SARS-CoV-2 Receptor ACE2 Is an Interferon-Stimulated Gene in Human Airway Epithelial Cells and Is Detected in Specific Cell Subsets across Tissues

Carly G K Ziegler; Samuel J Allon; Sarah K Nyquist; Ian M Mbano; Vincent N Miao; Constantine N Tzouanas; Yuming Cao; Ashraf S Yousif; Julia Bals; Blake M Hauser; Jared Feldman; Christoph Muus; Marc H Wadsworth 2nd; Samuel W Kazer; Travis K Hughes; Benjamin Doran; G James Gatter; Marko Vukovic; Faith Taliaferro; Benjamin E Mead; Zhiru Guo; Jennifer P Wang; Delphine Gras; Magali Plaisant; Meshal Ansari; Ilias Angelidis; Heiko Adler; Jennifer M S Sucre; Chase J Taylor; Brian Lin; Avinash Waghray; Vanessa Mitsialis; Daniel F Dwyer; Kathleen M Buchheit; Joshua A Boyce; Nora A Barrett; Tanya M Laidlaw; Shaina L Carroll; Lucrezia Colonna; Victor Tkachev; Christopher W Peterson; Alison Yu; Hengqi Betty Zheng; Hannah P Gideon; Caylin G Winchell; Philana Ling Lin; Colin D Bingle; Scott B Snapper; Jonathan A Kropski; Fabian J Theis; Herbert B Schiller; Laure-Emmanuelle Zaragosi; Pascal Barbry; Alasdair Leslie; Hans-Peter Kiem; JoAnne L Flynn; Sarah M Fortune; Bonnie Berger; Robert W Finberg; Leslie S Kean; Manuel Garber; Aaron G Schmidt; Daniel Lingwood; Alex K Shalek; Jose Ordovas-Montanes; HCA Lung Biological Network. Electronic address: lung-network@humancellatlas.org; HCA Lung Biological Network

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

Cell. 2020 May 28;181(5):1016-1035.e19. doi: 10.1016/j.cell.2020.04.035. Epub 2020 Apr 27.

Authors

Carly G K Ziegler¹, Samuel J Allon², Sarah K Nyquist³, Ian M Mbano⁴, Vincent N Miao⁵, Constantine N Tzouanas⁵, Yuming Cao⁶, Ashraf S Yousif⁷, Julia Bals⁷, Blake M Hauser⁸, Jared Feldman⁹, Christoph Muus¹⁰, Marc H Wadsworth 2nd¹¹, Samuel W Kazer², Travis K Hughes¹², Benjamin Doran¹³, G James Gatter¹⁴, Marko Vukovic¹¹, Faith Taliaferro¹⁵, Benjamin E Mead¹¹, Zhiru Guo⁶, Jennifer P Wang⁶, Delphine Gras¹⁶, Magali Plaisant¹⁷, Meshal Ansari¹⁸, Ilias Angelidis¹⁹, Heiko Adler²⁰, Jennifer M S Sucre²¹, Chase J Taylor²², Brian Lin²³, Avinash Waghray²³, Vanessa Mitsialis²⁴, Daniel F Dwyer²⁵, Kathleen M Buchheit²⁵, Joshua A Boyce²⁵, Nora A Barrett²⁵, Tanya M Laidlaw²⁵, Shaina L Carroll²⁶, Lucrezia Colonna²⁷, Victor Tkachev²⁸, Christopher W Peterson²⁹, Alison Yu³⁰, Hengqi Betty Zheng³¹, Hannah P Gideon³², Caylin G Winchell³³, Philana Ling Lin³⁴, Colin D Bingle³⁵, Scott B Snapper²⁴, Jonathan A Kropski³⁶, Fabian J Theis³⁷, Herbert B Schiller¹⁹, Laure-Emmanuelle Zaragosi¹⁷, Pascal Barbry¹⁷, Alasdair Leslie³⁸, Hans-Peter Kiem²⁹, JoAnne L Flynn³², Sarah M Fortune³⁹, Bonnie Berger⁴⁰, Robert W Finberg⁶, Leslie S Kean²⁸, Manuel Garber⁶, Aaron G Schmidt⁸, Daniel Lingwood⁷, Alex K Shalek⁴¹, Jose Ordovas-Montanes⁴²; HCA Lung Biological Network. Electronic address: lung-network@humancellatlas.org; HCA Lung Biological Network

