Abstract

Schistosomiasis is a major global health burden, with praziquantel as the sole treatment. Its inability to prevent reinfection highlights the need for new interventions such as vaccines. Protein glycosylation is essential for parasite biology and immune evasion, yet remains poorly characterized in schistosomes. Here, we conduct N- and O-glycoproteomic and intact glycopeptides analyses of adult male and female Schistosoma mansoni , integrating single-cell transcriptomics. We uncover tissue-specific and sex-biased glycosylation patterns, with greater glycan complexity in the parenchyma and gut and reduced diversity in muscles and neurons. Female- and male-biased glycoproteins are linked to key sex-specific functions. We establish a glycan database for S. mansoni and identify unclassified glycans and HexA modifications. Disruption of glycosylation via RNAi targeting four glycosyltransferases significantly impairs parasite viability. We further show that several vaccine candidates are glycoproteins and characterize their glycosylation. This work provides a foundational glycoproteomic resource supporting the development of glycan and glycoprotein-based strategies for schistosomiasis control.