Muus, C. and Luecken, M.D. and Eraslan, G. and Sikkema, L. and Waghray, A. and Horváth, Péter (2021) Single-cell meta-analysis of SARS-CoV-2 entry genes across tissues and demographics. NATURE MEDICINE, 27 (3). pp. 546-559. ISSN 1078-8956
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Official URL: http://doi.org/10.1038/s41591-020-01227-z
Abstract
Angiotensin-converting enzyme 2 (ACE2) and accessory proteases (TMPRSS2 and CTSL) are needed for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cellular entry, and their expression may shed light on viral tropism and impact across the body. We assessed the cell-type-specific expression of ACE2, TMPRSS2 and CTSL across 107 single-cell RNA-sequencing studies from different tissues. ACE2, TMPRSS2 and CTSL are coexpressed in specific subsets of respiratory epithelial cells in the nasal passages, airways and alveoli, and in cells from other organs associated with coronavirus disease 2019 (COVID-19) transmission or pathology. We performed a meta-analysis of 31 lung single-cell RNA-sequencing studies with 1,320,896 cells from 377 nasal, airway and lung parenchyma samples from 228 individuals. This revealed cell-type-specific associations of age, sex and smoking with expression levels of ACE2, TMPRSS2 and CTSL. Expression of entry factors increased with age and in males, including in airway secretory cells and alveolar type 2 cells. Expression programs shared by ACE2+TMPRSS2+ cells in nasal, lung and gut tissues included genes that may mediate viral entry, key immune functions and epithelial–macrophage cross-talk, such as genes involved in the interleukin-6, interleukin-1, tumor necrosis factor and complement pathways. Cell-type-specific expression patterns may contribute to the pathogenesis of COVID-19, and our work highlights putative molecular pathways for therapeutic intervention. © 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.
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| Additional Information: | Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, United States John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, United States Institute of Computational Biology, Helmholtz Zentrum München, Neuherberg, Germany Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, United States Departments of Internal Medicine and Pediatrics, Pulmonary and Critical Care Unit, Massachusetts General Hospital, Boston, MA, United States Harvard Stem Cell Institute, Cambridge, MA, United States Department of Cell Biology, Duke University Medical School, Durham, NC, United States Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, United States Division of Respiratory Medicine, Department of Pediatrics, University of California, San Diego, La Jolla, CA, United States Comprehensive Pneumology Center (CPC)/Institute of Lung Biology and Disease (ILBD), Helmholtz Zentrum München, Member of the German Center for Lung Research (DZL), Munich, Germany Institute of Computational Biology, Helmholtz Zentrum München, Munich, Germany Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, United States Center for Epigenomics, University of California San Diego School of Medicine, La Jolla, CA, United States Department of Cellular and Molecular Medicine, University of California San Diego School of Medicine, La Jolla, CA, United States Division of Rheumatology, Inflammation, and Immunity, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States Broad Institute of MIT and Harvard, Cambridge, MA, United States Whitehead Institute for Biomedical Research, Cambridge, MA, United States Department of Environmental Health, Harvard T. H. Chan School of Public Health, Boston, MA, United States Pulmonary, Critical Care and Sleep Medicine, Yale University School of Medicine, New Haven, CT, United States Institute for Medical Engineering and Science & Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, United States Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, United States SciLifeLab, Department of Gene Technology, KTH Royal Institute of Technology, Stockolm, Sweden Department for Genomics & Immunoregulation, LIMES-Institute, University of Bonn, Bonn, Germany Université Côte d’Azur, CNRS, IPMC, Sophia-Antipolis, France Wellcome Sanger Institute, Hinxton, United Kingdom Division of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden Translational Genomics Research Institute, Phoenix, AZ, United States Department of Medicine, Boston University School of Medicine, Boston, MA, United States Bioinformatics Program, Boston University School of Medicine, Boston, MA, United States Precision