Project 466736

SARS-CoV-2 is the virus responsible for the ongoing Coronavirus Disease of 2019 (COVID-19) pandemic. The symptoms of COVID-19 vary from mild illness to severe disease leading to hospitalization or death. Severe COVID-19 is characterized by an abnormal inflammatory immune response that causes life-threatening lung damage. Our laboratory recently showed that SARS-CoV-2 may contribute to this inflammation by disassembling cellular structures called processing bodies (PBs), which otherwise suppress the production of many inflammatory immune proteins. Our laboratory demonstrated that SARS-CoV-2 disassembles PBs via its nucleocapsid (N) protein, a structural protein that coats the viral genome to help assemble new viral particles, and that counteracts the cellular immune response to promote viral replication. My project thus seeks to investigate the mechanism of N-mediated PB disassembly to better characterize processes leading to the inflammation seen in severe COVID-19. Notably, the SARS-CoV-2 Alpha, Delta, and Omicron variants of concern (VOCs) have mutations in N that have been shown to change the protein's structure, leading to enhanced N function and a consequent increase in viral replication and disease severity. Thus, I hypothesize that modification of specific structural features of N can promote N interaction with PBs, leading to PB disassembly. By investigating how N structure affects PB disassembly, my project will improve our understanding of a process that may contribute to the inflammation caused by SARS-CoV-2 infection, allowing for the identification of possible drug targets for the treatment of severe COVID-19. Additionally, my project will shed light on how N mutations found in VOCs may contribute to their enhanced virulence.