SARS CORONAVIRUS ANTAGONIZES INNATE IMMUNE SIGNALING INITIATED BY RIG-I BUT IS RECOGNIZED BY TLR SIGNALING VIA THE ADAPTOR MOLECULE TRIF Public Deposited

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  • March 19, 2019
Creator
  • Totura, Allison
    • Affiliation: School of Medicine, Department of Microbiology and Immunology
Abstract
  • The recent emergence of highly pathogenic coronaviruses Severe Acute Respiratory Syndrome coronavirus (SARS-CoV) and Middle East Respiratory Syndrome coronavirus (MERS-CoV) is a concern for global public health, as there is a lack of efficacious vaccine platforms and antiviral therapeutic strategies. Pathogen Recognition Receptors (PRRs) are cellular sensors that enable hosts to differentiate between "self" vs. "non-self" and initiate innate immune responses against invading pathogens, like coronaviruses. Agonists and antagonists of PRRs have proposed utility as vaccine adjuvants or antiviral compounds, and highly pathogenic coronaviruses encode multiple strategies to modulate host cell intrinsic immune responses to viral infection so it is imperative to discern the function of PRRs in the pathogenesis of highly pathogenic coronaviruses. The role of PRRs including Toll-like Receptors (TLRs) and RIG-I-like receptors (RLRs) in the pathogenesis of SARS-CoV is the focus of this dissertation. We demonstrate that mice deficient in the TLR3/TLR4 adaptor TRIF are highly susceptible to SARS-CoV infection, showing increased SARS-related disease signs and mortality; TLR3-/- and TLR4-/- mice are more susceptible to SARS-CoV than wild type mice, but experience only mild disease with no mortality in response to infection. Aberrant cellular signaling programs were observed following infection of TRIF-/- mice, similarly to those seen in human patients with poor disease outcome following SARS-CoV or MERS-CoV infection. These findings highlight the importance of TLR signaling in generating a balanced protective innate immune response to highly pathogenic coronavirus infections, and should inform the design and use of TLR agonists and antagonists in coronavirus-specific vaccine and antiviral strategies. In addition, we demonstrate modulation of a host PRR by the SARS-CoV nonstructural protein 7 (nsp7) to subvert host innate immune responses. Nsp7, a replicase protein required for coronavirus viability, antagonizes interferon responses via the RIG-I signaling pathway. IFN antagonism activity is mapped to critical residues in the N-terminal 20 amino acids of SARS-CoV nsp7. The nsp7 protein from other mammalian coronaviruses, including nsp7 from coronaviruses of bats, interacts with RIG-I to block IFN expression in a conserved manner. This suggests that the nsp7 proteins of zoonotic coronaviruses are pre-positioned to antagonize human sensing machinery, perhaps contributing to cross-species transmission and pathogenic potential in alternative hosts. In sum, these studies contribute to our understanding of host detection of highly pathogenic coronaviruses and viral antagonism of the host innate immune response.
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  • In Copyright
Advisor
  • Whitmire, Jason
  • Moorman, Nathaniel
  • Pickles, Raymond J.
  • Baric, Ralph S.
  • Heise, Mark
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2014
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  • Chapel Hill, NC
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