In severe COVID-19, SARS-CoV-2 induces a chronic, TGF-β-dominated adaptive immune response

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; Lehmann, Katrin; Matz, Mareen; Ostendorf, Lennard; Heiberger, Lukas; Chang, Hyun-Dong; Bauherr, Sandy; Maurer, Marcus; Schoenrich, Guenther; Raftery, Martin; Kallinich, Tilmann; Mall, Marcus Alexander; Angermair, Stefan; Treskatsch, Sascha; Doerner, Thomas; Corman, Victor M; 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

Here we have analyzed the dynamics of the adaptive immune response triggered by SARS-CoV-2 in severely affected COVID-19 patients, as reflected by activated B cells egressing into the blood, at the single cell level. Early on, before seroconversion in response to SARS-CoV-2 spike protein, activated peripheral B cells displayed a type 1 interferon-induced gene expression signature. After seroconversion, activated B cells lost this signature, expressed IL-21- and TGF-{beta}-induced gene expression signatures, and mostly IgG1 and IgA1. In the sustained immune reaction of the COVID-19 patients, until day 59, activated peripheral B cells shifted to expression of IgA2, reflecting instruction by TGF-{beta}. Despite the continued generation of activated B cells, those cells were not found in the lungs of deceased COVID-19 patients, nor did the IgA2 bind to dominant antigens of SARS-CoV-2. In severe COVID-19, SARS-CoV-2 thus triggers a chronic immune reaction distracted from itself and instructed by TGF-{beta}.