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

Maudry Laurent-Rolle, Elena F. Boer, Kirk J. Lubick, James B. Wolfinbarger, Aaron B. Carmody, Barry Rockx, Wenjun Liu, Joseph Ashour, W. Lesley Shupert, Michael R. Holbrook, Alan Barrett, Peter W. Mason, Marshall E. Bloom, Adolfo García-Sastre, Alexander A. Khromykh, Sonja M. Best

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)3503-3515
Number of pages13
JournalJournal of Virology
Volume84
Issue number7
DOIs
StatePublished - Apr 2010

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West Nile virus
Interferon Type I
interferons
antagonists
proteins
Flaviviridae
Flavivirus
mutation
Mutation
flavivirus NS5 protein
Viral Nonstructural Proteins
infection
interferon-beta
Viruses
Newcastle disease virus
viruses
burden of disease
Arthropods
Interferon-beta
Virus Diseases

ASJC Scopus subject areas

  • Immunology
  • Virology

Cite this

Laurent-Rolle, M., Boer, E. F., Lubick, K. J., Wolfinbarger, J. B., Carmody, A. B., Rockx, B., ... Best, S. 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. https://doi.org/10.1128/JVI.01161-09

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; Mason, Peter W.; Bloom, Marshall E.; García-Sastre, Adolfo; Khromykh, Alexander A.; Best, Sonja M.

In: Journal of Virology, Vol. 84, No. 7, 04.2010, p. 3503-3515.

Research output: Contribution to journalArticle

Laurent-Rolle, M, Boer, EF, Lubick, KJ, Wolfinbarger, JB, Carmody, AB, Rockx, B, Liu, W, Ashour, J, Shupert, WL, Holbrook, MR, Barrett, A, Mason, PW, Bloom, ME, García-Sastre, A, Khromykh, AA & Best, SM 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, vol. 84, no. 7, pp. 3503-3515. https://doi.org/10.1128/JVI.01161-09
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 ; Mason, Peter W. ; Bloom, Marshall E. ; García-Sastre, Adolfo ; Khromykh, Alexander A. ; Best, Sonja M. / The NS5 protein of the virulent West Nile virus NY99 strain is a potent antagonist of type I interferon-mediated JAK-STAT signaling. In: Journal of Virology. 2010 ; Vol. 84, No. 7. pp. 3503-3515.
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AU - Ashour, Joseph

AU - Shupert, W. Lesley

AU - Holbrook, Michael R.

AU - Barrett, Alan

AU - Mason, Peter W.

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