There is pressing urgency to better understand the pathogenesis of the severe acute respiratory syndrome (SARS) coronavirus (CoV) clade SARS-CoV-2. SARS-CoV-2, like SARS-CoV, utilizes ACE2 to bind host cells. While initial SARS-CoV-2 cell entry and infection depend on ACE2 in concert with the protease TMPRSS2 for spike (S) protein activation, the specific cell subsets targeted by SARS-CoV-2 in host tissues, and the factors that regulate ACE2 expression, remain unknown. Here, we leverage human and non-human primate (NHP) single-cell RNA-sequencing (scRNA-seq) datasets to uncover the cell subsets that may serve as cellular targets of SARS-CoV-2. We identify ACE2/TMPRSS2 co-expressing cells within type II pneumocytes, absorptive enterocytes, and nasal goblet secretory cells. Strikingly, we discover that ACE2 is an interferon-stimulated gene (ISG) in human barrier tissue epithelial cells. Thus, SARS-CoV-2 may exploit IFN-driven upregulation of ACE2, a key tissue-protective mediator during lung injury, to enhance infection.
Ziegler, Carly and Allon, Samuel J. and Nyquist, Sarah K. and Mbano, Ian and Miao, Vincent N. and Cao, Yuming and Yousif, Ashraf S. and Bals, Julia and Hauser, Blake M. and Feldman, Jared and Muus, Christoph and Wadsworth II, Marc H. and Kazer, Samuel and Hughes, Travis K. and Doran, Benjamin and Gatter, G. James and Vukovic, Marko and Tzouanas, Constantine N. and Taliaferro, Faith and Guo, Zhiru and Wang, Jennifer P. and Dwyer, Daniel F. and Buchheit, Kathleen M. and Boyce, Joshua and Barrett, Nora A. and Laidlaw, Tanya M. and Carroll, Shaina L. and Colonna, Lucrezia and Tkachev, Victor and Yu, Alison and Zheng, Henqi Betty and Gideon, Hannah P. and Winchell, Caylin G. and Lin, Philana L. and Berger, Bonnie and Leslie, Alasdair and Flynn, JoAnne L. and Fortune, Sarah M. and Finberg, Robert W. and Kean, Leslie and Garber, Manuel and Schmidt, Aaron and Lingwood, Daniel and Shalek, Alex K. and Ordovas-Montanes, Jose and Lung Biological Network, HCA, SARS-CoV-2 Receptor ACE2 is an Interferon-Stimulated Gene in Human Airway Epithelial Cells and Is Enriched in Specific Cell Subsets Across Tissues. Available at SSRN: https://ssrn.com/abstract=3555145 or http://dx.doi.org/10.2139/ssrn.3555145
This version of the paper has not been formally peer reviewed.