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

Cell. 2021 Sep 2;184(18):4713-4733.e22. doi: 10.1016/j.cell.2021.07.023. Epub 2021 Jul 23.


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, 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.

Keywords: COVID-19; SARS-CoV-2; anti-viral; correlates of immunity; epithelial immunity; human; interferon; nasal mucosa; scRNA-seq.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Bystander Effect
  • COVID-19 / genetics
  • COVID-19 / immunology*
  • COVID-19 / virology*
  • Cohort Studies
  • Female
  • Humans
  • Immunity*
  • Male
  • Middle Aged
  • Nasopharynx / pathology
  • Nasopharynx / virology
  • RNA, Viral / analysis
  • RNA, Viral / genetics
  • Respiratory Mucosa / pathology
  • Respiratory Mucosa / virology
  • SARS-CoV-2 / physiology*
  • Severity of Illness Index*
  • Transcription, Genetic
  • Viral Load


  • RNA, Viral