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

Ziegler CGK, Allon SJ, Nyquist SK, Mbano IM, Miao VN, Tzouanas CN, Cao Y, Yousif AS, Bals J, Hauser BM, Feldman J, Muus C, Wadsworth MH, Kazer SW, Hughes TK, Doran B, Gatter GJ, Vukovic M, Taliaferro F, Mead BE, Guo Z, Wang JP, Gras D, Plaisant M, Ansari M, Angelidis I, Adler H, Sucre JMS, Taylor CJ, Lin B, Waghray A, Mitsialis V, Dwyer DF, Buchheit KM, Boyce JA, Barrett NA, Laidlaw TM, Carroll SL, Colonna L, Tkachev V, Peterson CW, Yu A, Zheng HB, Gideon HP, Winchell CG, Lin PL, Bingle CD, Snapper SB, Kropski JA, Theis FJ, Schiller HB, Zaragosi LE, Barbry P, Leslie A, Kiem HP, Flynn JL, Fortune SM, Berger B, Finberg RW, Kean LS, Garber M, Schmidt AG, Lingwood D, Shalek AK, Ordovas-Montanes J (2020)

Publication Type: Journal article

Publication year: 2020

Journal

Book Volume: 181

Pages Range: 1016-1035.e19

Journal Issue: 5

DOI: 10.1016/j.cell.2020.04.035

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. 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.

Involved external institutions

Harvard University United States (USA) (US) Massachusetts Institute of Technology (MIT) United States (USA) (US) Africa Health Research Institute (AHRI) South Africa (ZA) University of Massachusetts Amherst (UMass) United States (USA) (US) Ragon Institute of MGH, MIT and Harvard United States (USA) (US) Eli and Edythe L. Broad Institute of MIT and Harvard United States (USA) (US) Aix-Marseille University / Aix-Marseille Université France (FR) University of Côte d'Azur / Université Côte d'Azur France (FR) Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt (HMGU) / Helmholtz Munich Germany (DE) Deutsches Zentrum für Lungenforschung e.V. (DZL) Germany (DE) Vanderbilt University United States (USA) (US) Massachusetts General Hospital United States (USA) (US) Boston Children's Hospital United States (USA) (US) Brigham and Women's Hospital (BWH) United States (USA) (US) University of California, Berkeley United States (USA) (US) University of Washington United States (USA) (US) Fred Hutchinson Cancer Research Center United States (USA) (US) University of Pittsburgh United States (USA) (US) University of Sheffield United Kingdom (GB)

How to cite

APA:

Ziegler, C.G.K., Allon, S.J., Nyquist, S.K., Mbano, I.M., Miao, V.N., Tzouanas, C.N.,... Ordovas-Montanes, J. (2020). 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, 181(5), 1016-1035.e19. https://doi.org/10.1016/j.cell.2020.04.035

MLA:

Ziegler, Carly G. K., et al. "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 181.5 (2020): 1016-1035.e19.

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