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SARS-CoV-2 Receptor ACE2 Is an Interferon-Stimulated Gene in Human Airway Epithelial Cells and Is Detected in Specific Cell Subsets across Tissues.
Cell. 2020 05 28; 181(5):1016-1035.e19.Cell

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.

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Authors+Show Affiliations

Ziegler CGK
Program in Health Sciences & Technology, Harvard Medical School & Massachusetts Institute of Technology, Boston, MA 02115, USA; Institute for Medical Engineering & Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Harvard Graduate Program in Biophysics, Harvard University, Cambridge, MA 02138, USA.
Allon SJ
Institute for Medical Engineering & Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Nyquist SK
Institute for Medical Engineering & Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Program in Computational & Systems Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Computer Science & Artificial Intelligence Lab, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Mbano IM
Africa Health Research Institute, Durban, South Africa; School of Laboratory Medicine and Medical Sciences, College of Health Sciences, University of KwaZulu-Natal, Durban, South Africa.
Miao VN
Program in Health Sciences & Technology, Harvard Medical School & Massachusetts Institute of Technology, Boston, MA 02115, USA; Institute for Medical Engineering & Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Tzouanas CN
Program in Health Sciences & Technology, Harvard Medical School & Massachusetts Institute of Technology, Boston, MA 02115, USA; Institute for Medical Engineering & Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Cao Y
University of Massachusetts Medical School, Worcester, MA 01655, USA.
Yousif AS
Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA.
Bals J
Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA.
Hauser BM
Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA; Department of Microbiology, Harvard Medical School, Boston, MA 02115, USA.
Feldman J
Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA; Department of Microbiology, Harvard Medical School, Boston, MA 02115, USA; Program in Virology, Harvard Medical School, Boston, MA 02115, USA.
Muus C
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; John A. Paulson School of Engineering & Applied Sciences, Harvard University, Cambridge, MA 02138, USA.
Wadsworth MH
Institute for Medical Engineering & Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Kazer SW
Institute for Medical Engineering & Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Hughes TK
Program in Health Sciences & Technology, Harvard Medical School & Massachusetts Institute of Technology, Boston, MA 02115, USA; Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Program in Immunology, Harvard Medical School, Boston, MA 02115, USA.
Doran B
Institute for Medical Engineering & Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115, USA; Division of Gastroenterology, Hepatology, and Nutrition, Boston Children's Hospital, Boston, MA 02115, USA.
Gatter GJ
Institute for Medical Engineering & Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Vukovic M
Institute for Medical Engineering & Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Taliaferro F
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Division of Gastroenterology, Hepatology, and Nutrition, Boston Children's Hospital, Boston, MA 02115, USA.
Mead BE
Institute for Medical Engineering & Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Guo Z
University of Massachusetts Medical School, Worcester, MA 01655, USA.
Wang JP
University of Massachusetts Medical School, Worcester, MA 01655, USA.
Gras D
Aix-Marseille University, INSERM, INRA, C2VN, Marseille, France.
Plaisant M
Université Côte d'Azur, CNRS, IPMC, Sophia-Antipolis, France.
Ansari M
Comprehensive Pneumology Center & Institute of Lung Biology and Disease, Helmholtz Zentrum München, Munich, Germany; German Center for Lung Research, Munich, Germany; Institute of Computational Biology, Helmholtz Zentrum München, Munich, Germany.
Angelidis I
Comprehensive Pneumology Center & Institute of Lung Biology and Disease, Helmholtz Zentrum München, Munich, Germany; German Center for Lung Research, Munich, Germany.
Adler H
German Center for Lung Research, Munich, Germany; Research Unit Lung Repair and Regeneration, Helmholtz Zentrum München, Munich, Germany.
Sucre JMS
Division of Neonatology, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Taylor CJ
Divison of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Lin B
Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
Waghray A
Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
Mitsialis V
Division of Gastroenterology, Hepatology, and Nutrition, Boston Children's Hospital, Boston, MA 02115, USA; Division of Gastroenterology, Brigham and Women's Hospital, Boston, MA 02115, USA.
Dwyer DF
Division of Allergy and Clinical Immunology, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
Buchheit KM
Division of Allergy and Clinical Immunology, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
Boyce JA
