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:, Ziegler, C. G. K., Allon, S. J., Nyquist, S. K., Mbano, I. M., Miao, V. N., Tzouanas, C. N., Cao, Y., Yousif, A. S., Bals, J., Hauser, B. M., Feldman, J., Muus, C., Wadsworth, M. H., Kazer, S. W., Hughes, T. K., Doran, B., Gatter, G. J., Vukovic, M., Taliaferro, F., Mead, B. E., Guo, Z., Wang, J. P., Gras, D., Plaisant, M., Ansari, M., Angelidis, I., Adler, H., Sucre, J. M. S., Taylor, C. J., Lin, B., Waghray, A., Mitsialis, V., Dwyer, D. F., Buchheit, K. M., Boyce, J. A., Barrett, N. A., Laidlaw, T. M., Carroll, S. L., Colonna, L., Tkachev, V., Peterson, C. W., Yu, A., Zheng, H. B., Gideon, H. P., Winchell, C. G., Lin, P. L., Bingle, C. D., Snapper, S. B., Kropski, J. A. & Theis, F. J., 28-May-2020, In : Cell. 181, 5, p. 1016-1035.e19 40 p.

Research output: Contribution to journalArticleAcademicpeer-review

  • 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 Taliaferro
  • Benjamin 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

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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