectively. Antibodies to JEV and WNV were detected in five (5%) and none of the samples, respectively. Results provide evidence for prior exposure of migrating northern pintails to H5 AIV which couldhave implications for viral shedding and disease occurrence. Results also provide evidence for limited involvement of this species in the transmission and spread of flaviviruses during spring migration.

Environmental and biological factors influencing Culex pipiens quinquefasciatus Say (Diptera: Culicidae) vector competence for Saint Louis encephalitis virus.

PubMed

Richards, Stephanie L; Lord, Cynthia C; Pesko, Kendra; Tabachnick, Walter J

2009-08-01

Complex interactions between environmental and biological factors influence the susceptibility of Culex pipiens quinquefasciatus to St. Louis encephalitis virus and could affect the epidemiology of virus transmission. Similar interactions could have epidemiologic implications for other vector-virus systems. We conducted an experiment to examine four such factors in combination: mosquito age, extrinsic incubation temperature (EIT), virus dose, and colony. The proportion of mosquitoes with body infections or disseminated infections varied between colonies, and was dependant on age, EIT, and dose. We also show that the probability of a body or leg infection interacted in complex ways between colonies, ages, EITs, and doses. The complex interactive effects of environmental and biological factors must be taken into account for studies of vector competence and epidemiology, especially when laboratory studies are used to generalize to natural transmission dynamics where the extent of variation is largely unknown.

West Nile Virus Infection in Sheep.

PubMed

Rimoldi, G; Mete, A; Adaska, J M; Anderson, M L; Symmes, K P; Diab, S

2017-01-01

West Nile virus (WNV) infection has been detected in many species of birds and mammals, but scant information is available about the disease in small ruminants. West Nile virus was diagnosed in 6 sheep with neurological signs and encephalitis, in California between 2002 and 2014. All sheep had severe lymphoplasmacytic meningoencephalitis. Lymphoplasmacytic myelitis was also detected in 2 sheep where the spinal cord was examined. Brain tissue was positive for WNV detected by polymerase chain reaction in 6 of 6 sheep and by immunohistochemistry (IHC) in 5 of 6 sheep. Viral antigen was not detected by IHC in extraneural tissues in the 3 sheep examined. West Nile virus RNA was sequenced from 2 of 6 sheep, and each one clusters closely with WNV isolated from mosquito pools from nearby locations at similar times. West Nile virus was the most common cause of viral encephalitis in sheep diagnosed at this laboratory between 2002 and 2014, accounting for 6 of 9 sheep.

World Reference Center for Arboviruses

DTIC Science & Technology

1991-05-08

Japanese encephalitis virus and acted as sentinels. By molecular hniques it was shown that the dengue-2 viruses in Venezuela and Brazil are very...12 A. Molecular epidemiology of dengue viruses ................... 12 B. Vaccinia virus recombinants expressing Japanese...of Kagoshima virus (strain KC-05Y84) to the Palyam group. Plaque reduction neutralization tests were done with eight viruses of the Palyam serogroup

Encephalitis Hospitalization Rates and Inpatient Mortality in the United States, 2000-2010

PubMed Central

George, Benjamin P.

2014-01-01

Background Encephalitis rates by etiology and acute-phase outcomes for encephalitis in the 21st century are largely unknown. We sought to evaluate cause-specific rates of encephalitis hospitalizations and predictors of inpatient mortality in the United States. Methods Using the Nationwide Inpatient Sample (NIS) from 2000 to 2010, a retrospective observational study of 238,567 patients (mean [SD] age, 44.8 [24.0] years) hospitalized within non-federal, acute care hospitals in the U.S. with a diagnosis of encephalitis was conducted. Hospitalization rates were calculated using population-level estimates of disease from the NIS and population estimates from the United States Census Bureau. Adjusted odds of mortality were calculated for patients included in the study. Results In the U.S. from 2000–2010, there were 7.3±0.2 encephalitis hospitalizations per 100,000 population (95% CI: 7.1–7.6). Encephalitis hospitalization rates were highest among females (7.6±0.2 per 100,000) and those <1 year and >65 years of age with rates of 13.5±0.9 and 14.1±0.4 per 100,000, respectively. Etiology was unknown for approximately 50% of cases. Among patients with identified etiology, viral causes were most common (48.2%), followed by Other Specified causes (32.5%), which included predominantly autoimmune conditions. The most common infectious agents were herpes simplex virus, toxoplasma, and West Nile virus. Comorbid HIV infection was present in 7.7% of hospitalizations. Average length of stay was 11.2 days with mortality of 5.6%. In regression analysis, patients with comorbid HIV/AIDS or cancer had increased odds of mortality (odds ratio [OR]  = 1.70; 95% CI: 1.30–2.22 and OR = 2.26; 95% CI: 1.88–2.71, respectively). Enteroviral, postinfectious, toxic, and Other Specified causes were associated with lower odds vs. herpes simplex encephalitis. Conclusions While encephalitis and encephalitis-related mortality impose a considerable burden in the U.S. in the 21st Century, the reported demographics of hospitalized encephalitis patients may be changing. PMID:25192177

Hospitalized Children With Encephalitis in the United States: A Pediatric Health Information System Database Study.

