Rory Mulloy, University of Calgary

Danyel Evseev University of Calgary, Noga Sharlin, University of Calgary, Maxwell P. Bui-Marinos, University of Calgary, Émile Lacasse, Université Laval, Isabelle Dubuc, Université Laval, Louis Flamand, Université Laval, Arinjay Banerjee, VIDO, Denys Khaperskyy, Dalhousie University, Jennifer A. Corcoran, University of Calgary

Discovering & Evolving

Viruses have been spilling over into the human population for millions of years, and each time a virus emerges, it must adapt to its new host. Understanding the host-specific barriers to infection is paramount for pandemic forecasting and necessary to understand the breadth of the human antiviral response. Here, we show that shortly after the emergence of SARS-CoV-2 into the human population, the virus evolved to produce a new protein, a truncated form of the nucleocapsid protein called N*M210. By constructing recombinant viruses, we show that N*M210 production increases virus fitness compared to wild-type viruses, likely explaining the preservation of N*M210 in currently circulating variants. We show that N*M210 is a double stranded RNA-binding protein and improves virus fitness by inhibiting multiple arms of the cellular antiviral response, including inhibiting stress granule formation. Stress granules (SGs) are cytoplasmic RNA granules that form in response to stress, including infection. The role of SGs in viral infection is incompletely understood; however, we illustrate that N*M210 confers a fitness advantage specifically due to its ability to block SGs, as N*M210 fails to promote virus replication in SG-null cells. Taken together, these data support a model where SARS-CoV-2 has evolved to produce N*M210, which potently inhibits SG formation. Despite continued replication in bat cells, SARS-CoV-2-like bat viruses to not appear to share the N*M210-enhancing mutation. This observation suggests i) N*M210 synthesis represents an adaptation to replication in humans and ii) SGs may be a barrier to bat-human zoonosis.