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, Carly G.K.; Allon, Samuel J.; Nyquist, Sarah K.; Mbano, Ian M.; Miao, Vincent N.; Tzouanas, Constantine N.; Cao, Yuming; Yousif, Ashraf S.; Bals, Julia; Hauser, Blake M.; Feldman, Jared; Muus, Christoph; Wadsworth, Marc H.; Kazer, Samuel W.; Hughes, Travis K.; Doran, Benjamin; Gatter, G. James; Vukovic, Marko; Taliaferro, Faith; Mead, Benjamin E.; Guo, Zhiru; Wang, Jennifer P.; Gras, Delphine; Plaisant, Magali; Ansari, Meshal; Angelidis, Ilias; Adler, Heiko; Sucre, Jennifer M.S.; Taylor, Chase J.; Lin, Brian; Waghray, Avinash; Mitsialis, Vanessa; Dwyer, Daniel F.; Buchheit, Kathleen M.; Boyce, Joshua A.; Barrett, Nora A.; Laidlaw, Tanya M.; Carroll, Shaina L.; Colonna, Lucrezia; Tkachev, Victor; Peterson, Christopher W.; Yu, Alison; Zheng, Hengqi Betty; Gideon, Hannah P.; Winchell, Caylin G.; Lin, Philana Ling; Bingle, Colin D.; Snapper, Scott B.; Kropski, Jonathan A.; Theis, Fabian J.; Schiller, Herbert B.; Zaragosi, Laure-Emmanuelle; Barbry, Pascal; Leslie, Alasdair; Kiem, Hans-Peter; Flynn, JoAnne L.; Fortune, Sarah M.; Berger, Bonnie; Finberg, Robert W.; Kean, Leslie S.; Garber, Manuel; Schmidt, Aaron G.; Lingwood, Daniel; Shalek, Alex K.; Ordovas-Montanes, Jose

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.