SARS-CoV-2 Receptor ACE2 Is an Interferon-Stimulated Gene in Human Airway Epithelial Cells and Is Detected in Specific Cell Subsets across Tissues
Carly G.K. Ziegler, Samuel J. Allon, Sarah K. Nyquist, Ian 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 A. Doran, G. James Gatter, Marko Vukovic, Faith Taliaferro, Benjamin E. Mead, Zhiru Guo, Jennifer 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 Zheng, Hannah P. Gideon, Caylin G. Winchell, Philana Ling Lin, Colin D. Bingle, Scott B. Snapper, Jonathan A. Kropski, Fabian J. Theis, Herbert B. Schiller, Laure‐Emmanuelle Zaragosi, Pascal Barbry, Alasdair Leslie, Hans‐Peter Kiem, JoAnne L. Flynn, Sarah M. Fortune, Bonnie Berger, Robert W. Finberg, Leslie S. Kean, Manuel Garber, Aaron G. Schmidt, Daniel Lingwood, Alex K. Shalek, José Ordovás-Montañés, Nicholas E. Banovich, Pascal Barbry, Alvis Brāzma, Tushar Desai, Thu Elizabeth Duong, Oliver Eickelberg, Christine S. Falk, Michael Farzan, Ian A. Glass, Muzlifah Haniffa, Péter Horváth, Deborah Hung, Naftali Kaminski, Mark A. Krasnow, Jonathan A. Kropski, Malte Kühnemund, Robert Lafyatis, Haeock Lee, Sylvie Leroy, Sten Linnarson, Joakim Lundeberg, Kerstin Meyer, Alexander Misharin, Martijn C. Nawijn, Marko Nikolić, José Ordovás-Montañés, Dana Pe’er, Joseph E. Powell, Stephen R. Quake, Jayaraj Rajagopal, Purushothama Rao Tata, Emma L. Rawlins, Aviv Regev, Paul A. Reyfman, Mauricio Rojas
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.