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SARS-CoV-2 in severe COVID-19 induces a TGF-β-dominated chronic immune response that does not target itself

Ferreira-Gomes, Marta; Kruglov, Andrey; Durek, Pawel; Heinrich, Frederik; Tizian, Caroline; Heinz, Gitta Anne; Pascual-Reguant, Anna; Du, Weijie; Mothes, Ronja; Fan, Chaofan; Frischbutter, Stefan; Habenicht, Katharina; Budzinski, Lisa; Ninnemann, Justus; Jani, Peter K.; Guerra, Gabriela Maria; Lehmann, Katrin; Matz, Mareen; Ostendorf, Lennard; Heiberger, Lukas; Chang, Hyun-Dong; Bauherr, Sandy; Maurer, Marcus; Schönrich, Günther; Raftery, Martin; Kallinich, Tilmann; Mall, Marcus Alexander; Angermair, Stefan; Treskatsch, Sascha; Dörner, Thomas; Corman, Victor Max; Diefenbach, Andreas; Volk, Hans-Dieter; Elezkurtaj, Sefer; Winkler, Thomas H.; Dong, Jun; Hauser, Anja Erika; Radbruch, Helena; Witkowski, Mario; Melchers, Fritz; Radbruch, Andreas; Mashreghi, Mir-Farzin

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.
Published in: Nature Communications, 10.1038/s41467-021-22210-3, Springer Nature