SARS-CoV-2 in severe COVID-19 induces a TGF-β-dominated chronic immune response that does not target itself.
Marta Ferreira-Gomes, Andrey Kruglov, Pawel Durek, Frederik Heinrich, Caroline Tizian, Gitta Anne Heinz, Anna Pascual-Reguant, Weijie Du, Ronja Mothes, Chaofan Fan, Stefan Frischbutter, Katharina Habenicht, Lisa Budzinski, Justus Ninnemann, Peter K Jani, Gabriela Maria Guerra, Katrin Lehmann, Mareen Matz, Lennard Ostendorf, Lukas Heiberger, Hyun-Dong Chang, Sandy Bauherr, Marcus Maurer, Günther Schönrich, Martin Raftery, Tilmann Kallinich, Marcus Alexander Mall, Stefan Angermair, Sascha Treskatsch, Thomas Dörner, Victor Max Corman, Andreas Diefenbach, Hans-Dieter Volk, Sefer Elezkurtaj, Thomas H Winkler, Jun Dong, Anja Erika Hauser, Helena Radbruch, Mario Witkowski, Fritz Melchers, Andreas Radbruch, Mir-Farzin Mashreghi
Author Information
Marta Ferreira-Gomes: Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association, Berlin, Germany. ORCID
Andrey Kruglov: Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association, Berlin, Germany.
Pawel Durek: Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association, Berlin, Germany.
Frederik Heinrich: Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association, Berlin, Germany.
Caroline Tizian: Laboratory of Innate Immunity, Department of Microbiology and Infection Immunology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
Gitta Anne Heinz: Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association, Berlin, Germany. ORCID
Anna Pascual-Reguant: Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association, Berlin, Germany. ORCID
Weijie Du: Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association, Berlin, Germany.
Ronja Mothes: Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association, Berlin, Germany.
Chaofan Fan: Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association, Berlin, Germany.
Stefan Frischbutter: Dermatological Allergology, Department of Dermatology and Allergy, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany. ORCID
Lisa Budzinski: Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association, Berlin, Germany. ORCID
Justus Ninnemann: Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association, Berlin, Germany.
Peter K Jani: Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association, Berlin, Germany.
Gabriela Maria Guerra: Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association, Berlin, Germany.
Katrin Lehmann: Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association, Berlin, Germany.
Mareen Matz: BIH Center for Regenerative Therapies (BCRT), Charité Universitätsmedizin Berlin, Berlin, Germany.
Lennard Ostendorf: Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association, Berlin, Germany. ORCID
Lukas Heiberger: Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association, Berlin, Germany.
Hyun-Dong Chang: Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association, Berlin, Germany. ORCID
Sandy Bauherr: Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association, Berlin, Germany. ORCID
Marcus Maurer: Dermatological Allergology, Department of Dermatology and Allergy, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany. ORCID
Günther Schönrich: Institute of Virology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.
Martin Raftery: Institute of Virology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.
Tilmann Kallinich: Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association, Berlin, Germany.
Marcus Alexander Mall: Berlin Institute of Health (BIH), Berlin, Germany. ORCID
Stefan Angermair: Department of Anesthesiology and Intensive Care Medicine, Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany. ORCID
Sascha Treskatsch: Department of Anesthesiology and Intensive Care Medicine, Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.
Thomas Dörner: Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association, Berlin, Germany.
Victor Max Corman: Institute of Virology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany. ORCID
Andreas Diefenbach: Laboratory of Innate Immunity, Department of Microbiology and Infection Immunology, Charité-Universitätsmedizin Berlin, Berlin, Germany. ORCID
Hans-Dieter Volk: BIH Center for Regenerative Therapies (BCRT), Charité Universitätsmedizin Berlin, Berlin, Germany. ORCID
Sefer Elezkurtaj: Institute of Pathology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.
Thomas H Winkler: Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany. ORCID
Jun Dong: Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association, Berlin, Germany.
Anja Erika Hauser: Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association, Berlin, Germany. ORCID
Helena Radbruch: Department of Neuropathology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany. ORCID
Mario Witkowski: Laboratory of Innate Immunity, Department of Microbiology and Infection Immunology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
Fritz Melchers: Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association, Berlin, Germany.
Andreas Radbruch: Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association, Berlin, Germany. ORCID
Mir-Farzin Mashreghi: Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association, Berlin, Germany. mashreghi@drfz.de. ORCID
The pathogenesis of severe COVID-19 reflects an inefficient immune reaction to SARS-CoV-2. Here we analyze, at the single cell level, plasmablasts egressed into the blood to study the dynamics of adaptive immune response in COVID-19 patients requiring intensive care. Before seroconversion in response to SARS-CoV-2 spike protein, peripheral plasmablasts display a type 1 interferon-induced gene expression signature; however, following seroconversion, plasmablasts lose this signature, express instead gene signatures induced by IL-21 and TGF-β, and produce mostly IgG1 and IgA1. In the sustained immune reaction from COVID-19 patients, plasmablasts shift to the expression of IgA2, thereby reflecting an instruction by TGF-β. Despite their continued presence in the blood, plasmablasts are not found in the lungs of deceased COVID-19 patients, nor does patient IgA2 binds to the dominant antigens of SARS-CoV-2. Our results thus suggest that, in severe COVID-19, SARS-CoV-2 triggers a chronic immune reaction that is instructed by TGF-β, and is distracted from itself.
References
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[PMID: 24477908]
Blood. 2010 Dec 9;116(24):5181-90
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Grants
ERDF 2014-2020, EFRE 1.8/11, Deutsches Rheuma-Forschungszentrum/EC | European Regional Development Fund (Europski Fond za Regionalni Razvoj)
COVID19-014 01KI2043A CoVER-Ab/Bundesministerium für Bildung und Forschung (Federal Ministry of Education and Research)
ERC-2010-AdG.20100317 Grant 268978/EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council)
