Decoding serum N-Glycome signatures across COVID-19 symptomatic stages

SARS-CoV-2 infection causes a wide spectrum of clinical manifestations, ranging from asymptomatic cases to fatal outcomes. Although significant progress has been made in understanding SARS-CoV-2, the identification of reliable biomarkers for early risk assessment and disease severity prediction remains an unmet clinical need. In this study, we characterized the serum N-glycome profiles of a cohort comprising COVID-19 patients with mild to severe symptoms and healthy controls. After enzymatic deglycosylation, serum samples were analyzed using HILIC-FLD-QTOF-MS. In case-control comparisons, COVID-19 patients exhibited a significant decrease in oligomannose and hybrid-type glycans, along with an increase in tetra-antennary and tetra-galactosylated structures. In addition, four N-glycan structures were identified as having diagnostic potential to distinguish COVID-19 cases from healthy controls. When comparing severely symptomatic COVID-19 patients to those with mild symptoms and healthy controls, a significant increase was observed in antennary fucosylated N-glycans (SLex). Moreover, ROC analysis demonstrated that an isomer of Hex5HexNAc4Neu5Ac had strong diagnostic potential (AUC > 0.8) in distinguishing severely symptomatic COVID-19 patients from healthy controls. Our study reveals a novel association between antennary fucosylation and an isomer of Hex5HexNAc4Neu5Ac in severe COVID-19, highlighting its potential relevance for biomarker discovery.