Current Understanding of West Nile Virus Clinical Manifestations, Immune Responses, Neuroinvasion, and Immunotherapeutic Implications.
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SUBMITTER: Bai F
PROVIDER: S-EPMC6963678 | biostudies-literature | 2019 Oct
REPOSITORIES: biostudies-literature
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Current Understanding of West Nile Virus Clinical Manifestations, Immune Responses, Neuroinvasion, and Immunotherapeutic Implications.
Bai Fengwei F Thompson E Ashley EA Vig Parminder J S PJS Leis A Arturo AA
Pathogens (Basel, Switzerland) 20191016 4
West Nile virus (WNV) is the most common mosquito-borne virus in North America. WNV-associated neuroinvasive disease affects all ages, although elderly and immunocompromised individuals are particularly at risk. WNV neuroinvasive disease has killed over 2300 Americans since WNV entered into the United States in the New York City outbreak of 1999. Despite 20 years of intensive laboratory and clinical research, there are still no approved vaccines or antivirals available for human use. However, ra ...[more]
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Project description:BackgroundA challenge to the design of improved therapeutic agents and prevention strategies for neuroinvasive infection and associated disease is the lack of known natural immune correlates of protection. A relevant model to study such correlates is offered by the Collaborative Cross (CC), a panel of recombinant inbred mouse strains that exhibit a range of disease manifestations upon infection.MethodsWe performed an extensive screen of CC-F1 lines infected with West Nile virus (WNV), including comprehensive immunophenotyping, to identify groups of lines that exhibited viral neuroinvasion or neuroinvasion with disease and lines that remained free of WNV neuroinvasion and disease.ResultsOur data reveal that protection from neuroinvasion and disease is multifactorial and that several immune outcomes can contribute. Immune correlates identified include decreased suppressive activity of regulatory T cells at steady state, which correlates with peripheral restriction of the virus. Further, a rapid contraction of WNV-specific CD8+ T cells in the brain correlated with protection from disease.ConclusionsThese immune correlates of protection illustrate additional networks and pathways of the WNV immune response that cannot be observed in the C57BL/6 mouse model. Additionally, correlates of protection exhibited before infection, at baseline, provide insight into phenotypic differences in the human population that may predict clinical outcomes upon infection.
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Project description:West Nile virus (WNV) can cause severe human neurological diseases including encephalitis and meningitis. The mechanisms by which WNV enters the central nervous system (CNS) and host-factors that are involved in WNV neuroinvasion are not completely understood. The proinflammatory chemokine osteopontin (OPN) is induced in multiple neuroinflammatory diseases and is responsible for leukocyte recruitment to sites of its expression. In this study, we found that WNV infection induced OPN expression in both human and mouse cells. Interestingly, WNV-infected OPN deficient (Opn -/-) mice exhibited a higher survival rate (70%) than wild type (WT) control mice (30%), suggesting OPN plays a deleterious role in WNV infection. Despite comparable levels of viral load in circulating blood cells and peripheral organs in the two groups, WNV-infected polymorphonuclear neutrophil (PMN) infiltration and viral burden in brain of Opn -/- mice were significantly lower than in WT mice. Importantly, intracerebral administration of recombinant OPN into the brains of Opn -/- mice resulted in increased WNV-infected PMN infiltration and viral burden in the brain, which was coupled to increased mortality. The overall results suggest that OPN facilitates WNV neuroinvasion by recruiting WNV-infected PMNs into the brain.