Cardiology Laboratory, The Broad Institute, Cambridge, MA, United States Institute of Transplant Immunology, Hannover Medical School, MHH, Hannover, Germany German Center for Infectious Diseases (DZIF), Braunschweig, Germany Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla, CA, United States European Molecular Biology Laboratory, European Bioinformatics Institute, Hinxton, United Kingdom Boston University School of Medicine, Boston, MA, United States Boston University Medical Center, Boston, MA, United States Institute of Computational Biology, Helmholtz Zentrum München, Munich, Germany TUM School of Life Sciences Weihenstephan, Technical University of Munich, Freising, Germany Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom Department of Biochemistry and Wall Center for Pulmonary Vascular Disease, Stanford, CA, United States Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States Divisions of Pulmonary Biology; Perinatal Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States Center for Epigenomics, University of California-San Diego School of Medicine, La Jolla, CA, United States Department of Cellular and Molecular Medicine, University of California-San Diego School of Medicine, La Jolla, CA, United States Division of Pulmonary Sciences and Critical Care Medicine, School of Medicine, University of Colorado, Aurora, CO, United States Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, New TerritoriesSAR, Hong Kong Genomics and Immunoregulation, Life & Medical Sciences (LIMES) Institute, University of Bonn, Bonn, Germany Division of Pulmonary Medicine, Department of Pediatrics, Stanford University, Stanford, CA, United States SciLifeLab, Department of Gene Technology, KTH Royal Institute of Technology, Stockholm, Sweden Gurdon Institute, University of Cambridge, Cambridge, United Kingdom Cellular Genetics Programme, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, United Kingdom Cardiovascular and Metabolic Sciences, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany Division of Hematology/Oncology, Boston Children’s Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, United States Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany Berlin Institute of Health (BIH), Center for Digital Health, Berlin, Germany European Molecular Biology Laboratory—European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, United Kingdom Wellcome Sanger Institute, Cellular Genetics Programme Wellcome Genome Campus, Hinxton, United Kingdom Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA, United States Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Charlestown, MA, United States Pulmonology Department, Université Côte d’Azur, CHU Nice, Nice, France CNRS, Institut de Pharmacologie Moléculaire et Cellulaire, Sophia-Antipolis, France Helmholtz Zentrum München, Institute of Lung Biology and Disease, Group Systems Medicine of Chronic Lung Disease, Member of the German Center for Lung Research (DZL), Munich, Germany 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 Ophthalmology, Harvard Medical School and Massachusetts Eye and Ear, Boston, MA, United States Computational and Systems Biology, CSAIL, Institute for Medical Engineering and Science & Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, United States Department of Pediatric Pulmonology and Pediatric Allergology, Beatrix Children’s Hospital, University of Groningen, University Medical Center Groningen, Groningen, Netherlands GRIAC Research Institute, University of Groningen, University Medical Center Groningen, Groningen, Netherlands Biosciences Institute, Faculty of Medical Sciences, Newcastle University, International Centre for Life, Newcastle upon Tyne, United Kingdom Department of Genetics, Harvard Medical School, Boston, MA, United States Department of Cardiology, University Heart & Vascular Center, University of Hamburg, Hamburg, Germany Section of Pulmonary, Critical Care, and Sleep Medicine, Yale University School of Medicine, New Haven, CT, United States Division of Computational Biomedicine, Department of Medicine, Boston University School of Medicine, Boston, MA, United 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United States Division of Neonatology, Department of Pediatrics, University of Rochester Medical Center, Rochester, NY, United States Program in Pediatric Molecular and Personalized Medicine, Department of Pediatrics, University of Rochester Medical Center, Rochester, NY, United States Department of Pediatrics, University of California-San Diego School of Medicine, La Jolla, CA, United States Department of