title: A determinant of Sindbis virus neurovirulence enables efficient disruption of Jak/STAT signaling.
abstract: Previous studies with Venezuelan equine encephalitis virus and Sindbis virus (SINV) indicate that alphaviruses are capable of suppressing the cellular response to type I and type II interferons (IFNs) by disrupting Jak/STAT signaling; however, the relevance of this signaling inhibition toward pathogenesis has not been investigated. The relative abilities of neurovirulent and nonneurovirulent SINV strains to downregulate Jak/STAT signaling were compared to determine whether the ability to inhibit IFN signaling correlates with virulence potential. The adult mouse neurovirulent strain AR86 was found to rapidly and robustly inhibit tyrosine phosphorylation of STAT1 and STAT2 in response to IFN-γ and/or IFN-β. In contrast, the closely related SINV strains Girdwood and TR339, which do not cause detectable disease in adult mice, were relatively inefficient inhibitors of STAT1/2 activation. Decreased STAT activation in AR86-infected cells was associated with decreased activation of the IFN receptor-associated tyrosine kinases Tyk2, Jak1, and Jak2. To identify the viral factor(s) involved, we infected cells with several panels of AR86/Girdwood chimeric viruses. Surprisingly, we found that a single amino acid determinant, threonine at nsP1 position 538, which is required for AR86 virulence, was also required for efficient disruption of STAT1 activation, and this determinant fully restored STAT1 inhibition when it was introduced into the avirulent Girdwood background. These data indicate that a key virulence determinant plays a critical role in downregulating the response to type I and type II IFNs, which suggests that the ability of alphaviruses to inhibit Jak/STAT signaling relates to their in vivo virulence potential.
authors.affiliation: Department of Genetics, The Carolina Vaccine Institute, University of North Carolina at Chapel Hill, 9039 Burnett-Womack Bldg., CB #7292, Chapel Hill, NC 27599, USA.
authors.forename: Jason D
authors.initials: JD
authors.lastname: Simmons
authors.forename: Amy C
authors.initials: AC
authors.lastname: Wollish
authors.forename: Mark T
authors.initials: MT
authors.lastname: Heise
mesh_terms: D000818:Animals; D002522:Chlorocebus aethiops; D015536:Down-Regulation; D007370:Interferon Type I; D007371:Interferon-gamma; D053612:Janus Kinases / Q000378:metabolism*; D051379:Mice; D010766:Phosphorylation; D050791:STAT Transcription Factors / Q000378:metabolism*; D015398:Signal Transduction; D012845:Sindbis Virus / Q000472:pathogenicity*; D013045:Species Specificity; D014709:Vero Cells; D014774:Virulence
chemical_list: D007370:Interferon Type I; D050791:STAT Transcription Factors; D007371:Interferon-gamma; D053612:Janus Kinases