Inhibition of type I and type II interferon signaling by alphavirus nonstructural proteins Public Deposited

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  • March 21, 2019
Creator
  • Simmons, Jason Davis
    • Affiliation: School of Medicine, Department of Microbiology and Immunology
Abstract
  • Alphaviruses are mosquito-borne pathogens that represent an emerging threat due their capacity to cause large outbreaks of infectious disease ranging from severe arthritis, as observed with the current chikungunya virus outbreak in the Indian Ocean, to potentially fatal encephalitis, as witnessed by periodic outbreaks of Venezeulan equine encephalitis virus (VEEV). Type I interferon (IFN) plays a crucial role in limiting alphavirus replication and pathogenic strains must employ mechanisms to downregulate this response. In these studies, we have identified a previously unrecognized mechanism by which VEEV and Sindbis virus (SINV) inhibit the response to both type I and type II IFNs, which presumably would limit the antiviral effects of these cytokines within infected cells. Studies with VEEV, as well as propagation-defective replicon particles devoid of the viral structural genes, indicated that the viral nonstructural proteins (nsPs) disrupt critical signaling events downstream of type I and type II IFN receptor activation, as indicated by failed activation and nuclear localization of STAT1, a transcription factor central to multiple signaling pathways. Notably, these inhibitory events occurred upstream and independently of global transcriptional shutoff, which was previously proposed to be the mechanism by which alphaviruses downregulate IFN induction and signaling. Our subsequent studies with SINV demonstrated that other alphaviruses also antagonize Jak/STAT activation and that the efficiency of this inhibition correlated tightly with the relative virulence of SINV strains. Importantly, we were able to map this effect to a single amino acid determinant that was required for efficient STAT inhibition by AR86, an adult mouse neurovirulent SINV strain. This determinant, threonine at nsP1 538, was critical for adult mouse neurovirulence and could rescue efficient STAT inhibition when introduced into an avirulent virus. These studies strongly suggest that STAT signaling inhibition by alphaviruses plays an important role in their capacity to cause disease, and they set the stage for future in vivo studies designed to assess the role that Jak/STAT signaling inhibition plays during alphavirus pathogenesis.
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  • "... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Microbiology and Immunology."
Advisor
  • Heise, Mark
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  • Chapel Hill, NC
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  • Open access
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