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The Molecular Mechanism of Host Responses to Viral Infection

  • Author(s): Schock, Suruchi Nandu
  • Advisor(s): Winoto, Astar
  • et al.

All living organisms, including humans, are constantly under attack by various pathogens such as viruses. Activation of appropriate host innate immune pathways like interferon and/or cell death is often critical for efficient viral clearance. Using biochemical and immunological methods, I have studied these two aspects of the antiviral response. I initially examined the role and regulation of the virus-induced host protein Tripartite Motif Containing Protein 21 (TRIM21) and the adaptor molecule Fas-Associated Death Domain (FADD) in the context of RNA virus infection. I found that TRIM21 functions in concert with FADD to negatively regulate ubiquitination of the transcription factor IRF7, thereby functioning in a negative feedback loop for the viral-induced interferon response. I have also identified the presence of a novel complex consisting of FADD, TRIM21 and RIP1 where TRIM21 and RIP1 regulate each other's ubiquitination status. FADD and RIP1 have been recently implicated in an alternative form of programmed cell death: necroptosis, whose physiological function is not completely clear but it has been suggested to serve as a backup host pathway to fight viral infection. To investigate this possibility, I have screened seven viruses for their ability to induce necroptosis. I found two of them, Sendai virus and MHV68, are capable of inducing necroptosis, particularly in conditions when apoptosis is blocked. I found that MHV68 activates the cytoplasmic sensor molecule STING, leading to production of tumor necrosis factor (TNF) and subsequently causing necroptotic death. In contrast, Sendai virus induced death occurs independently of TNF or the adaptor STING. Instead, Sendai virus-mediated necroptosis requires the RNA sensor RIG-I in conjunction with the deubiquitin protein CYLD and several Sendai virus proteins, leading to de-ubiquitination of RIP1 and formation of RIP1/3 necrosome to promote necroptosis. These data are consistent with the notion that necroptosis may be an additional antiviral mechanism that hosts can employ when apoptosis is blocked. Necrotic cells can then release inflammatory contents which may help alert the immune system. These findings offer insight into the complex host-pathogen relationship, and with continued study may help guide the judicious development of antiviral drugs and vaccines.

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