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.
- 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., 2nd
- 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.
- Schiller, H. B.
- Zaragosi, L. E.
- Barbry, P.
- Leslie, A.
- Kiem, H. P.
- Flynn, J. L.
- Fortune, S. M.
- Berger, B.
- Finberg, R. W.
- Kean, L. S.
- Garber, M.
- Schmidt, A. G.
- Lingwood, D.
- Shalek, A. K.
- Ordovas-Montanes, J.
- H. C. A. Lung Biological Network. Electronic address: lung-network@humancellatlas.org
- H. C. A. Lung Biological Network
Keywords
- Adolescent
- Alveolar Epithelial Cells/immunology/*metabolism
- Animals
- Betacoronavirus/physiology
- Cell Line
- Cells, Cultured
- Child
- Coronavirus Infections/virology
- Enterocytes/immunology/*metabolism
- Goblet Cells/immunology/*metabolism
- HIV Infections/immunology
- Humans
- Influenza, Human/immunology
- Interferon Type I/immunology/*metabolism
- Lung/cytology/pathology
- Macaca mulatta
- Mice
- Mycobacterium tuberculosis
- Nasal Mucosa/*cytology/immunology
- Pandemics
- Peptidyl-Dipeptidase A/*genetics/metabolism
- Pneumonia, Viral/virology
- Receptors, Virus/genetics
- Serine Endopeptidases/metabolism
- Single-Cell Analysis
- Tuberculosis/immunology
- Up-Regulation
- *ace2
- *covid-19
- *isg
- *SARS-CoV-2
- *human
- *influenza
- *interferon
- *mouse
- *non-human primate
- *scRNA-seq
- Neogene Therapeutics, Asimov, and Syros Pharmaceuticals
- a co-founder of and
- equity holder in Celsius Therapeutics
- and an equity holder in Immunitas
- Therapeutics. A.K.S. reports compensation for consulting and/or SAB membership
- from Merck, Honeycomb Biotechnologies, Cellarity, Cogen Therapeutics, Orche Bio,
- and Dahlia Biosciences. L.S.K. is on the SAB for HiFiBio
- she reports research
- funding from Kymab Limited, Bristol Meyers Squibb, Magenta Therapeutics, BlueBird
- Bio, and Regeneron Pharmaceuticals and consulting fees from Equillium,
- FortySeven, Inc, Novartis, Inc, EMD Serono, Gilead Sciences, and Takeda
- Pharmaceuticals. A.S. is an employee of Johnson and Johnson. N.K. is an inventor
- on a patent using thyroid hormone mimetics in acute lung injury that is now being
- considered for intervention in COVID-19 patients. J.L. is a scientific consultant
- for 10X Genomics, Inc. O.R.R, is a co-inventor on patent applications filed by
- the Broad Institute to inventions relating to single-cell genomics applications,
- such as in PCT/US2018/060860 and US Provisional Application No. 62/745,259. S.T.
- in the last three years was a consultant at Genentech, Biogen, and Roche and is a
- member of the SAB of Foresite Labs. M.H.W. is now an employee of Pfizer. F.J.T.
- reports receiving consulting fees from Roche Diagnostics GmbH and ownership
- interest in Cellarity, Inc. P.H. is a co-inventor on a patent using artificial
- intelligence and high-resolution microscopy for COVID-19 infection testing based
- on serology.
