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      Genetic Variation in OAS1 Is a Risk Factor for Initial Infection with West Nile Virus in Man

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          West Nile virus (WNV) is a re-emerging pathogen that can cause fatal encephalitis. In mice, susceptibility to WNV has been reported to result from a single point mutation in oas1b, which encodes 2′–5′ oligoadenylate synthetase 1b, a member of the type I interferon-regulated OAS gene family involved in viral RNA degradation. In man, the human ortholog of oas1b appears to be OAS1. The ‘A’ allele at SNP rs10774671 of OAS1 has previously been shown to alter splicing of OAS1 and to be associated with reduced OAS activity in PBMCs. Here we show that the frequency of this hypofunctional allele is increased in both symptomatic and asymptomatic WNV seroconverters (Caucasians from five US centers; total n = 501; OR = 1.6 [95% CI 1.2–2.0], P = 0.0002 in a recessive genetic model). We then directly tested the effect of this SNP on viral replication in a novel ex vivo model of WNV infection in primary human lymphoid tissue. Virus accumulation varied markedly among donors, and was highest for individuals homozygous for the ‘A’ allele ( P<0.0001). Together, these data identify OAS1 SNP rs10774671 as a host genetic risk factor for initial infection with WNV in humans.

          Author Summary

          When humans are exposed to infectious agents, the outcome may vary: some remain uninfected, some who become infected remain asymptomatic, and symptomatic individuals may develop clinical manifestations that vary in number and severity. Both host and environmental factors are thought to influence outcome. Here we show that a specific human mutation that results in reduced function in a known antiviral gene named OAS1 is associated with increased rate of infection with West Nile virus, a member of the flavivirus family. OAS1 codes for a component of the type I interferon signaling system; its homologue in mice has been shown previously to be important for flavivirus susceptibility. Individuals carrying two copies of the hypofunctional variant of OAS1 were found more frequently than expected among both asymptomatic and symptomatic WNV-positive individuals. To investigate further, we developed a novel model of WNV replication using human tonsil tissue in which high variability in replication was observed among donors. We found that the highest virus accumulation occurred in donors with two copies of the hypofunctional OAS1 variant. Together these data suggest that OAS1 activity may influence the probability of initial infection, but not the severity or symptomatic quality of infection, after WNV exposure in man.

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          Most cited references 43

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          Origin of the West Nile virus responsible for an outbreak of encephalitis in the northeastern United States.

          In late summer 1999, an outbreak of human encephalitis occurred in the northeastern United States that was concurrent with extensive mortality in crows (Corvus species) as well as the deaths of several exotic birds at a zoological park in the same area. Complete genome sequencing of a flavivirus isolated from the brain of a dead Chilean flamingo (Phoenicopterus chilensis), together with partial sequence analysis of envelope glycoprotein (E-glycoprotein) genes amplified from several other species including mosquitoes and two fatal human cases, revealed that West Nile (WN) virus circulated in natural transmission cycles and was responsible for the human disease. Antigenic mapping with E-glycoprotein-specific monoclonal antibodies and E-glycoprotein phylogenetic analysis confirmed these viruses as WN. This North American WN virus was most closely related to a WN virus isolated from a dead goose in Israel in 1998.
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            West Nile fever--a reemerging mosquito-borne viral disease in Europe.

             Z Hubalek,  J Halouzka (1999)
            West Nile virus causes sporadic cases and outbreaks of human and equine disease in Europe (western Mediterranean and southern Russia in 1962-64, Belarus and Ukraine in the 1970s and 1980s, Romania in 1996-97, Czechland in 1997, and Italy in 1998). Environmental factors, including human activities, that enhance population densities of vector mosquitoes (heavy rains followed by floods, irrigation, higher than usual temperature, or formation of ecologic niches that enable mass breeding of mosquitoes) could increase the incidence of West Nile fever.
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              Epidemic West Nile encephalitis, New York, 1999: results of a household-based seroepidemiological survey.

              In the summer of 1999, West Nile virus was recognised in the western hemisphere for the first time when it caused an epidemic of encephalitis and meningitis in the metropolitan area of New York City, NY, USA. Intensive hospital-based surveillance identified 59 cases, including seven deaths in the region. We did a household-based seroepidemiological survey to assess more clearly the public-health impact of the epidemic, its range of illness, and risk factors associated with infection. We used cluster sampling to select a representative sample of households in an area of about 7.3 km(2) at the outbreak epicentre. All individuals aged 5 years or older were eligible for interviews and phlebotomy. Serum samples were tested for IgM and IgG antibodies specific for West Nile virus. 677 individuals from 459 households participated. 19 were seropositive (weighted seroprevalence 2.6% [95% CI 1.2-4.1). Six (32%) of the seropositive individuals reported a recent febrile illness compared with 70 of 648 (11%) seronegative participants (difference 21% [0-47]). A febrile syndrome with fatigue, headache, myalgia, and arthralgia was highly associated with seropositivity (prevalence ratio 7.4 [1.5-36.6]). By extrapolation from the 59 diagnosed meningoencephalitis cases, we conservatively estimated that the New York outbreak consisted of 8200 (range 3500-13000) West Nile viral infections, including about 1700 febrile infections. During the 1999 West Nile virus outbreak, thousands of symptomless and symptomatic West Nile viral infections probably occurred, with fewer than 1% resulting in severe neurological disease.

                Author and article information

                Role: Editor
                PLoS Pathog
                PLoS Pathogens
                Public Library of Science (San Francisco, USA )
                February 2009
                February 2009
                27 February 2009
                : 5
                : 2
                [1 ]Molecular Signaling Section, Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America
                [2 ]Section on Intercellular Interactions, Laboratory of Cellular and Molecular Biology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, United States of America
                [3 ]Comparative Medicine Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, United States of America
                [4 ]Illinois Department of Public Health, Division of Laboratories, Chicago, Illinois, United States of America
                [5 ]Colorado Department of Public Health and Environment, Denver, Colorado, United States of America
                [6 ]Biostatistics Research Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America
                [7 ]American Red Cross, Gaithersburg, Maryland, United States of America
                The Rockefeller University, United States of America
                Author notes

                Conceived and designed the experiments: JKL AL DHM PMM. Performed the experiments: JKL AL LH JMW. Analyzed the data: JKL DHM LH DF PMM. Contributed reagents/materials/analysis tools: AL JMW BJ HJ JP GAF DK DF SLS LM PMM. Wrote the paper: JKL DHM PMM.

                This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.
                Page count
                Pages: 12
                Research Article
                Immunology/Innate Immunity
                Infectious Diseases/Viral Infections
                Virology/Host Antiviral Responses

                Infectious disease & Microbiology


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