Collaborators

Nicholas Banovich, Pascal Barbry, Alvis Brazma, Tushar Desai, Thu Elizabeth Duong, Oliver Eickelberg, Christine Falk, Michael Farzan, Ian Glass, Muzlifah Haniffa, Peter Horvath, Deborah Hung, Naftali Kaminski, Mark Krasnow, Jonathan A Kropski, Malte Kuhnemund, Robert Lafyatis, Haeock Lee, Sylvie Leroy, Sten Linnarson, Joakim Lundeberg, Kerstin Meyer, Alexander Misharin, Martijn Nawijn, Marko Z Nikolic, Jose Ordovas-Montanes, Dana Pe'er, Joseph Powell, Stephen Quake, Jay Rajagopal, Purushothama Rao Tata, Emma L Rawlins, Aviv Regev, Paul A Reyfman, Mauricio Rojas, Orit Rosen, Kourosh Saeb-Parsy, Christos Samakovlis, Herbert Schiller, Joachim L Schultze, Max A Seibold, Alex K Shalek, Douglas Shepherd, Jason Spence, Avrum Spira, Xin Sun, Sarah Teichmann, Fabian Theis, Alexander Tsankov, Maarten van den Berge, Michael von Papen, Jeffrey Whitsett, Ramnik Xavier, Yan Xu, Laure-Emmanuelle Zaragosi, Kun Zhang

Affiliations

¹ 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.
² 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.
³ 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.
⁴ 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.
⁵ 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.
⁶ University of Massachusetts Medical School, Worcester, MA 01655, USA.
⁷ Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA.
⁸ Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA; Department of Microbiology, Harvard Medical School, Boston, MA 02115, USA.
⁹ 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.
¹⁰ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; John A. Paulson School of Engineering & Applied Sciences, Harvard University, Cambridge, MA 02138, USA.
¹¹ 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.
¹² 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.
¹³ 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.
¹⁴ 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.
¹⁵ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Division of Gastroenterology, Hepatology, and Nutrition, Boston Children's Hospital, Boston, MA 02115, USA.
¹⁶ Aix-Marseille University, INSERM, INRA, C2VN, Marseille, France.
¹⁷ Université Côte d'Azur, CNRS, IPMC, Sophia-Antipolis, France.
¹⁸ 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.
¹⁹ Comprehensive Pneumology Center & Institute of Lung Biology and Disease, Helmholtz Zentrum München, Munich, Germany; German Center for Lung Research, Munich, Germany.
²⁰ German Center for Lung Research, Munich, Germany; Research Unit Lung Repair and Regeneration, Helmholtz Zentrum München, Munich, Germany.
²¹ Division of Neonatology, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
²² Divison of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
²³ Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
²⁴ 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.
²⁵ Division of Allergy and Clinical Immunology, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
²⁶ University of California, Berkeley, CA 94720, USA.
²⁷ University of Washington, Seattle, WA 98195, USA.
²⁸ 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.
²⁹ Stem Cell & Gene Therapy Program, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Department of Medicine, University of Washington, Seattle, WA 98195, USA.
³⁰ 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.
³¹ University of Washington, Seattle, WA 98195, USA; Division of Gastroenterology and Hepatology, Seattle Children's Hospital, Seattle, WA 98145, USA.
³² 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.
³³ 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.
³⁴ 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.
³⁵ Department of Infection, Immunity & Cardiovascular Disease, The Medical School and The Florey Institute for Host Pathogen Interactions, University of Sheffield, Sheffield, S10 2TN, UK.
³⁶ 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.
³⁷ Institute of Computational Biology, Helmholtz Zentrum München, Munich, Germany.
³⁸ 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.
³⁹ 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.
⁴⁰ Computer Science & Artificial Intelligence Lab, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Mathematics, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
⁴¹ 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.
⁴² 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.

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.

Publication types

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

MeSH terms

Adolescent
Alveolar Epithelial Cells / immunology
Alveolar Epithelial Cells / metabolism*
Angiotensin-Converting Enzyme 2
Animals
Betacoronavirus / physiology
COVID-19
Cell Line
Cells, Cultured
Child
Coronavirus Infections / virology
Enterocytes / immunology
Enterocytes / metabolism*
Goblet Cells / immunology
Goblet Cells / metabolism*
HIV Infections / immunology
Humans
Influenza, Human / immunology
Interferon Type I / immunology
Interferon Type I / metabolism*
Lung / cytology
Lung / pathology
Macaca mulatta
Mice
Mycobacterium tuberculosis
Nasal Mucosa / cytology*
Nasal Mucosa / immunology
Pandemics
Peptidyl-Dipeptidase A / genetics*
Peptidyl-Dipeptidase A / metabolism
Pneumonia, Viral / virology
Receptors, Virus / genetics
SARS-CoV-2
Serine Endopeptidases / metabolism
Single-Cell Analysis
Tuberculosis / immunology
Up-Regulation

Substances

Interferon Type I
Receptors, Virus
Peptidyl-Dipeptidase A
ACE2 protein, human
Ace2 protein, mouse
Angiotensin-Converting Enzyme 2
Serine Endopeptidases
TMPRSS2 protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding