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 and Mir-Farzin Mashreghi ()
Additional contact information
Marta Ferreira-Gomes: Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association
Andrey Kruglov: Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association
Pawel Durek: Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association
Frederik Heinrich: Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association
Caroline Tizian: Charité-Universitätsmedizin Berlin
Gitta Anne Heinz: Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association
Anna Pascual-Reguant: Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association
Weijie Du: Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association
Ronja Mothes: Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association
Chaofan Fan: Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association
Stefan Frischbutter: Humboldt-Universität zu Berlin, and Berlin Institute of Health
Katharina Habenicht: Friedrich-Alexander-University Erlangen-Nuremberg
Lisa Budzinski: Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association
Justus Ninnemann: Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association
Peter K. Jani: Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association
Gabriela Maria Guerra: Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association
Katrin Lehmann: Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association
Mareen Matz: Charité Universitätsmedizin Berlin
Lennard Ostendorf: Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association
Lukas Heiberger: Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association
Hyun-Dong Chang: Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association
Sandy Bauherr: Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association
Marcus Maurer: Humboldt-Universität zu Berlin, and Berlin Institute of Health
Günther Schönrich: Humboldt-Universität zu Berlin, and Berlin Institute of Health
Martin Raftery: Humboldt-Universität zu Berlin, and Berlin Institute of Health
Tilmann Kallinich: Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association
Marcus Alexander Mall: Berlin Institute of Health (BIH)
Stefan Angermair: Humboldt-Universität zu Berlin, and Berlin Institute of Health
Sascha Treskatsch: Humboldt-Universität zu Berlin, and Berlin Institute of Health
Thomas Dörner: Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association
Victor Max Corman: Humboldt-Universität zu Berlin, and Berlin Institute of Health
Andreas Diefenbach: Charité-Universitätsmedizin Berlin
Hans-Dieter Volk: Charité Universitätsmedizin Berlin
Sefer Elezkurtaj: Humboldt-Universität zu Berlin, and Berlin Institute of Health
Thomas H. Winkler: Friedrich-Alexander-University Erlangen-Nuremberg
Jun Dong: Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association
Anja Erika Hauser: Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association
Helena Radbruch: Humboldt-Universität zu Berlin, and Berlin Institute of Health
Mario Witkowski: Charité-Universitätsmedizin Berlin
Fritz Melchers: Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association
Andreas Radbruch: Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association
Mir-Farzin Mashreghi: Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-22210-3

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