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. Analysis of single-cell RNA-seq datasets from human, non-human primate, and mouse barrier tissues identifies putative cellular targets of SARS-CoV-2 on the basis of ACE2 and TMPRSS2 expression. ACE2 represents a previously unappreciated interferon-stimulated gene in human, but not mouse, epithelial tissues, identifying anti-viral induction of a host tissue-protective mechanism, but also a potential means for viral exploitation of the host response.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1016-1035.e19 |
| Journal | Cell |
| Volume | 181 |
| Issue number | 5 |
| DOIs | |
| State | Published - May 28 2020 |
Funding
We are grateful to the study participants who made this work possible. We would like to thank Bruce Horwitz, Ivan Zanoni, Matt Sampson, Michael Retchin, Peter Winter, Andrew Navia, Jamie Cohen, and Audrey Sporrij for discussions. Mengyang (Vicky) Li Horst, Timothy Tickle, Jonathan Bistline, Jean Chang, Eric Weitz, Eno-Abasi Augustine-Akpan, and Devon Bush for development and support of the Broad Institute Single Cell Portal. This work was supported in part by the Searle Scholars Program , the Beckman Young Investigator Program , the Pew-Stewart Scholars Program for Cancer Research , a Sloan Fellowship in Chemistry, the MIT Stem Cell Initiative through Fondation MIT , the NIH ( 5U24AI118672 and BAA-NIAID-NIHAI201700104 ), and the Bill and Melinda Gates Foundation to A.K.S., as well as NIH R56 AI139053 to J.L.F and P.L.L., and the Aeras Foundation to J.L.F. B.B. and S.K.N. are partially supported by NIH 5R01GM081871 . We acknowledge support from the Damon Runyon Cancer Research Foundation ( DRG-2274-16 ) and Richard and Susan Smith Family Foundation to J.O.-M; from a National Science Foundation Graduate Research Fellowship ( 1122374 ) to S.K.N., S.J.A., and C.N.T.; from a Fannie and John Hertz Foundation Fellowship to C.N.T.; by T32GM007753 from the National Institute of General Medical Sciences to C.G.K.Z. This work was further supported by the UMass Center for Clinical and Translational Science Project Pilot Program ; and the Office of the Assistant Secretary of Defense for Health Affairs , through the Peer Reviewed Medical Research Program ( W81XWH-15-1-0317 ) to R.W.F. We also acknowledge support from NIH grants AI078908 , HL111113 , HL117945 , R37AI052353 , R01AI136041 , R01HL136209 , and U19AI095219 to J.A.B.; by grants from the NIH and National Heart, Lung, and Blood Institute ( U19 HL129902 ) to H.P.K and L.S.K; from National Institute of Allergy and Infectious Diseases ( UM1 AI126623 ) to H.P.K.; and to P.B. from the Fondation pour la Recherche Médicale ( DEQ20180339158 ), and the Agence Nationale pour la Recherche ( ANR-19-CE14-0027 ); and by the following grants to L.S.K: NIH/NIAID U19 AI051731 , NIH/NHLBI R01 HL095791 NIH/NIAID R33-AI116184 , NIH/NIAID U19 AI117945 , and DHHS/NIH 1UM1AI126617 . B.E.M. was supported by the Massachusetts Institute of Technology - GlaxoSmithKline (MIT-GSK) Gertrude B. Elion Postdoctoral Fellowship; T.M.L. by the NIH/NHLBI 1R01HL128241-01, K.M.B. by NIH/NIAID K23AI139352; and D.L. by NIH R01AI137057, DP2DA042422, and R01AI124378. This publication is part of the Human Cell Atlas ( www.humancellatlas.org/publications ). A.R. is an SAB member of ThermoFisher Scientific, 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. We are grateful to the study participants who made this work possible. We would like to thank Bruce Horwitz, Ivan Zanoni, Matt Sampson, Michael Retchin, Peter Winter, Andrew Navia, Jamie Cohen, and Audrey Sporrij for discussions. Mengyang (Vicky) Li Horst, Timothy Tickle, Jonathan Bistline, Jean Chang, Eric Weitz, Eno-Abasi Augustine-Akpan, and Devon Bush for development and support of the Broad Institute Single Cell Portal. This work was supported in part by the Searle Scholars Program, the Beckman Young Investigator Program, the Pew-Stewart Scholars Program for Cancer Research, a Sloan Fellowship in Chemistry, the MIT Stem Cell Initiative through Fondation MIT, the NIH (5U24AI118672 and BAA-NIAID-NIHAI201700104), and the Bill and Melinda Gates Foundation to A.K.S. as well as NIH R56 AI139053 to J.L.F and P.L.L. and the Aeras Foundation to J.L.F. B.B. and S.K.N. are partially supported by NIH 5R01GM081871. We acknowledge support from the Damon Runyon Cancer Research Foundation (DRG-2274-16) and Richard and Susan Smith Family Foundation to J.O.-M; from a National Science Foundation Graduate Research Fellowship (1122374) to S.K.N. S.J.A. and C.N.T.; from a Fannie and John Hertz Foundation Fellowship to C.N.T.; by T32GM007753 from the National Institute of General Medical Sciences to C.G.K.Z. This work was further supported by the UMass Center for Clinical and Translational Science Project Pilot Program; and the Office of the Assistant Secretary of Defense for Health Affairs, through the Peer Reviewed Medical Research Program (W81XWH-15-1-0317) to R.W.F. We also acknowledge support from NIH grants AI078908, HL111113, HL117945, R37AI052353, R01AI136041, R01HL136209, and U19AI095219 to J.A.B.; by grants from the NIH and National Heart, Lung, and Blood Institute (U19 HL129902) to H.P.K and L.S.K; from National Institute of Allergy and Infectious Diseases (UM1 AI126623) to H.P.K.; and to P.B. from the Fondation pour la Recherche M?dicale (DEQ20180339158), and the Agence Nationale pour la Recherche (ANR-19-CE14-0027); and by the following grants to L.S.K: NIH/NIAID U19 AI051731, NIH/NHLBI R01 HL095791 NIH/NIAID R33-AI116184, NIH/NIAID U19 AI117945, and DHHS/NIH 1UM1AI126617. B.E.M. was supported by the Massachusetts Institute of Technology - GlaxoSmithKline (MIT-GSK) Gertrude B. Elion Postdoctoral Fellowship; T.M.L. by the NIH/NHLBI 1R01HL128241-01, K.M.B. by NIH/NIAID K23AI139352; and D.L. by NIH R01AI137057, DP2DA042422, and R01AI124378. This publication is part of the Human Cell Atlas (www.humancellatlas.org/publications). Document S1 details contributions of all authors. A.R. is an SAB member of ThermoFisher Scientific, 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.
Keywords
- ACE2
- COVID-19
- ISG
- SARS-CoV-2
- human
- influenza
- interferon
- mouse
- non-human primate
- scRNA-seq
ASJC Scopus subject areas
- General Biochemistry, Genetics and Molecular Biology
