SARS-CoV-2 Receptor ACE2 Is an Interferon-Stimulated Gene in Human Airway Epithelial Cells and Is Detected in Specific Cell Subsets across Tissues
- PMID: 32413319
- PMCID: PMC7252096
- DOI: 10.1016/j.cell.2020.04.035
SARS-CoV-2 Receptor ACE2 Is an Interferon-Stimulated Gene in Human Airway Epithelial Cells and Is Detected in Specific Cell Subsets across Tissues
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.
Keywords: ACE2; COVID-19; ISG; SARS-CoV-2; human; influenza; interferon; mouse; non-human primate; scRNA-seq.
Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.
Conflict of interest statement
Declaration of Interests 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.
Figures
Similar articles
-
Gene expression and in situ protein profiling of candidate SARS-CoV-2 receptors in human airway epithelial cells and lung tissue.Eur Respir J. 2020 Sep 3;56(3):2001123. doi: 10.1183/13993003.01123-2020. Print 2020 Sep. Eur Respir J. 2020. PMID: 32675206 Free PMC article.
-
Type 2 and interferon inflammation regulate SARS-CoV-2 entry factor expression in the airway epithelium.Nat Commun. 2020 Oct 12;11(1):5139. doi: 10.1038/s41467-020-18781-2. Nat Commun. 2020. PMID: 33046696 Free PMC article.
-
Antiviral Activity of Type I, II, and III Interferons Counterbalances ACE2 Inducibility and Restricts SARS-CoV-2.mBio. 2020 Sep 10;11(5):e01928-20. doi: 10.1128/mBio.01928-20. mBio. 2020. PMID: 32913009 Free PMC article.
-
ACE2, TMPRSS2 distribution and extrapulmonary organ injury in patients with COVID-19.Biomed Pharmacother. 2020 Nov;131:110678. doi: 10.1016/j.biopha.2020.110678. Epub 2020 Aug 24. Biomed Pharmacother. 2020. PMID: 32861070 Free PMC article. Review.
-
SARS-CoV-2 pandemic and research gaps: Understanding SARS-CoV-2 interaction with the ACE2 receptor and implications for therapy.Theranostics. 2020 Jun 12;10(16):7448-7464. doi: 10.7150/thno.48076. eCollection 2020. Theranostics. 2020. PMID: 32642005 Free PMC article. Review.
Cited by
-
Exploring viral respiratory coinfections: Shedding light on pathogen interactions.PLoS Pathog. 2024 Sep 24;20(9):e1012556. doi: 10.1371/journal.ppat.1012556. eCollection 2024 Sep. PLoS Pathog. 2024. PMID: 39316558 Free PMC article. Review. No abstract available.
-
Pathophysiological dynamics in the contact, coagulation, and complement systems during sepsis: Potential targets for nafamostat mesilate.J Intensive Med. 2024 Apr 10;4(4):453-467. doi: 10.1016/j.jointm.2024.02.003. eCollection 2024 Oct. J Intensive Med. 2024. PMID: 39310056 Free PMC article. Review.
-
The Functions of SARS-CoV-2 Receptors in Diabetes-Related Severe COVID-19.Int J Mol Sci. 2024 Sep 5;25(17):9635. doi: 10.3390/ijms25179635. Int J Mol Sci. 2024. PMID: 39273582 Free PMC article. Review.
-
Single-cell sequencing analysis of multiple myeloma heterogeneity and identification of new theranostic targets.Cell Death Dis. 2024 Sep 14;15(9):672. doi: 10.1038/s41419-024-07027-4. Cell Death Dis. 2024. PMID: 39271659 Free PMC article.
-
SARS-CoV-2 Modulation of HIV Latency Reversal in a Myeloid Cell Line: Direct and Bystander Effects.Viruses. 2024 Aug 17;16(8):1310. doi: 10.3390/v16081310. Viruses. 2024. PMID: 39205284 Free PMC article.
References
-
- Bao L., Deng W., Gao H., Xiao C., Liu J., Xue J., Lv Q., Liu J., Yu P., Xu Y. Reinfection could not occur in SARS-CoV-2 infected rhesus macaques. bioRxiv. 2020 doi: 10.1101/2020.03.13.990226. - DOI
Publication types
MeSH terms
Substances
Grants and funding
- R01 HL128241/HL/NHLBI NIH HHS/United States
- R01 HL095791/HL/NHLBI NIH HHS/United States
- R01 HL118185/HL/NHLBI NIH HHS/United States
- K08 HL130595/HL/NHLBI NIH HHS/United States
- R01 HL117945/HL/NHLBI NIH HHS/United States
- R33 AI116184/AI/NIAID NIH HHS/United States
- U19 AI095219/AI/NIAID NIH HHS/United States
- U19 AI057229/AI/NIAID NIH HHS/United States
- MR/R006237/1/MRC_/Medical Research Council/United Kingdom
- DP2 DA042422/DA/NIDA NIH HHS/United States
- UM1 AI126623/AI/NIAID NIH HHS/United States
- R01 GM081871/GM/NIGMS NIH HHS/United States
- U19 HL129902/HL/NHLBI NIH HHS/United States
- MR/S005579/1/MRC_/Medical Research Council/United Kingdom
- R37 AI052353/AI/NIAID NIH HHS/United States
- K12 HL143886/HL/NHLBI NIH HHS/United States
- MR/S035907/1/MRC_/Medical Research Council/United Kingdom
- K23 AI139352/AI/NIAID NIH HHS/United States
- MR/S036334/1/MRC_/Medical Research Council/United Kingdom
- R01 HL145372/HL/NHLBI NIH HHS/United States
- T32 GM007753/GM/NIGMS NIH HHS/United States
- U19 AI051731/AI/NIAID NIH HHS/United States
- K08 HL146943/HL/NHLBI NIH HHS/United States
- R01 AI078908/AI/NIAID NIH HHS/United States
- MR/K017047/1/MRC_/Medical Research Council/United Kingdom
- P30 DK034854/DK/NIDDK NIH HHS/United States
- T32 GM087237/GM/NIGMS NIH HHS/United States
- K23 HL111113/HL/NHLBI NIH HHS/United States
- R01 HL136209/HL/NHLBI NIH HHS/United States
- MR/P009581/1/MRC_/Medical Research Council/United Kingdom
- R01 AI124378/AI/NIAID NIH HHS/United States
- U24 AI118672/AI/NIAID NIH HHS/United States
- R01 AI136041/AI/NIAID NIH HHS/United States
- UM1 AI126617/AI/NIAID NIH HHS/United States
- P01 HL132821/HL/NHLBI NIH HHS/United States
- R56 AI139053/AI/NIAID NIH HHS/United States
- R01 AI137057/AI/NIAID NIH HHS/United States
- MR/R015635/1/MRC_/Medical Research Council/United Kingdom
LinkOut - more resources
Full Text Sources
Other Literature Sources
Molecular Biology Databases
Miscellaneous