SARS-CoV-2 infection triggers profibrotic macrophage responses and lung fibrosis
Open accessAbstract
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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SARS-CoV-2 triggers a profibrotic response in CD14+CD163+ macrophages that promotes pulmonary fibrosis and acute respiratory distress syndrome.
“SARS-CoV-2 triggers a profibrotic response in CD14+CD163+ macrophages, which promotes manifest pulmonary fibrosis and acute respiratory distress syndrome (Box 1)”
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- Authors
- 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., Djudjaj, S., Erhard, F., Geffers, R., Pott, F., Kazmierski, J., Radke, J., Pergantis, P., Baßler, K., Conrad, C., Aschenbrenner, A. C., Sawitzki, B., Landthaler, M., Wyler, E., Horst, D., Hippenstiel, S., Hocke, A., Heppner, F. L., Uhrig, A., Garcia, C., Machleidt, F., Herold, S., Elezkurtaj, S., Thibeault, C., Witzenrath, M., Cochain, C., Suttorp, N., Drosten, C., Goffinet, C., Kurth, F., Schultze, J. L., Radbruch, H., Ochs, M., Eils, R., Müller-Redetzky, H., Hauser, A. E., Luecken, M. D., Theis, F. J., Conrad, C., Wolff, T., Boor, P., Selbach, M., Saliba, A.-E., & Sander, L. E.
- Affiliations
- Charité – Universitätsmedizin Berlin (DE)
- Helmholtz Institute for RNA-based Infection Research (DE)
- Max Delbrück Center (DE)
- Helmholtz Munich (DE)
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin (DE)
- Robert Koch Institute (DE)
- Humboldt-Universität zu Berlin (DE)
- University of Bonn (DE)
- German Rheumatism Research Centre (DE)
- Universitätsklinikum Aachen (DE)
- University of Würzburg (DE)
- Helmholtz Centre for Infection Research (DE)
- German Center for Lung Research (DE)
- German Center for Neurodegenerative Diseases (DE)
- Universitätsklinikum Gießen und Marburg (DE)
- Universitätsklinikum Würzburg (DE)
- German Center for Infection Research (DE)
- University Medical Center Hamburg-Eppendorf (DE)
- Corresponding author
- Saliba, Antoine-Emmanuel
- Sander, Leif Erik
- ORCID
- Wendisch, Daniel
- Dietrich, Oliver
- Mari, Tommaso
- von Stillfried, Saskia
- Ibarra, Ignacio L.
- Mittermaier, Mirja
- Chua, Robert Lorenz
- Knoll, Rainer
- Timm, Sara
- Brumhard, Sophia
- Krammer, Tobias
- Zauber, Henrik
- Hiller, Anna Luisa
- Pascual-Reguant, Anna
- Mothes, Ronja
- Bülow, Roman David
- Schulze, Jessica
- Leipold, Alexander M.
- Djudjaj, Sonja
- Erhard, Florian
- Geffers, Robert
- Pott, Fabian
- Kazmierski, Julia
- Radke, Josefine
- Pergantis, Panagiotis
- Baßler, Kevin
- Aschenbrenner, Anna C.
- Sawitzki, Birgit
- Landthaler, Markus
- Wyler, Emanuel
- Horst, David
- Hippenstiel, Stefan
- Hocke, Andreas
- Heppner, Frank L.
- Uhrig, Alexander
- Machleidt, Felix
- Herold, Susanne
- Elezkurtaj, Sefer
- Thibeault, Charlotte
- Witzenrath, Martin
- Cochain, Clément
- Suttorp, Norbert
- Drosten, Christian
- Goffinet, Christine
- Kurth, Florian
- Schultze, Joachim L.
- Radbruch, Helena
- Ochs, Matthias
- Eils, Roland
- Müller-Redetzky, Holger
- Hauser, Anja E.
- Luecken, Malte D.
- Theis, Fabian J.
- Conrad, Christian
- Wolff, Thorsten
- Boor, Peter
- Selbach, Matthias
- Saliba, Antoine-Emmanuel
- Sander, Leif Erik
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2021-12
- Volume
- 184
- Issue
- 26
- Pages
- 6243-6261.e27
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC8626230
- OpenAlex
- W3216618416
- Cited by
- 528
- References
- 149
- Citations by year
- 2026: 52 · 2025: 109 · 2024: 122 · 2023: 146 · 2022: 97 · 2021: 1
- FWCI
- 29.77
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 386 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (submittedVersion)
- Site cant be reached (submittedVersion, other-oa)
- DZNE Pub (submittedVersion)
- RWTH Publications (RWTH Aachen) (submittedVersion, other-oa)
- HZI (Helmholtz Centre for Infection Research) (submittedVersion, cc-by-nc-nd)
- RWTH Publications (RWTH Aachen)
- Topics
- Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Keywords
- SARS-CoV-2, COVID-19 pandemic, acute respiratory distress syndrome, pulmonary fibrosis, idiopathic pulmonary fibrosis, monocyte-to-macrophage differentiation, lung ultrastructure
- MeSH terms
- COVID-19, SARS-CoV-2, CD163 Antigen, Cell Communication, Fibroblasts, Gene Expression Regulation, Humans, Macrophages, Phenotype, Receptors, Cell Surface, Respiratory Distress Syndrome, Tomography, X-Ray Computed, Transcription, Genetic, Antigens, Differentiation, Myelomonocytic, Cohort Studies, Antigens, CD, Proteome, Idiopathic Pulmonary Fibrosis, Mesenchymal Stem Cells
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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