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.
Highlights
The pathogenesis of severe COVID-19 reflects an inefficient immune reaction to SARS-CoV2
Circulating plasmablasts are clonally expanded and their antibodies are somatically mutated, but not specific for SARS-CoV-2 S or N protein. These results point to TGF-β as a key cytokine regulating a chronic immune reaction in severe COVID-19, an immune reaction which is no longer directed to SARS-CoV-2
To analyze the adaptive immune response triggered by SARS-CoV-2 in severely affected COVID-19 patients, we initially focused on plasmablasts of the peripheral blood, considering them as biosensors of the ongoing immune reaction and effectors of humoral immunity[5,16]
Summary
The pathogenesis of severe COVID-19 reflects an inefficient immune reaction to SARS-CoV2. Plasmablasts expressing IgM, i.e. not yet class switched, were most frequent in healthy controls and in the COVID-19 patients early at ICU, at frequencies of up to 18% (Fig. 2c). Continued switch instruction by TGF-β is evident from the expression of Iα1 and Iα2 switch transcripts in the plasmablasts of clusters 2 and 3 of patients #3–#8 (Supplementary Fig. 3a, b).
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