Biological Sciences, University of California, San Diego, La Jolla, CA, United States Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States Divisions of Pulmonary Biology and Biomedical Informatics, Perinatal Institute, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, United States Division of Pulmonary and Critical Care Medicine, Department of Medicine, Massachusetts General Hospital, Boston, MA, United States Infectious Disease and Microbiome Program, Broad Institute of Harvard and MIT, Cambridge, MA, United States Infectious Diseases Division, Department of Medicine, Massachusetts General Hospital, Boston, MA, United States European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, United Kingdom Division of Pulmonary and Critical Care Medicine, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States Biosciences Institute, Faculty of Medical Sciences, Newcastle University, International Centre for Life, Bioscience West Building, Newcastle upon Tyne, United Kingdom Charité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany Roswell Park Comprehensive Cancer Center, Buffalo, NY, United 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Medicine, University of Washington, Seattle, WA, United States Brigham and Women’s Hospital, Harvard Medical School, and Broad Institute of MIT and Harvard, Cambridge, MA, United States Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, United Kingdom Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom Department of Dermatology and NIHR Newcastle Biomedical Research Centre, Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom Division of Pulmonary and Critical Care Medicine and Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States Synthetic and Systems Biology Unit, Hungarian Academy of Sciences, Biological Research Center (BRC), Szeged, Hungary Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin, Germany Berlin Institute of Health (BIH), Berlin, Germany Charité–Universitätsmedizin, Berlin, Germany Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, United States Infectious Disease and Microbiome Program and Core Faculty Member, Broad Institute of MIT & Harvard, Cambridge, MA, United States Division of Pulmonary, Critical Care and Sleep Medicine, National Jewish Health, Division of Pulmonary Medicine and Critical Care Sciences, University of Colorado Denver, Denver, CO, United States Department of Medicine, Harvard Medical School and Massachusetts General Hospital Cancer Center, Boston, MA, United States Lung Repair and Regeneration Unit, Helmholtz-Zentrum Munich, Ludwig-Maximilians-University, University Hospital Grosshadern, Member of the German Center of Lung Research (DZL), Munich, Germany Department of Pediatric Pulmonology and Pediatric Allergology, Beatrix Children’s Hospital, University of Groningen, University Medical Center Groningen (UMCG), Groningen Research Institute for Asthma and COPD, Groningen, Netherlands Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, United States Department of Veterans Affairs Medical Center, Nashville, TN, United States Cartana AB, Stockholm, Sweden Division of Rheumatology, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, United States Broad Institute of Harvard and MIT, Cambridge, MA, United States Department of Systems Biology, Harvard Medical School, Boston, MA, United States Department of Biomedicine and Health Sciences, The Catholic University of Korea, Seoul, South Korea FHU OncoAge, CNRS, Inserm, IRCAN team 3, Pulmonology Department, Université Côte d’Azur, CHU de Nice, Nice, France Department of Biochemistry and Wall Center for Pulmonary Vascular Disease, Stanford University, Stanford, CA, United States Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, United Kingdom Wellcome Trust Sanger Institute, 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Cambridge, MA, United States Department of Surgery, University of Cambridge and NIHR Cambridge Biomedical Research Centre, Cambridge, United Kingdom SciLifeLab, Department of Molecular Biosciences, Stockholm University, Stockholm, Sweden Cardiopulmonary Institute, Justus Liebig University, Giessen, Germany PRECISE Platform for Single Cell Genomics & Epigenomics, Germany Center for Neurodegenerative Diseases and University of Bonn, Bonn, Germany Berlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine, Berlin, Germany Harvard Medical School, Boston, MA, United States Ocular Genomics Institute, Department of Ophthalmology, Massachusetts Eye and Ear, Boston, MA, United States Department of Pediatrics; Center for Genes, Environment, and Health; National