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      Characterization of Virulent West Nile Virus Kunjin Strain, Australia, 2011

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          Abstract

          An encephalitis outbreak among horses was caused by a pathogenic variant of Kunjin virus.

          Abstract

          To determine the cause of an unprecedented outbreak of encephalitis among horses in New South Wales, Australia, in 2011, we performed genomic sequencing of viruses isolated from affected horses and mosquitoes. Results showed that most of the cases were caused by a variant West Nile virus (WNV) strain, WNV NSW2011, that is most closely related to WNV Kunjin (WNV KUN), the indigenous WNV strain in Australia. Studies in mouse models for WNV pathogenesis showed that WNV NSW2011 is substantially more neuroinvasive than the prototype WNV KUN strain. In WNV NSW2011, this apparent increase in virulence over that of the prototype strain correlated with at least 2 known markers of WNV virulence that are not found in WNV KUN. Additional studies are needed to determine the relationship of the WNV NSW2011 strain to currently and previously circulating WNV KUN strains and to confirm the cause of the increased virulence of this emerging WNV strain.

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          Most cited references 23

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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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            A single positively selected West Nile viral mutation confers increased virogenesis in American crows.

            West Nile virus (WNV), first recognized in North America in 1999, has been responsible for the largest arboviral epiornitic and epidemic of human encephalitis in recorded history. Despite the well-described epidemiological patterns of WNV in North America, the basis for the emergence of WNV-associated avian pathology, particularly in the American crow (AMCR) sentinel species, and the large scale of the North American epidemic and epiornitic is uncertain. We report here that the introduction of a T249P amino acid substitution in the NS3 helicase (found in North American WNV) in a low-virulence strain was sufficient to generate a phenotype highly virulent to AMCRs. Furthermore, comparative sequence analyses of full-length WNV genomes demonstrated that the same site (NS3-249) was subject to adaptive evolution. These phenotypic and evolutionary results provide compelling evidence for the positive selection of a mutation encoding increased viremia potential and virulence in the AMCR sentinel bird species.
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              The NS5 protein of the virulent West Nile virus NY99 strain is a potent antagonist of type I interferon-mediated JAK-STAT signaling.

              Flaviviruses transmitted by arthropods represent a tremendous disease burden for humans, causing millions of infections annually. All vector-borne flaviviruses studied to date suppress host innate responses to infection by inhibiting alpha/beta interferon (IFN-alpha/beta)-mediated JAK-STAT signal transduction. The viral nonstructural protein NS5 of some flaviviruses functions as the major IFN antagonist, associated with inhibition of IFN-dependent STAT1 phosphorylation (pY-STAT1) or with STAT2 degradation. West Nile virus (WNV) infection prevents pY-STAT1 although a role for WNV NS5 in IFN antagonism has not been fully explored. Here, we report that NS5 from the virulent NY99 strain of WNV prevented pY-STAT1 accumulation, suppressed IFN-dependent gene expression, and rescued the growth of a highly IFN-sensitive virus (Newcastle disease virus) in the presence of IFN, suggesting that this protein can function as an efficient IFN antagonist. In contrast, NS5 from Kunjin virus (KUN), a naturally attenuated subtype of WNV, was a poor suppressor of pY-STAT1. Mutation of a single residue in KUN NS5 to the analogous residue in WNV-NY99 NS5 (S653F) rendered KUN NS5 an efficient inhibitor of pY-STAT1. Incorporation of this mutation into recombinant KUN resulted in 30-fold greater inhibition of JAK-STAT signaling than with the wild-type virus and enhanced KUN replication in the presence of IFN. Thus, a naturally occurring mutation is associated with the function of NS5 in IFN antagonism and may influence virulence of WNV field isolates.
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                Author and article information

                Journal
                Emerg Infect Dis
                Emerging Infect. Dis
                EID
                Emerging Infectious Diseases
                Centers for Disease Control and Prevention
                1080-6040
                1080-6059
                May 2012
                : 18
                : 5
                : 792-800
                Affiliations
                Elizabeth Macarthur Agriculture Institute, Menangle, New South Wales, Australia (M.J. Frost, J. Zhang, X. Gu, R. Davis, C. Hornitzky, K.E. Arzey, D. Finlaison, P. Hick, A. Read, P.D. Kirkland);
                The University of Queensland, St Lucia, Queensland, Australia (J.H. Edmonds, N.A Prow, J. Hobson-Peters, F.J. May, R.A. Hall, A. A. Khromykh);
                University of Sydney and Westmead Hospital, Westmead, New South Wales, Australia (S.L. Doggett, J. Haniotis, R.C. Russell)
                Author notes
                Address for correspondence: Peter D. Kirkland, Virology Laboratory, Elizabeth Macarthur Agricultural Institute, PMB 4008, Narellan, NSW 2567, Australia; email: peter.kirkland@ 123456dpi.nsw.gov.au
                Article
                11-1720
                10.3201/eid1805.111720
                3358055
                22516173
                Categories
                Research
                Research

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