Molecular pathogenesis of the Sindbis-group virus strain AR86 Public Deposited

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  • March 21, 2019
Creator
  • Suthar, Mehul Shamal
    • Affiliation: School of Medicine, Department of Microbiology and Immunology
Abstract
  • Sindbis virus infection of mice has provided valuable insight into the viral and host factors that contribute to virus-induced neurologic disease. In an effort to further define the viral genetic elements that contribute to adult mouse neurovirulence, the virulent Sindbis-group virus strain AR86 was compared to the closely related (22 single amino acid coding differences and the presence or absence of an 18 amino acid sequence in nsP3), but avirulent Girdwood strain. Detailed mapping studies identified three major determinants in the nonstructural region at nsP1 538 (Ile to Thr; avirulent to virulent), an 18 amino acid deletion in nsP3 (positions 386-403), and nsP3 537 (Opal to Cys; avirulent to virulent), as well as a single determinant in the structural genes at E2 243 (Leu to Ser; avirulent to virulent) that were essential for AR86 adult mouse neurovirulence. Of these four virulence determinants, we found that the virulence determinant at nsP1 538 plays a particularly important role. This determinant has been shown to regulate viral nonstructural processing, viral RNA synthesis, and play a major role in regulating adult mouse neurovirulence. Analysis of the effect of the nsP1 538 determinant on modulating the host antiviral response demonstrated that an attenuating mutation at nsP1 538 resulted in enhanced type I interferon induction. While most alphaviruses have been shown to inhibit type I interferon induction through virus-induced host cell shutoff, we demonstrated that the Sindbis-group virus strain AR86 inhibits type I interferon induction through an additional mechanism by inhibiting the activation of interferon regulatory factor 3 (IRF-3), a key mediator of type I interferon induction. In an effort to extend these findings, we examined virus interactions with the type I interferon induction signaling pathway. We found that although AR86 genomic RNA is efficiently recognized by retinoic-acid inducible gene I (RIG-I), a host cytoplasmic sensor of viral dsRNA, AR86 virus actively antagonized IRF-3 activation induced from an exogenous source of dsRNA. Furthermore, the viral nonstructural proteins (nsPs), when expressed independently of virus infection, inhibited RIG-I and melanoma-differentiation-associated gene 5 (Mda5), a related host cytoplasmic sensor of viral dsRNA, signaling. Strikingly, co-expression of the viral nsPs proteins led to the loss of RIG-I, Mda5, and IRF-3 expression in a manner that was dependent on the nsP2 protease. These results demonstrate that the viral nonstructural proteins specifically antagonize the type I interferon induction signaling pathway and suggest that the virus may directly target components of the type I interferon induction signaling pathway. The results from these studies have provided significant insight into the viral and host factors that mediate virus-induced disease and have advanced our understanding of the mechanisms underlying alphavirus pathogenesis.
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  • In Copyright
Advisor
  • Heise, Mark
Degree granting institution
  • University of North Carolina at Chapel Hill
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  • Open access
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