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

HCA Lung Biological Network. Electronic address:, Carly G K Ziegler, Samuel J Allon, Sarah K Nyquist, Ian M Mbano, Vincent N Miao, Constantine N Tzouanas, Yuming Cao, Ashraf S Yousif, Julia Bals, Blake M Hauser, Jared Feldman, Christoph Muus, Marc H Wadsworth, Samuel W Kazer, Travis K Hughes, Benjamin Doran, G James Gatter, Marko Vukovic, Faith TaliaferroBenjamin E Mead, Zhiru Guo, Jennifer P Wang, Delphine Gras, Magali Plaisant, Meshal Ansari, Ilias Angelidis, Heiko Adler, Jennifer M S Sucre, Chase J Taylor, Brian Lin, Avinash Waghray, Vanessa Mitsialis, Daniel F Dwyer, Kathleen M Buchheit, Joshua A Boyce, Nora A Barrett, Tanya M Laidlaw, Shaina L Carroll, Lucrezia Colonna, Victor Tkachev, Christopher W Peterson, Alison Yu, Hengqi Betty Zheng, Hannah P Gideon, Caylin G Winchell, Philana Ling Lin, Colin D Bingle, Scott B Snapper, Jonathan A Kropski, Fabian J Theis

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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. Analysis of single-cell RNA-seq datasets from human, non-human primate, and mouse barrier tissues identifies putative cellular targets of SARS-CoV-2 on the basis of ACE2 and TMPRSS2 expression. ACE2 represents a previously unappreciated interferon-stimulated gene in human, but not mouse, epithelial tissues, identifying anti-viral induction of a host tissue-protective mechanism, but also a potential means for viral exploitation of the host response.

Original languageEnglish
Pages (from-to)1016-1035.e19
Number of pages40
Issue number5
Publication statusPublished - 28-May-2020


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

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