Impaired local intrinsic immunity to SARS-CoV-2 infection in severe COVID-19

Ziegler, Carly G.K.; Miao, Vincent N.; Owings, Anna H.; Navia, Andrew W.; Tang, Ying; Bromley, Joshua D.; Lotfy, Peter; Sloan, Meredith; Laird, Hannah; Williams, Haley B.; George, Micayla; Drake, Riley S.; Christian, Taylor; Parker, Adam; Sindel, Campbell B.; Burger, Molly W.; Pride, Yilianys; Hasan, Mohammad; Abraham, George E.; Senitko, Michal; Robinson, Tanya O.; Shalek, Alex K.; Glover, Sarah C.; Horwitz, Bruce H.; Ordovas-Montanes, Jose

SARS-CoV-2 infection can cause severe respiratory COVID-19. However, many individuals present with isolated upper respiratory symptoms, suggesting potential to constrain viral pathology to the nasopharynx. Which cells SARS-CoV-2 primarily targets and how infection influences the respiratory epithelium remains incompletely understood. We performed scRNA-seq on nasopharyngeal swabs from 58 healthy and COVID-19 participants. During COVID-19, we observe expansion of secretory, loss of ciliated, and epithelial cell repopulation via deuterosomal expansion. In mild/moderate COVID-19, epithelial cells express anti-viral/interferon-responsive genes, while cells in severe COVID-19 have muted anti-viral responses despite equivalent viral loads. SARS-CoV-2 RNA+ host-target cells are highly heterogenous, including developing ciliated, interferon-responsive ciliated, AZGP1 high goblet, and KRT13+ “hillock”-like cells, and we identify genes associated with susceptibility, resistance, or infection response. Our study defines protective and detrimental responses to SARS-CoV-2, the direct viral targets of infection, and suggests that failed nasal epithelial anti-viral immunity may underlie and precede severe COVID-19.