biostudies-literatureIdris FPMO | National Research Foundation Singapore (NRF)MOH | National Medical Research Council (NMRC)2995-3020https://www.ebi.ac.uk/biostudies/studies/S-EPMC12603335biostudies-literatureUnknown17(11)Non-structural protein 1 (NS1) of dengue virus (DENV) harbours two conserved N-glycosylation sites at positions 130 and 207, whose biological roles have remained elusive. Using a clinically relevant mouse model of severe dengue, we showed that DENV that lacked N207 glycans on NS1 was significantly attenuated, and this phenotype was dominant over wild-type virulent DENV. Mice infected with this mutant exhibited accelerated viral clearance, milder lymphopenia and more functional DENV-specific CD8⁺ T cells. Bulk and single-cell RNA sequencing, cytokine measurements and immune-phenotyping revealed blunted innate inflammatory responses early post-infection, which correlated with reduced PD-L1 expression on innate immune cells and reduced PD-1⁺ T-cells in mice infected withEMBO molecular medicineGlycans on non-structural protein 1 prevent premature T-cell mediated dengue virus clearance.PMC12603335MOH-000087NRF-CRP27-2021-0003Copping JMAlonso SAllison JRIdris FTan ETXLi QHOoi JSGWalsh INg LYWan CMarzinek JKBond PJChan KRTorta FLim SYNguyen-Khuong TTing DHRBenke PIfalseGlycans on non-structural protein 1 prevent premature T-cell mediated dengue virus clearance.Non-structural protein 1 (NS1) of dengue virus (DENV) harbours two conserved N-glycosylation sites at positions 130 and 207, whose biological roles have remained elusive. Using a clinically relevant mouse model of severe dengue, we showed that DENV that lacked N207 glycans on NS1 was significantly attenuated, and this phenotype was dominant over wild-type virulent DENV. Mice infected with this mutant exhibited accelerated viral clearance, milder lymphopenia and more functional DENV-specific CD8⁺ T cells. Bulk and single-cell RNA sequencing, cytokine measurements and immune-phenotyping revealed blunted innate inflammatory responses early post-infection, which correlated with reduced PD-L1 expression on innate immune cells and reduced PD-1⁺ T-cells in mice infected with2025-01-01T00:00:00Z2025 Nov2026-06-06T15:45:20.495Z2026-06-02T03:09:20.855ZS-EPMC126033354096294110.1038/s44321-025-00311-6