SARS-CoV-2 Receptor ACE2 Is an Interferon-Stimulated Gene in Human Airway Epithelial Cells and Is Detected in Specific Cell Subsets across Tissues

Cell. 2020 May 28;181(5):1016-1035.e19. doi: 10.1016/j.cell.2020.04.035. Epub 2020 Apr 27.

Abstract

There is pressing urgency to understand the pathogenesis of the severe acute respiratory syndrome coronavirus clade 2 (SARS-CoV-2), which causes the disease COVID-19. SARS-CoV-2 spike (S) protein binds angiotensin-converting enzyme 2 (ACE2), and in concert with host proteases, principally transmembrane serine protease 2 (TMPRSS2), promotes cellular entry. The cell subsets targeted by SARS-CoV-2 in host tissues and the factors that regulate ACE2 expression remain unknown. Here, we leverage human, non-human primate, and mouse single-cell RNA-sequencing (scRNA-seq) datasets across health and disease to uncover putative targets of SARS-CoV-2 among tissue-resident cell subsets. We identify ACE2 and TMPRSS2 co-expressing cells within lung type II pneumocytes, ileal absorptive enterocytes, and nasal goblet secretory cells. Strikingly, we discovered that ACE2 is a human interferon-stimulated gene (ISG) in vitro using airway epithelial cells and extend our findings to in vivo viral infections. Our data suggest that SARS-CoV-2 could exploit species-specific interferon-driven upregulation of ACE2, a tissue-protective mediator during lung injury, to enhance infection.

Keywords: ACE2; COVID-19; ISG; SARS-CoV-2; human; influenza; interferon; mouse; non-human primate; scRNA-seq.

Publication types

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

MeSH terms

  • Adolescent
  • Alveolar Epithelial Cells / immunology
  • Alveolar Epithelial Cells / metabolism*
  • Animals
  • Betacoronavirus / physiology
  • Cell Line
  • Cells, Cultured
  • Child
  • Coronavirus Infections / virology
  • Enterocytes / immunology
  • Enterocytes / metabolism*
  • Goblet Cells / immunology
  • Goblet Cells / metabolism*
  • HIV Infections / immunology
  • Humans
  • Influenza, Human / immunology
  • Interferon Type I / immunology
  • Interferon Type I / metabolism*
  • Lung / cytology
  • Lung / pathology
  • Macaca mulatta
  • Mice
  • Mycobacterium tuberculosis
  • Nasal Mucosa / cytology*
  • Nasal Mucosa / immunology
  • Pandemics
  • Peptidyl-Dipeptidase A / genetics*
  • Peptidyl-Dipeptidase A / metabolism
  • Pneumonia, Viral / virology
  • Receptors, Virus / genetics
  • Serine Endopeptidases / metabolism
  • Single-Cell Analysis
  • Tuberculosis / immunology
  • Up-Regulation

Substances

  • Interferon Type I
  • Receptors, Virus
  • Peptidyl-Dipeptidase A
  • angiotensin converting enzyme 2
  • Serine Endopeptidases
  • TMPRSS2 protein, human

Supplementary concepts

  • COVID-19
  • severe acute respiratory syndrome coronavirus 2