PubMed

Bagdure, Dayanand; Custer, Jason W; Rao, Suchitra; Messacar, Kevin; Dominguez, Samuel; Beam, Brandon W; Bhutta, Adnan

2016-08-01

Given the paucity of data on resource utilization among children with encephalitis, the objective of this study was to describe the epidemiology and evaluate resource utilization and discharge data of children with encephalitis admitted to US hospitals from 2004 to 2013. We conducted a retrospective cohort study utilizing the Pediatric Health Information System database of children aged 0 to 18 years with the International Classification of Diseases, Ninth Revision codes for encephalitis from 2004 to 2013. Only the initial admissions were included, and the age group analyzed was 0 to 18 years. Among 7298 children with encephalitis, 2933 (40%) were admitted to a pediatric intensive care unit. The median age was nine years, the overall median length of stay was 16 days, and children requiring critical care had a median length of stay of 25 days. Children in the pediatric intensive care unit were more likely to have seizures (P <0.001) and head magnetic resonance imaging (P <0.001) than children on the floor. Similarly, children requiring critical care were more likely to have a broad diagnostic evaluation sent including cerebrospinal fluid cultures, blood bacterial and fungal cultures, western equine encephalitis antibody, St. Louis equine encephalitis antibody, varicella-zoster serology, human immunodeficiency virus 1 antibody, human immunodeficiency virus DNA polymerase chain reaction, acid-fast stain, and Lyme disease serology. Seventeen percent of children were treated with intravenous immunoglobulin, and 4% underwent plasmapheresis. There was a trend of increasing use of intravenous immunoglobulin and plasmapheresis in children with encephalitis over the study period. A total of 5944 (81%) children were discharged home, and the mortality in this cohort was 3% (230). The mean charges for hospitalization for a child with encephalitis was $64,604 and for those requiring critical care was $260,012. Encephalitis is a significant cause of morbidity and mortality in children. Children with encephalitis admitted to the pediatric intensive care unit are more likely to have seizures and to undergo a more extensive evaluation to determine the cause of encephalitis. Use of plasmapheresis and intravenous immunoglobulin is on the rise in hospitalized children. Prospective studies are necessary to better understand treatment and intervention strategies for children with encephalitis and their impact on outcomes. Copyright © 2016 Elsevier Inc. All rights reserved.

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

Meagher, Robert J.; Ball, Cameron Scott; Langevin, Stanley A.

In this study, collection of mosquitoes and testing for vector-borne viruses is a key surveillance activity that directly influences the vector control efforts of public health agencies, including determining when and where to apply insecticides. Vector control districts in California routinely monitor for three human pathogenic viruses including West Nile virus (WNV), Western equine encephalitis virus (WEEV), and St. Louis encephalitis virus (SLEV). Reverse transcription quantitative polymerase chain reaction (RT-qPCR) offers highly sensitive and specific detection of these three viruses in a single multiplex reaction, but this technique requires costly, specialized equipment that is generally only available in centralized publicmore » health laboratories. We report the use of reverse transcription loop-mediated isothermal amplification (RT-LAMP) to detect WNV, WEEV, and SLEV RNA extracted from pooled mosquito samples collected in California, including novel primer sets for specific detection of WEEV and SLEV, targeting the nonstructural protein 4 (nsP4) gene of WEEV and the 3’ untranslated region (3’-UTR) of SLEV. Our WEEV and SLEV RT-LAMP primers allowed detection of <0.1 PFU/reaction of their respective targets in <30 minutes, and exhibited high specificity without cross reactivity when tested against a panel of alphaviruses and flaviviruses. Furthermore, the SLEV primers do not cross-react with WNV, despite both viruses being closely related members of the Japanese encephalitis virus complex. The SLEV and WEEV primers can also be combined in a single RT-LAMP reaction, with discrimination between amplicons by melt curve analysis. Although RT-qPCR is approximately one order of magnitude more sensitive than RT-LAMP for all three targets, the RT-LAMP technique is less instrumentally intensive than RT-qPCR and provides a more cost-effective method of vector-borne virus surveillance.« less