Division of Allergy and Clinical Immunology, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
Barrett NA
Division of Allergy and Clinical Immunology, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
Laidlaw TM
Division of Allergy and Clinical Immunology, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
Carroll SL
University of California, Berkeley, CA 94720, USA.
Colonna L
University of Washington, Seattle, WA 98195, USA.
Tkachev V
Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115, USA; Dana Farber Cancer Institute, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA.
Peterson CW
Stem Cell & Gene Therapy Program, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Department of Medicine, University of Washington, Seattle, WA 98195, USA.
Yu A
Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115, USA; Division of Gastroenterology and Hepatology, Seattle Children's Hospital, Seattle, WA 98145, USA.
Zheng HB
University of Washington, Seattle, WA 98195, USA; Division of Gastroenterology and Hepatology, Seattle Children's Hospital, Seattle, WA 98145, USA.
Gideon HP
Department of Microbiology & Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219, USA; Center for Vaccine Research, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
Winchell CG
Department of Microbiology & Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219, USA; Center for Vaccine Research, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA; Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Lin PL
Center for Vaccine Research, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA; UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA 15224, USA; Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA.
Bingle CD
Department of Infection, Immunity & Cardiovascular Disease, The Medical School and The Florey Institute for Host Pathogen Interactions, University of Sheffield, Sheffield, S10 2TN, UK.
Snapper SB
Division of Gastroenterology, Hepatology, and Nutrition, Boston Children's Hospital, Boston, MA 02115, USA; Division of Gastroenterology, Brigham and Women's Hospital, Boston, MA 02115, USA.
Kropski JA
Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN 37240, USA; Department of Veterans Affairs Medical Center, Nashville, TN 37212, USA.
Theis FJ
Institute of Computational Biology, Helmholtz Zentrum München, Munich, Germany.
Schiller HB
Comprehensive Pneumology Center & Institute of Lung Biology and Disease, Helmholtz Zentrum München, Munich, Germany; German Center for Lung Research, Munich, Germany.
Zaragosi LE
Université Côte d'Azur, CNRS, IPMC, Sophia-Antipolis, France.
Barbry P
Université Côte d'Azur, CNRS, IPMC, Sophia-Antipolis, France.
Leslie A
Africa Health Research Institute, Durban, South Africa; School of Laboratory Medicine and Medical Sciences, College of Health Sciences, University of KwaZulu-Natal, Durban, South Africa; Department of Infection & Immunity, University College London, London, UK.
Kiem HP
Stem Cell & Gene Therapy Program, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Department of Medicine, University of Washington, Seattle, WA 98195, USA.
Flynn JL
Department of Microbiology & Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219, USA; Center for Vaccine Research, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
Fortune SM
Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
Berger B
Computer Science & Artificial Intelligence Lab, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Mathematics, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Finberg RW
University of Massachusetts Medical School, Worcester, MA 01655, USA.
Kean LS
Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115, USA; Dana Farber Cancer Institute, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA.
Garber M
University of Massachusetts Medical School, Worcester, MA 01655, USA.
Schmidt AG
Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA; Department of Microbiology, Harvard Medical School, Boston, MA 02115, USA.
Lingwood D
Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA.
Shalek AK
Program in Health Sciences & Technology, Harvard Medical School & Massachusetts Institute of Technology, Boston, MA 02115, USA; Institute for Medical Engineering & Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Harvard Graduate Program in Biophysics, Harvard University, Cambridge, MA 02138, USA; Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Program in Computational & Systems Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Program in Immunology, Harvard Medical School, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA. Electronic address: shalek@mit.edu.
Ordovas-Montanes J
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Program in Immunology, Harvard Medical School, Boston, MA 02115, USA; Division of Gastroenterology, Hepatology, and Nutrition, Boston Children's Hospital, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA. Electronic address: jose.ordovas-montanes@childrens.harvard.edu.
HCA Lung Biological Network. Electronic address: lung-network@humancellatlas.org
No affiliation info available
HCA Lung Biological Network
No affiliation info available

