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.