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

PubMed

Markoff, L

2000-05-26

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

Non-Hemagglutinating Flaviviruses: Molecular Mechanisms for the Emergence of New Strains via Adaptation to European Ticks

PubMed Central

Khasnatinov, Maxim A.; Ustanikova, Katarina; Frolova, Tatiana V.; Pogodina, Vanda V.; Bochkova, Nadezshda G.; Levina, Ludmila S.; Slovak, Mirko; Kazimirova, Maria; Labuda, Milan; Klempa, Boris; Eleckova, Elena; Gould, Ernest A.; Gritsun, Tamara S.

2009-01-01

Tick-borne encephalitis virus (TBEV) causes human epidemics across Eurasia. Clinical manifestations range from inapparent infections and fevers to fatal encephalitis but the factors that determine disease severity are currently undefined. TBEV is characteristically a hemagglutinating (HA) virus; the ability to agglutinate erythrocytes tentatively reflects virion receptor/fusion activity. However, for the past few years many atypical HA-deficient strains have been isolated from patients and also from the natural European host tick, Ixodes persulcatus. By analysing the sequences of HA-deficient strains we have identified 3 unique amino acid substitutions (D67G, E122G or D277A) in the envelope protein, each of which increases the net charge and hydrophobicity of the virion surface. Therefore, we genetically engineered virus mutants each containing one of these 3 substitutions; they all exhibited HA-deficiency. Unexpectedly, each genetically modified non-HA virus demonstrated increased TBEV reproduction in feeding Ixodes ricinus, not the recognised tick host for these strains. Moreover, virus transmission efficiency between infected and uninfected ticks co-feeding on mice was also intensified by each substitution. Retrospectively, the mutation D67G was identified in viruses isolated from patients with encephalitis. We propose that the emergence of atypical Siberian HA-deficient TBEV strains in Europe is linked to their molecular adaptation to local ticks. This process appears to be driven by the selection of single mutations that change the virion surface thus enhancing receptor/fusion function essential for TBEV entry into the unfamiliar tick species. As the consequence of this adaptive mutagenesis, some of these mutations also appear to enhance the ability of TBEV to cross the human blood-brain barrier, a likely explanation for fatal encephalitis. Future research will reveal if these emerging Siberian TBEV strains continue to disperse westwards across Europe by adaptation to the indigenous tick species and if they are associated with severe forms of TBE. PMID:19802385

Induction of virus-specific effector immune cell response limits virus replication and severe disease in mice infected with non-lethal West Nile virus Eg101 strain.

PubMed

Kumar, Mukesh; Roe, Kelsey; O'Connell, Maile; Nerurkar, Vivek R

2015-09-22

West Nile virus (WNV) is a neurotropic flavivirus that has emerged globally as a significant cause of viral encephalitis in humans. Herein, we investigated the immunological responses induced by two phylogenetically related WNV strains of lineage 1, WNV NY99, and WNV Eg101. Eight-week-old C57BL/6J mice were inoculated with WNV NY99 or WNV Eg101 and mortality, virus burden in the periphery and brain, type 1 interferon response, WNV-specific antibodies, leukocyte infiltration, and inflammatory responses were analyzed. As expected, WNV NY99 infected mice demonstrated high morbidity and mortality, whereas no morbidity and mortality was observed in WNV Eg101 infected mice. Virus titers were comparable in the serum of both WNV NY99 and WNV Eg101 infected mice at day 3 after inoculation; however, at day 6, the virus was cleared from WNV Eg101 infected mice but the virus titer remained high in the WNV NY99 infected mice. Virus was detected in the brains of both WNV NY99 and Eg101 infected mice, albeit significantly higher in the brains of WNV NY99 infected mice. Surprisingly, levels of type 1 interferon and WNV-specific antibodies were significantly higher in the serum and brains of WNV NY99 infected mice. Similarly, protein levels of multiple cytokines and chemokines were significantly higher in the serum and brains of WNV NY99 infected mice. In contrast, we observed significantly higher numbers of innate and adaptive immune cells in the spleens and brains of WNV Eg101 infected mice. Moreover, total number and percentage of IFN-γ and TNF-α producing WNV-specific CD8(+) T cells were also significantly high in WNV Eg101 infected mice. Our data demonstrate that induction of virus-specific effector immune cell response limits virus replication and severe WNV disease in Eg101 infected mice. Our data also demonstrate an inverse correlation between leukocyte accumulation and production of pro-inflammatory mediators in WNV-infected mice. Moreover, increased production of pro-inflammatory mediators was associated with high-virus titers and increased mortality in WNV NY99 infected mice.

