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

ABSTRACT

The human immune response to SARS-CoV-2 infection is highly variable, with less than 10% of infections resulting in severe COVID-19 requiring intensive care unit (ICU) treatment. Here we have analyzed the dynamics of the adaptive immune response in COVID-19 ICU patients at the level of single cell transcriptomes and B cell and T cell receptor (BCR, TCR) repertoires. Early after ICU admission, before seroconversion in response to SARS-CoV-2 spike protein, patients generate activated peripheral B cells with a type 1 interferon-induced gene expression signature. After seroconversion, patients display circulating activated B cells expressing an IL-21-induced gene expression signature and mainly IgG1 and IgA1, two isotypes induced by IL-21 and TGF-{beta}, respectively. In sustained COVID-19, the persistent immune reaction is shifted to IgA2-expressing activated peripheral B cells, displaying somatic hypermutation, and expressing TGF-{beta}-induced signature genes, like IgA germline transcripts. The switch from an IgG1 to an IgA2-dominated B cell response correlates with the appearance of SARS-CoV-2 reactive follicular T helper cells expressing IL-21 and/or TGF-{beta} in the blood. Despite the continued presence of IgA2-expressing B cells and IgA antibodies in the blood of progressed COVID-19 patients, IgA2 secreting cells were scarce in the lungs of deceased COVID-19 patients. In summary, in severely affected COVID-19 patients SARS-CoV-2 triggers chronic immune reactions which are controlled by TGF-{beta}, with most of the activated B cells being no longer specific for the SARS-CoV-2 spike protein and its receptor binding domain, nor for nucleoprotein. TGF-{beta} may candidate as a target to ameliorate detrimental immunopathology in those patients.