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SARS-CoV-2 infection triggers profibrotic macrophage responses and lung fibrosis.
Cell. 2021 12 22; 184(26):6243-6261.e27.Cell

Abstract

COVID-19-induced "acute respiratory distress syndrome" (ARDS) is associated with prolonged respiratory failure and high mortality, but the mechanistic basis of lung injury remains incompletely understood. Here, we analyze pulmonary immune responses and lung pathology in two cohorts of patients with COVID-19 ARDS using functional single-cell genomics, immunohistology, and electron microscopy. We describe an accumulation of CD163-expressing monocyte-derived macrophages that acquired a profibrotic transcriptional phenotype during COVID-19 ARDS. Gene set enrichment and computational data integration revealed a significant similarity between COVID-19-associated macrophages and profibrotic macrophage populations identified in idiopathic pulmonary fibrosis. COVID-19 ARDS was associated with clinical, radiographic, histopathological, and ultrastructural hallmarks of pulmonary fibrosis. Exposure of human monocytes to SARS-CoV-2, but not influenza A virus or viral RNA analogs, was sufficient to induce a similar profibrotic phenotype in vitro. In conclusion, we demonstrate that SARS-CoV-2 triggers profibrotic macrophage responses and pronounced fibroproliferative ARDS.

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Authors+Show Affiliations

Wendisch D
Charité - Universitätsmedizin Berlin, Department of Infectious Diseases and Respiratory Medicine, Charité, Universitätsmedizin Berlin, Berlin, Germany.
Dietrich O
Helmholtz Institute for RNA-based Infection Research (HIRI), Helmholtz-Center for Infection Research (HZI), Würzburg, Germany.
Mari T
Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Proteome Dynamics, Berlin, Germany.
von Stillfried S
Institute of Pathology, RWTH Aachen University Hospital, Aachen, Germany.
Ibarra IL
Institute of Computational Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
Mittermaier M
Charité - Universitätsmedizin Berlin, Department of Infectious Diseases and Respiratory Medicine, Charité, Universitätsmedizin Berlin, Berlin, Germany; Berlin Institute of Health (BIH), Berlin, Germany.
Mache C
Unit 17 Influenza and other Respiratory Viruses, Robert Koch Institute, Berlin, Germany.
Chua RL
Center for Digital Health, Berlin Institute of Health (BIH) and Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany.
Knoll R
Systems Medicine, Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Bonn, Germany; Genomics and Immunoregulation, Life & Medical Sciences (LIMES) Institute, University of Bonn, Germany.
Timm S
Core Facility Electron Microscopy, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
Brumhard S
Charité - Universitätsmedizin Berlin, Department of Infectious Diseases and Respiratory Medicine, Charité, Universitätsmedizin Berlin, Berlin, Germany.
Krammer T
Helmholtz Institute for RNA-based Infection Research (HIRI), Helmholtz-Center for Infection Research (HZI), Würzburg, Germany.
Zauber H
Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Proteome Dynamics, Berlin, Germany.
Hiller AL
Charité - Universitätsmedizin Berlin, Department of Infectious Diseases and Respiratory Medicine, Charité, Universitätsmedizin Berlin, Berlin, Germany.
Pascual-Reguant A
Charité - Universitätsmedizin Berlin, Department of Rheumatology and Clinical Immunology, Charité; Deutsches Rheumaforschungszentrum, Immunodynamics, a Leibniz Institute, Berlin, Germany.
Mothes R
Deutsches Rheumaforschungszentrum, Immunodynamics, a Leibniz Institute, Berlin, Germany; Charité - Universitätsmedizin Berlin, Department of Neuropathology, Berlin, Germany.
Bülow RD
Institute of Pathology, RWTH Aachen University Hospital, Aachen, Germany.
Schulze J
Unit 17 Influenza and other Respiratory Viruses, Robert Koch Institute, Berlin, Germany.
