1887

Abstract

A variant Australian West Nile virus (WNV) strain, WNV, 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 WNV was less virulent than the human-pathogenic American strain of WNV, New York 99 (WNV). To identify viral genes and mutations responsible for the difference in virulence between WNV and WNV 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 WNV, when substituted with that of WNV, 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 WNV NS3 to increased virus replication and evasion of IFN response in cells, and to virulence in mice. Other WNV 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 WNV and WNV strains, and accumulative mutations within these proteins would likely be required for the Australian WNV strain to become significantly more virulent.

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2015-06-01
2020-01-21
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