| S-EPMC5498593 | biostudies-literature
Project description:Purpose of reviewWest Nile virus (WNV) is the most important cause of epidemic encephalitis in the United States. We review articles published in the last 18 months related to the epidemiology, immunology, clinical features, and treatment of this disease.Recent findingsThere was a resurgence in WNV disease in the United States in 2012. The WNV strain now predominant in the United States (NA/WN02) differs from the initial emergent isolate in 1999 (NY99). However, differences in the genetics of currently circulating United States WNV strains do not explain variations in epidemic magnitude or disease severity. Innate and acquired immunity are critical in control of WNV, and in some cases pathways are central nervous system specific. The clinical features of infection are now well understood, although nonconfirmed observations of chronic viral excretion in urine remain controversial. There is no specific antiviral therapy for WNV, but studies of antivirals specific for other flaviviruses may identify agents with promise against WNV. Phase I and II human WNV vaccine clinical trials have established that well tolerated and immunogenic WNV vaccines can be developed.SummaryWNV remains an important public health problem. Although recent studies have significantly increased our understanding of host immune and genetic factors involved in control of WNV infection, no specific therapy is yet available. Development of a well tolerated, immunogenic, and effective vaccine against WNV is almost certainly feasible, but economic factors and the lack of predictability of the magnitude and location of outbreaks are problematic for designing phase III trials and ultimate licensure.
| S-EPMC4050660 | biostudies-literature
Project description:Although interferon-? [also known as type III interferon or interleukin-28 (IL-28)/IL-29] restricts infection by several viruses, its inhibitory mechanism has remained uncertain. We used recombinant interferon-? and mice lacking the interferon-? receptor (IFNLR1) to evaluate the effect of interferon-? on infection with West Nile virus, an encephalitic flavivirus. Cell culture studies in mouse keratinocytes and dendritic cells showed no direct antiviral effect of exogenous interferon-?, even though expression of interferon-stimulated genes was induced. We observed no differences in West Nile virus burden between wild-type and Ifnlr1(-/-) mice in the draining lymph nodes, spleen, or blood. We detected increased West Nile virus infection in the brain and spinal cord of Ifnlr1(-/-) mice, yet this was not associated with a direct antiviral effect in mouse neurons. Instead, we observed an increase in blood-brain barrier permeability in Ifnlr1(-/-) mice. Treatment of mice with pegylated interferon-?2 resulted in decreased blood-brain barrier permeability, reduced West Nile virus infection in the brain without affecting viremia, and improved survival against lethal virus challenge. An in vitro model of the blood-brain barrier showed that interferon-? signaling in mouse brain microvascular endothelial cells increased transendothelial electrical resistance, decreased virus movement across the barrier, and modulated tight junction protein localization in a protein synthesis- and signal transducer and activator of transcription 1 (STAT1)-independent manner. Our data establish an indirect antiviral function of interferon-? in which noncanonical signaling through IFNLR1 tightens the blood-brain barrier and restricts viral neuroinvasion and pathogenesis.
| S-EPMC4435724 | biostudies-literature
Project description:Although type III interferons (IFN), also known as IFN-λ or IL28/IL-29, restrict infection by several viruses, their mechanism of inhibitory action has remained uncertain. We used recombinant IFN-λ and mice lacking the IFN-λ receptor (IFNLR1) to evaluate the effect of IFN-λ on infection with West Nile virus (WNV), an encephalitic flavivirus. Cell culture studies in keratinocytes and dendritic cells showed no direct antiviral effect of exogenous IFN-λ even though ISGs were induced. Correspondingly, we observed no differences in WNV burden between wild-type and Ifnlr1-/- mice in the draining lymph node, spleen, and blood. However, we detected earlier dissemination and increased WNV infection in the brain and spinal cord of Ifnlr1-/- mice, yet this was not associated with a direct antiviral effect on infection of neurons. Instead, an increase in blood-brain barrier (BBB) permeability was observed in Ifnlr1-/- mice. Accordingly, treatment of mice with pegylated IFN-λ2 resulted in decreased BBB permeability, reduced WNV infection in the brain without impacting viremia, and improved survival against lethal virus challenge. An in vitro model of the BBB showed that IFN-λ signaling in brain microvascular endothelial cells increased transendothelial electrical resistance, decreased virus movement across the barrier, and modulated tight junction protein localization in a protein synthesis- and STAT1-independent manner. Our data establish a novel indirect antiviral function of IFN-λ in which non-canonical signaling through IFNLR1 tightens the BBB and restricts viral neuroinvasion and pathogenesis. This finding suggests new clinical applications for IFN-λ in treating viral or autoimmune diseases.