HLA and killer cell immunoglobulin-like receptor (KIRs) genotyping in patients with acute viral encephalitis

PubMed Central

Tuttolomondo, Antonino; Colomba, Claudia; Di Bona, Danilo; Casuccio, Alessandra; Di Raimondo, Domenico; Clemente, Giuseppe; Arnao, Valentina; Pecoraro, Rosaria; Ragonese, Paolo; Aiello, Anna; Accardi, Giulia; Maugeri, Rosario; Maida, Carlo; Simonetta, Irene; Della Corte, Vittoriano; Iacopino, Domenico Gerardo; Caruso, Calogero; Cascio, Antonio; Pinto, Antonio

2018-01-01

Introduction The HLA genes, as well as the innate immune KIR genes, are considered relevant determinants of viral outcomes but no study, to our knowledge, has evaluated their role in the clinical setting of acute viral encephalitis. Results Subjects with acute viral encephalitis in comparison to subjects without acute viral encephalitis showed a significantly higher frequency of 2DL1 KIR gene and AA KIR haplotypes and of HLA-C2 and HLA-A-Bw4 alleles. Subjects without acute viral encephalitis showed a higher frequency of interaction between KIR2DL2 and HLAC1. Multiple logistic regression analysis showed the detrimental effect of HLA-A haplotype and HLA-C1, HLA-A-BW4 HLA-B-BW4T alleles, whereas multiple logistic regression showed a protective effect of AB+BB KIR haplotype and a detrimental effect of interaction between KIR3DL1 and HLA-A-Bw4. Discussion Our findings of a lower frequency of activating receptors in patients with acute encephalitis compared to controls could result in a less efficient response of NK cells. This finding could represent a possible pathogenetic explanation of susceptibility to acute symptomatic encephalitis in patients with viral infection from potentially responsible viruses such as Herpes virus. Materials and Methods 30 Consecutive patients with symptomatic acute viral encephalitis and as controls, 36 consecutive subjects without acute encephalitis were analyzed. The following KIR genes were analyzed, KIR2DL1, 2DL2, 2DL3, 2DL5, 3DL1, 3DL2, 3DL3, 2DL4, 2DS1, 2DS2, 2DS3, 2DS4, 2DS5, 3DS1, 2 pseudogenes (2DP1 and 3DP1) and the common variants of KIR2DL5 (KIR2DL5A, KIR2DL5B). PMID:29707126

Use of clinical and neuroimaging characteristics to distinguish temporal lobe herpes simplex encephalitis from its mimics.

PubMed

Chow, Felicia C; Glaser, Carol A; Sheriff, Heather; Xia, Dongxiang; Messenger, Sharon; Whitley, Richard; Venkatesan, Arun

2015-05-01

We describe the spectrum of etiologies associated with temporal lobe (TL) encephalitis and identify clinical and radiologic features that distinguish herpes simplex encephalitis (HSE) from its mimics. We reviewed all adult cases of encephalitis with TL abnormalities on magnetic resonance imaging (MRI) from the California Encephalitis Project. We evaluated the association between specific clinical and MRI characteristics and HSE compared with other causes of TL encephalitis and used multivariate logistic modeling to identify radiologic predictors of HSE. Of 251 cases of TL encephalitis, 43% had an infectious etiology compared with 16% with a noninfectious etiology. Of infectious etiologies, herpes simplex virus was the most commonly identified agent (n = 60), followed by tuberculosis (n = 8) and varicella zoster virus (n = 7). Of noninfectious etiologies, more than half (n = 21) were due to autoimmune disease. Patients with HSE were older (56.8 vs 50.2 years; P = .012), more likely to be white (53% vs 35%; P = .013), more likely to present acutely (88% vs 64%; P = .001) and with a fever (80% vs 49%; P < .001), and less likely to present with a rash (2% vs 15%; P = .010). In a multivariate model, bilateral TL involvement (odds ratio [OR], 0.38; 95% confidence interval [CI], .18-.79; P = .010) and lesions outside the TL, insula, or cingulate (OR, 0.37; 95% CI, .18-.74; P = .005) were associated with lower odds of HSE. In addition to HSE, other infectious and noninfectious etiologies should be considered in the differential diagnosis for TL encephalitis, depending on the presentation. Specific clinical and imaging features may aid in distinguishing HSE from non-HSE causes of TL encephalitis. © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.