Leipold AM
Helmholtz Institute for RNA-based Infection Research (HIRI), Helmholtz-Center for Infection Research (HZI), Würzburg, Germany.
Djudjaj S
Institute of Pathology, RWTH Aachen University Hospital, Aachen, Germany.
Erhard F
Institute for Virology and Immunobiology, Julius-Maximilians-University Würzburg, Würzburg, Germany.
Geffers R
Genome Analytics, Helmholtz-Center for Infection Research (HZI), Braunschweig, Germany.
Pott F
Berlin Institute of Health (BIH), Berlin, Germany; Charité - Universitätsmedizin Berlin, Institute of Virology, Charité Universitätsmedizin Berlin, Berlin, Germany.
Kazmierski J
Berlin Institute of Health (BIH), Berlin, Germany; Charité - Universitätsmedizin Berlin, Institute of Virology, Charité Universitätsmedizin Berlin, Berlin, Germany.
Radke J
Berlin Institute of Health (BIH), Berlin, Germany; Charité - Universitätsmedizin Berlin, Department of Neuropathology, Berlin, Germany.
Pergantis P
Charité - Universitätsmedizin Berlin, Department of Infectious Diseases and Respiratory Medicine, Charité, Universitätsmedizin Berlin, Berlin, Germany.
Baβler K
Systems Medicine, Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Bonn, Germany; Genomics and Immunoregulation, Life & Medical Sciences (LIMES) Institute, University of Bonn, Germany.
Conrad C
Charité - Universitätsmedizin Berlin, Department of Infectious Diseases and Respiratory Medicine, Charité, Universitätsmedizin Berlin, Berlin, Germany.
Aschenbrenner AC
Systems Medicine, Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Bonn, Germany; Genomics and Immunoregulation, Life & Medical Sciences (LIMES) Institute, University of Bonn, Germany; PRECISE Platform for Genomics and Epigenomics at Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), and University of Bonn, Bonn, Germany; Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands.
Sawitzki B
Charité, Universitätsmedizin Berlin, Institute of Medical Immunology, Charité, Universitätsmedizin Berlin, Berlin, Germany.
Landthaler M
Berlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.
Wyler E
Berlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.
Horst D
Charité - Universitätsmedizin Berlin, Institute of Pathology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
Deutsche COVID-19 OMICS Initiative (DeCOI)
No affiliation info available
Hippenstiel S
Charité - Universitätsmedizin Berlin, Department of Infectious Diseases and Respiratory Medicine, Charité, Universitätsmedizin Berlin, Berlin, Germany; German Center for Lung Research (DZL), Germany.
Hocke A
Charité - Universitätsmedizin Berlin, Department of Infectious Diseases and Respiratory Medicine, Charité, Universitätsmedizin Berlin, Berlin, Germany; German Center for Lung Research (DZL), Germany.
Heppner FL
Charité - Universitätsmedizin Berlin, Department of Neuropathology, Berlin, Germany; Cluster of Excellence, NeuroCure, Berlin, Germany; German Center for Neurodegenerative Diseases (DZNE) Berlin, Berlin, Germany.
Uhrig A
Charité - Universitätsmedizin Berlin, Department of Infectious Diseases and Respiratory Medicine, Charité, Universitätsmedizin Berlin, Berlin, Germany.
Garcia C
Charité - Universitätsmedizin Berlin, Department of Infectious Diseases and Respiratory Medicine, Charité, Universitätsmedizin Berlin, Berlin, Germany.
Machleidt F
Charité - Universitätsmedizin Berlin, Department of Infectious Diseases and Respiratory Medicine, Charité, Universitätsmedizin Berlin, Berlin, Germany.
Herold S
German Center for Lung Research (DZL), Germany; Division of Infectious Diseases, Pulmonary and Critical Care Medicine, Department of Internal Medicine II, Universities of Giessen and Marburg Lung Center, Giessen, Germany; Institute of Lung Health (ILH), Giessen, Germany.
Elezkurtaj S
Charité - Universitätsmedizin Berlin, Institute of Pathology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