Jewish Health, Denver, CO, United States Cardiovascular Division, Brigham & Women’s Hospital, Boston, MA, United States Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA, United States Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, United States Institute for Medical Engineering and Science (IMES), Koch Institute for Integrative Cancer Research, and Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, United States Center for Biological Physics and Department of Physics, Arizona State University, Tempe, AZ, United States Department of Internal Medicine, Gastroenterology, University of Michigan Medical School, Ann Arbor, MI, United States Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, United States Department of Biomedical Engineering, University of Michigan College of Engineering, Ann Arbor, MI, United States Johnson & Johnson Innovation, Cambridge, MA, United States Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institute, Stockholm, Sweden Department of Physics/Cavendish Laboratory, University of Cambridge, Cambridge, United Kingdom Institute of Computational Biology, Helmholtz Zentrum München and Departments of Mathematics and Life Sciences, Technical University Munich, Munich, Germany Wellcome and MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, Cambridge, United Kingdom Department of Surgery, Cambridge Biomedical Campus, Cambridge, United Kingdom Department of Pulmonary Diseases and Tuberculosis, University of Groningen, GRIAC Research Institute, University Medical Center Groningen, Groningen, Netherlands Department of Pathology, Brigham and Women’s Hospital, and Harvard Medical School, Boston, MA, United States Broad Institute, Department of Molecular Biology and Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA, United States Koc University Research Center for Translational Medicine (KUTTAM), Istanbul, Turkey Microscopy Centre and Department of Applied Clinical Sciences and Biotechnology, University of L’Aquila, L’Aquila, Italy Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education and Department of Histology and Embryology of Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China Department of Bioengineering, University of California, San Diego, La Jolla, CA, United States Cited By :51 Export Date: 13 January 2022 CODEN: NAMEF Correspondence Address: Muus, C.; Klarman Cell Observatory, United States; email: muus@broadinstitute.org Correspondence Address: Luecken, M.D.; Institute of Computational Biology, Germany; email: malte.luecken@helmholtz-muenchen.de |
| Uncontrolled Keywords: | Aged; Aged; Adult; Adult; Female; Female; Middle Aged; Middle Aged; Male; Male; Humans; Metabolism; GENETICS; ARTICLE; AGE; Pathogenesis; human; Aged, 80 and over; MACROPHAGE; physiology; smoking; controlled study; nonhuman; information processing; sequence analysis; pathology; Organ Specificity; Demography; Demography; Demography; gender; immune system; Antibody Specificity; Gene Expression Profiling; Gene Expression Profiling; EPIDEMIOLOGY; human cell; Lung; Lung; virology; protein expression; interleukin 6; Tumor Necrosis Factor; virus transmission; human tissue; respiratory system; respiratory system; serine proteinase; Complement system; meta analysis; lung parenchyma; complement classical pathway; lung alveolus cell type 2; Virus Internalization; interleukin 1; virus entry; lung alveolus; secretory cell; cell specificity; Host-Pathogen Interactions; host pathogen interaction; nose; Serine Endopeptidases; Sequence Analysis, RNA; airway; virus gene; Single-Cell Analysis; single cell analysis; viral tropism; very elderly; angiotensin converting enzyme 2; procedures; Datasets as Topic; lung alveolus epithelium cell; airway epithelium cell; gene expression level; cathepsin L; cathepsin L; cathepsin L; alveolar epithelial cells; Angiotensin-converting enzyme 2; intestine tissue; COVID-19; coronavirus disease 2019; Severe acute respiratory syndrome coronavirus 2; single cell RNA seq; SARS-CoV-2; TMPRSS2 protein, human; CTSL protein, human; transmembrane protease serine 2; ACE2 protein, human; |
| Subjects: | Q Science / természettudomány > QH Natural history / természetrajz > QH301 Biology / biológia > QH3011 Biochemistry / biokémia Q Science / természettudomány > QR Microbiology / mikrobiológia > QR355 Virology / víruskutatás |
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| Depositing User: | MTMT SWORD |
| Date Deposited: | 07 Feb 2022 10:50 |
| Last Modified: | 07 Feb 2022 10:50 |
| URI: | http://real.mtak.hu/id/eprint/137491 |
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