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

Highlights

• scRNA-seq on nasopharyngeal swabs of 58 COVID-19 and healthy participants

• SARS-CoV-2 induces ciliated cell loss with secretory and deuterosomal expansion

• Early, muted anti-viral responses in nasal epithelia in severe COVID-19

• Host-virus co-detection maps cell tropism and intrinsic responses to SARS-CoV-2

Summary

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 cell expansion. In mild and 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.