Phenotypical and Functional Characterization of Unswitched Memory B cells verses Switched during SARS-CoV-2 Infection

Abstract

Abstract Memory B cells are comprised of unswitched (CD27+IgD+) and switched (CD27+IgD-) subsets. The origin and function of unswitched human memory B cells remains controversial, whereas switched memory B cells are primed to respond to recurrent infection. Unswitched memory B cells were described to be reduced in frequency with severe SARS-CoV2 infection and here we report on their activation status, BCR functionality, and contribution to virally-induced cytokine production. Analyses of whole blood from healthy individuals, people immunized against SARS-CoV2, and those with mild or severe SARS-CoV2 infection, confirm a loss of unswitched memory B cells during severe SARS-CoV2 infection and demonstrate this loss is associated with increased levels of systemic TNFα. We further report an increased frequency of ‘IgD+’ only memory B cells that correlate with an increase in IgG autoantibody levels (anti-chromatin, anti-cardiolipin, anti-smith) in severe SARS-CoV2 infection. Unswitched and switched memory B cells from severe SARS-CoV2 infection displayed evidence of heightened activation with concomitant reduction in expression of the inhibitory receptor CD72. Functionally, both populations of memory B cells from severe SARS-COV2 infection harbored a signaling competent BCR that displayed enhanced activity in the unswitched population. Finally, we demonstrate that B cells from mild SARS-CoV2 infection secrete pro-inflammatory cytokines IL-6 and TNFα. Importantly, unswitched memory B cells were a major producer of IL-6 and switched memory B cells were a major producer of TNFα in response to viral TLR ligands. Together these data suggest that B cells contribute to the inflammatory milieu during viral infection. Supported by grants from NIH R01 AI124474 (RP) and R01 AI136534 (RMT).