MeSH

AdolescentAlveolar Epithelial CellsAngiotensin-Converting Enzyme 2AnimalsBetacoronavirusCOVID-19Cell LineCells, CulturedChildCoronavirus InfectionsEnterocytesGoblet CellsHIV InfectionsHumansInfluenza, HumanInterferon Type ILungMacaca mulattaMiceMycobacterium tuberculosisNasal MucosaPandemicsPeptidyl-Dipeptidase APneumonia, ViralReceptors, VirusSARS-CoV-2Serine EndopeptidasesSingle-Cell AnalysisTuberculosisUp-Regulation

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

32413319

Clinical Trial Links

Low-field Magnetic Resonance Imaging in Pediatric Post Covid-19
Low-field Magnetic Resonance Imaging of Pediatric COVID-19

Citation

Ziegler, Carly G K., et al. "SARS-CoV-2 Receptor ACE2 Is an Interferon-Stimulated Gene in Human Airway Epithelial Cells and Is Detected in Specific Cell Subsets Across Tissues." Cell, vol. 181, no. 5, 2020, pp. 1016-1035.e19.
Ziegler CGK, Allon SJ, Nyquist SK, et al. SARS-CoV-2 Receptor ACE2 Is an Interferon-Stimulated Gene in Human Airway Epithelial Cells and Is Detected in Specific Cell Subsets across Tissues. Cell. 2020;181(5):1016-1035.e19.
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., Kazer, S. W., Hughes, T. K., Doran, B., Gatter, G. J., Vukovic, M., Taliaferro, F., ... Ordovas-Montanes, J. (2020). SARS-CoV-2 Receptor ACE2 Is an Interferon-Stimulated Gene in Human Airway Epithelial Cells and Is Detected in Specific Cell Subsets across Tissues. Cell, 181(5), 1016-e19. https://doi.org/10.1016/j.cell.2020.04.035
Ziegler CGK, et al. SARS-CoV-2 Receptor ACE2 Is an Interferon-Stimulated Gene in Human Airway Epithelial Cells and Is Detected in Specific Cell Subsets Across Tissues. Cell. 2020 05 28;181(5):1016-1035.e19. PubMed PMID: 32413319.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - SARS-CoV-2 Receptor ACE2 Is an Interferon-Stimulated Gene in Human Airway Epithelial Cells and Is Detected in Specific Cell Subsets across Tissues. AU - Ziegler,Carly G K, AU - Allon,Samuel J, AU - Nyquist,Sarah K, AU - Mbano,Ian M, AU - Miao,Vincent N, AU - Tzouanas,Constantine N, AU - Cao,Yuming, AU - Yousif,Ashraf S, AU - Bals,Julia, AU - Hauser,Blake M, AU - Feldman,Jared, AU - Muus,Christoph, AU - Wadsworth,Marc H,2nd AU - Kazer,Samuel W, AU - Hughes,Travis K, AU - Doran,Benjamin, AU - Gatter,G James, AU - Vukovic,Marko, AU - Taliaferro,Faith, AU - Mead,Benjamin E, AU - Guo,Zhiru, AU - Wang,Jennifer P, AU - Gras,Delphine, AU - Plaisant,Magali, AU - Ansari,Meshal, AU - Angelidis,Ilias, AU - Adler,Heiko, AU - Sucre,Jennifer M S, AU - Taylor,Chase J, AU - Lin,Brian, AU - Waghray,Avinash, AU - Mitsialis,Vanessa, AU - Dwyer,Daniel F, AU - Buchheit,Kathleen M, AU - Boyce,Joshua A, AU - Barrett,Nora A, AU - Laidlaw,Tanya M, AU - Carroll,Shaina L, AU - Colonna,Lucrezia, AU - Tkachev,Victor, AU - Peterson,Christopher W, AU - Yu,Alison, AU - Zheng,Hengqi Betty, AU - Gideon,Hannah P, AU - Winchell,Caylin G, AU - Lin,Philana Ling, AU - Bingle,Colin D, AU - Snapper,Scott B, AU - Kropski,Jonathan A, AU - Theis,Fabian J, AU - Schiller,Herbert B, AU - Zaragosi,Laure-Emmanuelle, AU - Barbry,Pascal, AU - Leslie,Alasdair, AU - Kiem,Hans-Peter, AU - Flynn,JoAnne L, AU - Fortune,Sarah M, AU - Berger,Bonnie, AU - Finberg,Robert W, AU - Kean,Leslie S, AU - Garber,Manuel, AU - Schmidt,Aaron G, AU - Lingwood,Daniel, AU - Shalek,Alex K, AU - Ordovas-Montanes,Jose, AU - ,, AU - ,, Y1 - 2020/04/27/ PY - 2020/03/13/received PY - 2020/04/03/revised PY - 2020/04/20/accepted PY - 2020/5/16/pubmed PY - 2020/6/6/medline PY - 2020/5/16/entrez KW - ACE2 KW - COVID-19 KW - ISG KW - SARS-CoV-2 KW - human KW - influenza KW - interferon KW - mouse KW - non-human primate KW - scRNA-seq SP - 1016 EP - 1035.e19 JF - Cell JO - Cell VL - 181 IS - 5 N2 - 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. SN - 1097-4172 UR - https://www.unboundmedicine.com/medline/citation/32413319/SARS_CoV_2_Receptor_ACE2_Is_an_Interferon_Stimulated_Gene_in_Human_Airway_Epithelial_Cells_and_Is_Detected_in_Specific_Cell_Subsets_across_Tissues_ DB - PRIME DP - Unbound Medicine ER -