A Multitrait Locus Regulates Sarbecovirus Pathogenesis
Alexandra Schäfer, Sarah R. Leist, Lisa E. Gralinski, David R. Martinez, Emma S. Winkler, Kenichi Okuda, Padraig Hawkins, Kendra L. Gully, Rachel L. Graham, D. Trevor Scobey, Timothy A. Bell, Pablo Hock, Ginger D. Shaw, Jennifer F. Loome, Emily A. Madden, Elizabeth J. Anderson, Victoria K. Baxter, Sharon Taft-Benz, Mark R. Zweigart, Samantha R. May, Stephanie Dong, Matthew Clark, Darla R. Miller, Rachel Lynch, Mark T. Heise, Roland Tisch, Richard C. Boucher, Fernando Pardo‐Manuel de Villena, Stephanie A. Montgomery, Michael Diamond, Martin T. Ferris, Ralph S. Baric
Abstract
Host genetic variation is an important determinant that predicts disease outcomes following infection. In the setting of highly pathogenic coronavirus infections genetic determinants underlying host susceptibility and mortality remain unclear. To elucidate the role of host genetic variation on sarbecovirus pathogenesis and disease outcomes, we utilized the Collaborative Cross (CC) mouse genetic reference population as a model to identify susceptibility alleles to SARS-CoV and SARS-CoV-2 infections. Our findings reveal that a multitrait loci found in chromosome 9 is an important regulator of sarbecovirus pathogenesis in mice. Within this locus, we identified and validated CCR9 and CXCR6 as important regulators of host disease outcomes. Specifically, both CCR9 and CXCR6 are protective against severe SARS-CoV, SARS-CoV-2, and SARS-related HKU3 virus disease in mice. This chromosome 9 multitrait locus may be important to help identify genes that regulate coronavirus disease outcomes in humans.