Understanding the Molecular Basis of Translation Inhibition by SARS-CoV-2 NSP14 and its Role in SARS-CoV-2 Immune Evasion

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PROJECT SUMMARY/ABSTRACT The COVID-19 pandemic has had a devastating worldwide impact on health and economy. There is still no effective treatment, and the full extent of COVID-19 pathogenesis remains unclear. In particular, mechanisms for SARS-CoV-2 evasion of host immune surveillance remain poorly understood. I am interested in exploring both SARS-CoV-2 viral factors that block cellular translation and their roles in viral immune evasion. I have discovered that SARS-CoV-2 nonstructural protein 14 (NSP14) inhibits host translation and subsequently suppresses the innate immune response. Furthermore, my data suggest that the guanine-N7- methytransferase (N7-MTase) activity of NSP14 is required to inhibit translation, which catalyzes N7- methylguanosine (m7G) modification at 5’ cap guanosine. However, how m7G modification restricts cellular translation is unclear. Moreover, our data also showed that NSP14 inhibits the expression of MHC-I molecules on the cell surface and this also depends on its N7-MTase activity. However, whether NSP14 dampens MHC-I antigen presentation and cytotoxic CD8+ T cell responses requires further study. I hypothesize that NSP14 induces RNA m7G modification in SARS-CoV-2 infection and that shuts down cellular translation. I further hypothesize that such activity restricts the MHC-I antigen presentation pathway to escape T cell responses. The central objectives in this proposal are to define the molecular mechanism by which SARS-CoV-2 NSP14 inhibits cellular translation and enhance our understanding of how SARS-CoV-2 escapes T cell-mediated immunity. In Aim 1, I will determine the role of RNA m7G modification in translation inhibition in SARS-CoV-2 infection. In Aim 2, I will define how NSP14 restricts MHC-I antigen presentation and T cell responses. These two aims will address how SARS-CoV-2 infection can affect T cell-mediated immunity. I expect that our findings will uncover new strategies to develop new antiviral therapeutics for COVID-19 and help gain new insights into understanding the biology of COVID-19 pathogenesis. My career goal is to become an independent investigator studying virus-host interaction of infectious diseases, with a special focus on translational regulation and viral immune evasion. The proposed K22 grant will provide me with advanced training and skills to build specific expertise necessary to execute the proposed project and become independent in this field, including expertise in: 1. Immunology and Virology, 2. post- transcriptional modification and translational regulation research, and 3. skills necessary to head an independent research laboratory. To achieve these goals, I have assembled a Professional/Scientific Advisory Committee consisting of experts in SARS-CoV-2 Virology, Immunobiology, RNA Biology, and Bioinformatics.