Thibeault C
Charité - Universitätsmedizin Berlin, Department of Infectious Diseases and Respiratory Medicine, Charité, Universitätsmedizin Berlin, Berlin, Germany.
Witzenrath M
Charité - Universitätsmedizin Berlin, Department of Infectious Diseases and Respiratory Medicine, Charité, Universitätsmedizin Berlin, Berlin, Germany; German Center for Lung Research (DZL), Germany.
Cochain C
Comprehensive Heart Failure Center Wuerzburg, University Hospital Würzburg, Germany; Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany.
Suttorp N
Charité - Universitätsmedizin Berlin, Department of Infectious Diseases and Respiratory Medicine, Charité, Universitätsmedizin Berlin, Berlin, Germany; German Center for Lung Research (DZL), Germany.
Drosten C
Charité - Universitätsmedizin Berlin, Institute of Virology, Charité Universitätsmedizin Berlin, Berlin, Germany; German Center for Infection Research (DZIF), Braunschweig, Germany.
Goffinet C
Berlin Institute of Health (BIH), Berlin, Germany; Charité - Universitätsmedizin Berlin, Institute of Virology, Charité Universitätsmedizin Berlin, Berlin, Germany.
Kurth F
Charité - Universitätsmedizin Berlin, Department of Infectious Diseases and Respiratory Medicine, Charité, Universitätsmedizin Berlin, Berlin, Germany; Department of Tropical Medicine, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany; I. Department of Medicine, University Medical Center, Hamburg-Eppendorf, Hamburg, Germany.
Schultze JL
Systems Medicine, Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Bonn, Germany; Genomics and Immunoregulation, Life & Medical Sciences (LIMES) Institute, University of Bonn, Germany; PRECISE Platform for Genomics and Epigenomics at Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), and University of Bonn, Bonn, Germany.
Radbruch H
Charité - Universitätsmedizin Berlin, Department of Neuropathology, Berlin, Germany.
Ochs M
Core Facility Electron Microscopy, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany; German Center for Lung Research (DZL), Germany; Institute of Functional Anatomy, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
Eils R
Center for Digital Health, Berlin Institute of Health (BIH) and Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany.
Müller-Redetzky H
Charité - Universitätsmedizin Berlin, Department of Infectious Diseases and Respiratory Medicine, Charité, Universitätsmedizin Berlin, Berlin, Germany.
Hauser AE
Charité - Universitätsmedizin Berlin, Department of Rheumatology and Clinical Immunology, Charité; Deutsches Rheumaforschungszentrum, Immunodynamics, a Leibniz Institute, Berlin, Germany.
Luecken MD
Institute of Computational Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
Theis FJ
Institute of Computational Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany; Department of Mathematics, Technische Universität München, Garching bei München, Germany.
Conrad C
Center for Digital Health, Berlin Institute of Health (BIH) and Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany.
Wolff T
Unit 17 Influenza and other Respiratory Viruses, Robert Koch Institute, Berlin, Germany.
Boor P
Institute of Pathology, RWTH Aachen University Hospital, Aachen, Germany.
Selbach M
Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Proteome Dynamics, Berlin, Germany; Charité-Universitätsmedizin Berlin, Berlin, Germany.
Saliba AE
Helmholtz Institute for RNA-based Infection Research (HIRI), Helmholtz-Center for Infection Research (HZI), Würzburg, Germany. Electronic address: emmanuel.saliba@helmholtz-hiri.de.
Sander LE
Charité - Universitätsmedizin Berlin, Department of Infectious Diseases and Respiratory Medicine, Charité, Universitätsmedizin Berlin, Berlin, Germany; German Center for Lung Research (DZL), Germany. Electronic address: leif-erik.sander@charite.de.

