α2,6-Sialylation is Upregulated in Severe COVID-19 Implicating the Complement Cascade

Abstract

Better understanding of the mechanisms of COVID-19 severity is desperately needed in current times. Although hyper-inflammation drives severe COVID-19, precise mechanisms triggering this cascade and what role glycosylation might play therein is unknown. Here we report the first high-throughput glycomic analysis of COVID-19 plasma samples and autopsy tissues. We find α2,6-sialylation is upregulated in plasma of patients with severe COVID-19 and in the lung. This glycan motif is enriched on members of the complement cascade, which show higher levels of sialylation in severe COVID-19. In the lung tissue, we observe increased complement deposition, associated with elevated α2,6-sialylation levels, corresponding to elevated markers of poor prognosis (IL-6) and fibrotic response. We also observe upregulation of the α2,6-sialylation enzyme ST6GAL1 in patients who succumbed to COVID-19. Our work identifies a heretofore undescribed relationship between sialylation and complement in severe COVID-19, potentially informing future therapeutic development.

Engineering Glyco‐Enzymes for Substrate Identification and Targeting

“…These findings show that glycoimmune checkpoint mechanisms may contribute to the immune evasion of HIV‐infected cells and offers glyco‐immunotherapy as a potential therapeutic approach. Additionally, the development of these agents lays the groundwork for using antibody‐sialidase conjugates as therapeutic agents in other disease states that exhibit hypersialylation, such as COVID‐19 [4d] …”