2015-01-08 | GSE64735 | GEO
Project description:The nonstructural (NS) proteins of West Nile virus (WNV) have been associated with participation in evasion of host innate immune defenses. In the present study, we characterized immune response to an attenuated WNV strain, which has a P38G substitution in the NS4B protein. The WNV NS4B-P38G mutant induced a lower level of viremia and no lethality in C57BL/6 (B6) mice following a systemic infection. Interestingly, there were higher type 1 IFNs and IL-1? responses compared to mice infected by wild-type WNV. NS4B-P38G mutant-infected mice also showed stronger effector and memory T cell responses. WNV specific antibody responses were not different between mice infected with these two viruses. As a consequence, all mice were protected from a secondary infection with a lethal dose of wild-type WNV following a primary infection with NS4B-P38G mutant. Moreover, NS4B-P38G mutant infection in cultured bone-marrow derived dendritic cells (DCs) were shown to have a reduced replication rate, but a higher level of innate cytokine production than wild-type WNV, some of which were dependent on Myd88 signaling. In conclusion, the NS4B-P38G mutant strain induces higher protective innate and adaptive immune response in mice, which results in a lower viremia and no lethality in either primary or secondary infection, suggesting a high potential as an attenuating mutation in a vaccine candidate.
| S-EPMC3114109 | biostudies-literature
Project description:The introduction of West Nile virus (WNV) into North America has been associated with relatively high rates of neurological disease and death in humans, birds, horses, and some other animals. Previous studies identified strains in both genetic lineage 1 and genetic lineage 2, including North American isolates of lineage 1, that were highly virulent in a mouse neuroinvasion model, while other strains were avirulent or significantly attenuated (D. W. C. Beasley, L. Li, M. T. Suderman, and A. D. T. Barrett, Virology 296:17-23, 2002). To begin to elucidate the basis for these differences, we compared a highly virulent New York 1999 (NY99) isolate with a related Old World lineage 1 strain, An4766 (ETH76a), which is attenuated for mouse neuroinvasion. Genomic sequencing of ETH76a revealed a relatively small number of nucleotide (5.1%) and amino acid (0.6%) differences compared with NY99. These differences were located throughout the genome and included five amino acid differences in the envelope protein gene. Substitution of premembrane and envelope genes of ETH76a into a NY99 infectious clone backbone yielded a virus with altered in vitro growth characteristics and a mouse virulence phenotype comparable to ETH76a. Further site-specific mutagenesis studies revealed that the altered phenotype was primarily mediated via loss of envelope protein glycosylation and that this was associated with altered stability of the virion at mildly acidic pH. Therefore, the enhanced virulence of North American WNV strains compared with other Old World lineage 1 strains is at least partly mediated by envelope protein glycosylation.
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Project description:BackgroundWest Nile Virus (WNV) is a mosquito-borne flavivirus that has caused ongoing seasonal epidemics in the United States since 1999. It is estimated that ≤1% of WNV-infected patients will develop neuroinvasive disease (West Nile encephalitis and/or myelitis) that can result in debilitating morbidities and long-term sequelae. It is essential to collect longitudinal information about the recovery process and to characterize predicative factors that may assist in therapeutic decision-making in the future.MethodsWe report a longitudinal study of the neurological outcomes (as measured by neurological examination, Glascow Coma Scale, and Modified Mini-Mental State Examination) for 55 subjects with WNV neuroinvasive disease (confirmed by positive CSF IgM) assessed on day 7, at discharge, and on days 14, 30, and 90. The neurological outcome measures were coma (presence and degree), global cognitive status, presence of cranial neuropathy, tremors and/or weakness.ResultsAt initial clinical presentation 93% presented with a significant neurological deficit (49% with weakness, 35% with tremor, and 16% with cranial neuropathy). The number of patients with a cognitive deficit fell from 25 at initial evaluation to 9 at their last evaluation. Cranial neuropathy was present in 9 at onset and in only 4 patients at study conclusion. Of the 19 patients who had a tremor at enrollment, 11 continued to exhibit a tremor at follow-up. Seven patients died after initial enrollment in the study, with 5 of those having presented in a coma. The factors that predict either severity or long-term recovery of neurological function include age (older individuals were weaker at follow-up examination), gender (males recovered better from coma), and presentation in a coma with cranial nerve deficits (had a poorer recovery particularly with regard to cognition).ConclusionsThis study represents one of the largest clinical investigations providing prospectively-acquired neurological outcomes data among American patients with WNV central nervous system disease. The findings show that the factors that influence prognosis from the initial presentation include age, gender, and specific neurological deficits at onset.Trial registrationClinicalTrials.gov identifier: NCT00138463 and NCT00069316.