MeSH

Antigens, CDAntigens, Differentiation, MyelomonocyticCOVID-19Cell CommunicationCohort StudiesFibroblastsGene Expression RegulationHumansIdiopathic Pulmonary FibrosisMacrophagesMesenchymal Stem CellsPhenotypeProteomeReceptors, Cell SurfaceRespiratory Distress SyndromeSARS-CoV-2Tomography, X-Ray ComputedTranscription, Genetic

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

34914922

Citation

Wendisch, Daniel, et al. "SARS-CoV-2 Infection Triggers Profibrotic Macrophage Responses and Lung Fibrosis." Cell, vol. 184, no. 26, 2021, pp. 6243-6261.e27.
Wendisch D, Dietrich O, Mari T, et al. SARS-CoV-2 infection triggers profibrotic macrophage responses and lung fibrosis. Cell. 2021;184(26):6243-6261.e27.
Wendisch, D., Dietrich, O., Mari, T., von Stillfried, S., Ibarra, I. L., Mittermaier, M., Mache, C., Chua, R. L., Knoll, R., Timm, S., Brumhard, S., Krammer, T., Zauber, H., Hiller, A. L., Pascual-Reguant, A., Mothes, R., Bülow, R. D., Schulze, J., Leipold, A. M., ... Sander, L. E. (2021). SARS-CoV-2 infection triggers profibrotic macrophage responses and lung fibrosis. Cell, 184(26), 6243-e27. https://doi.org/10.1016/j.cell.2021.11.033
Wendisch D, et al. SARS-CoV-2 Infection Triggers Profibrotic Macrophage Responses and Lung Fibrosis. Cell. 2021 12 22;184(26):6243-6261.e27. PubMed PMID: 34914922.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - SARS-CoV-2 infection triggers profibrotic macrophage responses and lung fibrosis. AU - Wendisch,Daniel, AU - Dietrich,Oliver, AU - Mari,Tommaso, AU - von Stillfried,Saskia, AU - Ibarra,Ignacio L, AU - Mittermaier,Mirja, AU - Mache,Christin, AU - Chua,Robert Lorenz, AU - Knoll,Rainer, AU - Timm,Sara, AU - Brumhard,Sophia, AU - Krammer,Tobias, AU - Zauber,Henrik, AU - Hiller,Anna Luisa, AU - Pascual-Reguant,Anna, AU - Mothes,Ronja, AU - Bülow,Roman David, AU - Schulze,Jessica, AU - Leipold,Alexander M, AU - Djudjaj,Sonja, AU - Erhard,Florian, AU - Geffers,Robert, AU - Pott,Fabian, AU - Kazmierski,Julia, AU - Radke,Josefine, AU - Pergantis,Panagiotis, AU - Baβler,Kevin, AU - Conrad,Claudia, AU - Aschenbrenner,Anna C, AU - Sawitzki,Birgit, AU - Landthaler,Markus, AU - Wyler,Emanuel, AU - Horst,David, AU - ,, AU - Hippenstiel,Stefan, AU - Hocke,Andreas, AU - Heppner,Frank L, AU - Uhrig,Alexander, AU - Garcia,Carmen, AU - Machleidt,Felix, AU - Herold,Susanne, AU - Elezkurtaj,Sefer, AU - Thibeault,Charlotte, AU - Witzenrath,Martin, AU - Cochain,Clément, AU - Suttorp,Norbert, AU - Drosten,Christian, AU - Goffinet,Christine, AU - Kurth,Florian, AU - Schultze,Joachim L, AU - Radbruch,Helena, AU - Ochs,Matthias, AU - Eils,Roland, AU - Müller-Redetzky,Holger, AU - Hauser,Anja E, AU - Luecken,Malte D, AU - Theis,Fabian J, AU - Conrad,Christian, AU - Wolff,Thorsten, AU - Boor,Peter, AU - Selbach,Matthias, AU - Saliba,Antoine-Emmanuel, AU - Sander,Leif Erik, Y1 - 2021/11/27/ PY - 2020/11/30/received PY - 2021/07/28/revised PY - 2021/11/23/accepted PY - 2021/12/17/pubmed PY - 2022/1/6/medline PY - 2021/12/16/entrez KW - ARDS KW - COVID-19 KW - IPF KW - SARS-CoV-2 KW - fibrosis KW - lung KW - macrophages KW - monocytes KW - proteomics KW - pulmonary fibrosis KW - single-cell transcriptomics SP - 6243 EP - 6261.e27 JF - Cell JO - Cell VL - 184 IS - 26 N2 - COVID-19-induced "acute respiratory distress syndrome" (ARDS) is associated with prolonged respiratory failure and high mortality, but the mechanistic basis of lung injury remains incompletely understood. Here, we analyze pulmonary immune responses and lung pathology in two cohorts of patients with COVID-19 ARDS using functional single-cell genomics, immunohistology, and electron microscopy. We describe an accumulation of CD163-expressing monocyte-derived macrophages that acquired a profibrotic transcriptional phenotype during COVID-19 ARDS. Gene set enrichment and computational data integration revealed a significant similarity between COVID-19-associated macrophages and profibrotic macrophage populations identified in idiopathic pulmonary fibrosis. COVID-19 ARDS was associated with clinical, radiographic, histopathological, and ultrastructural hallmarks of pulmonary fibrosis. Exposure of human monocytes to SARS-CoV-2, but not influenza A virus or viral RNA analogs, was sufficient to induce a similar profibrotic phenotype in vitro. In conclusion, we demonstrate that SARS-CoV-2 triggers profibrotic macrophage responses and pronounced fibroproliferative ARDS. SN - 1097-4172 UR - https://www.unboundmedicine.com/medline/citation/34914922/SARS_CoV_2_infection_triggers_profibrotic_macrophage_responses_and_lung_fibrosis_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0092-8674(21)01383-0 DB - PRIME DP - Unbound Medicine ER -