The NS5 protein of the virulent West Nile virus NY99 strain is a potent antagonist of type I interferon-mediated JAK-STAT signaling

Laurent-Rolle, Maudry, Boer, Elena F., Lubick, Kirk J., Wolfinbarger, James B., Carmody, Aaron B., Rockx, Barry, Liu, Wenjun, Ashour, Joseph, Shupert, W. Lesley, Holbrook, Michael R., Barrett, Alan D., Mason, Peter W., Bloom, Marshall E., Garcia-Sastre, Adolfo, Khromykh, Alexander A. and Best, Sonja M. (2010) The NS5 protein of the virulent West Nile virus NY99 strain is a potent antagonist of type I interferon-mediated JAK-STAT signaling. Journal of Virology, 84 7: 3503-3515. doi:10.1128/JVI.01161-09

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Author Laurent-Rolle, Maudry
Boer, Elena F.
Lubick, Kirk J.
Wolfinbarger, James B.
Carmody, Aaron B.
Rockx, Barry
Liu, Wenjun
Ashour, Joseph
Shupert, W. Lesley
Holbrook, Michael R.
Barrett, Alan D.
Mason, Peter W.
Bloom, Marshall E.
Garcia-Sastre, Adolfo
Khromykh, Alexander A.
Best, Sonja M.
Title The NS5 protein of the virulent West Nile virus NY99 strain is a potent antagonist of type I interferon-mediated JAK-STAT signaling
Journal name Journal of Virology   Check publisher's open access policy
ISSN 0022-538X
Publication date 2010-04-01
Sub-type Article (original research)
DOI 10.1128/JVI.01161-09
Open Access Status File (Publisher version)
Volume 84
Issue 7
Start page 3503
End page 3515
Total pages 13
Place of publication Washington, DC, United States
Publisher American Society for Microbiology
Collection year 2011
Language eng
Formatted abstract
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-α/β)-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. Copyright © 2010, American Society for Microbiology. All Rights Reserved.
Keyword Japanese encephalitis-virus
Tick-borne flavivirus
Dengue virus
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2011 Collection
School of Chemistry and Molecular Biosciences
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Created: Sun, 21 Mar 2010, 00:03:21 EST