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Project description:Although type III interferons (IFN), also known as IFN-λ or IL28/IL-29, restrict infection by several viruses, their mechanism of inhibitory action has remained uncertain. We used recombinant IFN-λ and mice lacking the IFN-λ receptor (IFNLR1) to evaluate the effect of IFN-λ on infection with West Nile virus (WNV), an encephalitic flavivirus. Cell culture studies in keratinocytes and dendritic cells showed no direct antiviral effect of exogenous IFN-λ even though ISGs were induced. Correspondingly, we observed no differences in WNV burden between wild-type and Ifnlr1-/- mice in the draining lymph node, spleen, and blood. However, we detected earlier dissemination and increased WNV infection in the brain and spinal cord of Ifnlr1-/- mice, yet this was not associated with a direct antiviral effect on infection of neurons. Instead, an increase in blood-brain barrier (BBB) permeability was observed in Ifnlr1-/- mice. Accordingly, treatment of mice with pegylated IFN-λ2 resulted in decreased BBB permeability, reduced WNV infection in the brain without impacting viremia, and improved survival against lethal virus challenge. An in vitro model of the BBB showed that IFN-λ signaling in brain microvascular endothelial cells increased transendothelial electrical resistance, decreased virus movement across the barrier, and modulated tight junction protein localization in a protein synthesis- and STAT1-independent manner. Our data establish a novel indirect antiviral function of IFN-λ in which non-canonical signaling through IFNLR1 tightens the BBB and restricts viral neuroinvasion and pathogenesis. This finding suggests new clinical applications for IFN-λ in treating viral or autoimmune diseases. Transcriptome profiling of bone-marrow derived Dendritic cells(BMDCs), treated with either Serum Free Media(Mock), interferon beta(IFNb), or interferon lambda(IFNL) for 6 hours.
2015-01-08 | E-GEOD-64735 | biostudies-arrayexpress
Project description:We described the rapid production of the domain III (DIII) of the envelope (E) protein in plants as a vaccine candidate for West Nile Virus (WNV). Using various combinations of vector modules of a deconstructed viral vector expression system, DIII was produced in three subcellular compartments in leaves of Nicotiana benthamiana by transient expression. DIII expressed at much higher levels when targeted to the endoplasmic reticulum (ER) than that targeted to the chloroplast or the cytosol, with accumulation level up to 73? ? g DIII per gram of leaf fresh weight within 4 days after infiltration. Plant ER-derived DIII was soluble and readily purified to >?95% homogeneity without the time-consuming process of denaturing and refolding. Further analysis revealed that plant-produced DIII was processed properly and demonstrated specific binding to an anti-DIII monoclonal antibody that recognizes a conformational epitope. Furthermore, subcutaneous immunization of mice with 5 and 25? ? g of purified DIII elicited a potent systemic response. This study provided the proof of principle for rapidly producing immunogenic vaccine candidates against WNV in plants with low cost and scalability.
| S-EPMC3996298 | biostudies-literature