Interrogating RNA-protein interactions underlying SARS-CoV-2 infection and antiviral defense

The global COVID-19 pandemic underscores the need to better understand its causative agent, SARS-CoV-2, and the various other emerging viruses threatening human health. Like many human viruses, SARS-CoV-2 utilizes RNA as its replicated genetic material and its template for translating the virus's proteins. Ongoing research into SARS-CoV-2 and other RNA viruses has largely focused on understanding the function of their encoded proteins, revealing key roles in host cell entry, viral replication, and immune suppression. In contrast, little is known about the set of viral RNAs and how they interact with host machinery as part of a virus's replication cycle in infected cells. My group discovered a large collection of viral and host proteins that bind the genomic and subgenomic RNAs of SARS-CoV-2 during infection. This collection provides an excellent starting point to work toward the goal of my proposed ERC Starting Grant project: decoding how these interactions shape the viral RNA life cycle and contribute to antiviral defense mechanisms. My overarching hypothesis is that SARS-CoV-2 dynamically modulates RNA-protein interactions in the host to facilitate functions of genomic and subgenomic viral RNAs at different stages of the replication cycle. To test this hypothesis, I have devised three research objectives: 1) Decode mechanisms of host-mediated control over the life cycle of SARS-CoV-2 RNAs. 2) Map with temporal resolution which host cell proteins engage each SARS-CoV-2 RNA type. 3) Elucidate the role of host proteins that moonlight as RNA binders in SARS-CoV-2 infections. If successful, this project will identify novel pro- and antiviral host factors in SARS-CoV-2 infections and reveal underlying RNA regulatory mechanisms. In turn, these insights will provide an RNA-centric view of viral infections and identify candidate factors and pathways as therapeutic targets to treat viral diseases.