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

Biology Biology
Cell Atlas Cell Atlas
Computational Methods Computational Methods
Genomics Genomics
Immunology Immunology
Infectious Disease Infectious Disease
Alex K. Shalek Alex K. Shalek
Andrew Navia Andrew Navia
Carly Ziegler Carly Ziegler
Josh Bromley Josh Bromley
José Ordovas-Montañes José Ordovas-Montañes
Micayla George Micayla George
Riley Drake Riley Drake
Vincent Miao Vincent Miao

Ziegler et al.▾ Ziegler, C.G.K.*, Miao, V.N.*, Owings, A.H.*, Navia, A.W.*, Tang, Y.*, Bromley, J.D.*, Lotfy, P., Sloan, M., Laird, H., Williams, H.B., 10, George, M., Drake, R.S., Christian, T., 6, Parker, A., Sindel, C.B., Burger, M.W., Pride, Y., Hasan, M., Abraham III, G.E., Senitko, M., Robinson, T.O., Shalek, A.K.#, Glover, S.C.#, Horwitz, B.H.#, Ordovas-Montanes, J.,


July, 2021


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, AZGP1high 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.