IgM N-glycosylation correlates with COVID-19 severity and rate of complement deposition

Abstract The glycosylation of IgG plays a critical role during human SARS-CoV-2, activating immune cells and inducing cytokine production. However, the role of IgM N-glycosylation has not been studied during acute viral infection in humans. In vitro evidence suggests that the glycosylation of IgM inhibits T cell proliferation and alters complement activation rates. The analysis of IgM N-glycosylation from healthy controls and hospitalized COVID-19 patients reveals that mannosylation and sialyation levels associate with COVID-19 severity. Specifically, we find increased di- and tri-sialylated glycans and altered mannose glycans in total serum IgM in severe COVID-19 patients when compared to moderate COVID-19 patients. This is in direct contrast with the decrease of sialic acid found on the serum IgG from the same cohorts. Moreover, the degree of mannosylation and sialylation correlated significantly with markers of disease severity: D-dimer, BUN, creatinine, potassium, and early anti-COVID-19 amounts of IgG, IgA, and IgM. Further, IL-16 and IL-18 cytokines showed similar trends with the amount of mannose and sialic acid present on IgM, implicating these cytokines' potential to impact glycosyltransferase expression during IgM production. When examining PBMC mRNA transcripts, we observe a decrease in the expression of Golgi mannosidases that correlates with the overall reduction in mannose processing we detect in the IgM N-glycosylation profile. Importantly, we found that IgM contains alpha-2,3 linked sialic acids in addition to the previously reported alpha-2,6 linkage. We also report that antigen-specific IgM antibody-dependent complement deposition is elevated in severe COVID-19 patients. Taken together, this work links the immunoglobulin M N-glycosylation with COVID-19 severity and highlights the need to understand the connection between IgM glycosylation and downstream immune function during human disease.