SARS-CoV-2 receptor ACE2 is an interferon-stimulated gene in human airway epithelial cells and is enriched in specific cell subsets across tissues

Biology Biology
Cell Atlas Cell Atlas
Computational Methods Computational Methods
Genomics Genomics
Immunology Immunology
Infectious Disease Infectious Disease
Medicine Medicine
Benjamin Doran Benjamin Doran
Carly Ziegler Carly Ziegler
Constantine Tzouanas Constantine Tzouanas
James Gatter James Gatter
Marc Wadsworth II Marc Wadsworth II
Marko Vukovic Marko Vukovic
Sam Allon Sam Allon
Sarah Nyquist Sarah Nyquist
Shaina Carroll Shaina Carroll
Vincent Miao Vincent Miao

Ziegler et al.▾ Ziegler, C.G.K.*, Allon, S.J.*, Nyquist, S.K.*, Mbano, I.*, Miao, V.N., Cao, Y., Yousif, A.S., Bals, J., Hauser, B.M., Feldman, J., Muus, C., Wadsworth II, M.H., Kazer, S.W., Hughes, T.K., Doran, B., Gatter, G.J., Vukovic, M., Tzouanas, C.N., Taliaferro, F., Guo, Z., Wang, J.P., Dwyer, D.F., Buchheit, K.M., Boyce, J.A., Barrett, N.A., Laidlaw, T.M., Carroll, S.L., Colonna, L., Tkachev, V., Yu, A., Zheng, H.B., Gideon, H.P., Winchell, C.G., Lin, P.L., Berger, B.A., Leslie, A., Flynn, J.L., Fortune, S.M., Finberg, R.W., Kean, L.S., Garber, M., Schmidt, A., Lingwood, D., Shalek, A.K.#, Ordovas-Montanes, J.#, HCA Lung Biological Network.


March, 2020


There is pressing urgency to better understand the pathogenesis of the severe acute respiratory syndrome (SARS) coronavirus (CoV) clade SARS-CoV-2, which causes the disease known as COVID-19. 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 tissue- resident cell subsets that may serve as the cellular targets of SARS-CoV-2. We identify ACE2 and TMPRSS2 co-expressing cells within type II pneumocytes in NHP lung, absorptive enterocytes in human and NHP terminal ileum, and human nasal goblet secretory cells. Strikingly, we discover, and extensively corroborate using publicly available data sets, that ACE2 is an interferon-stimulated gene (ISG) in human epithelial cells. We further validate this finding in primary upper airway human respiratory epithelial cells. Thus, SARS-CoV-2 may exploit IFN- driven upregulation of ACE2, a key tissue-protective mediator during lung injury, to enhance infection.