Glycans 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<sup>+</sup> 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<sup>+</sup> T-cells in mice infected with de-glycosylated DENV. PD-1 blockade demonstrated the involvement of premature T-cell apoptosis through the PD-L1/PD-1 axis in DENV pathogenesis. Collectively, our findings support that N207-de-glycosylated NS1 inhibits early inflammatory responses, which restricts PD-L1 upregulation on innate immune cells, which in turn limits PD-L1/PD-1 mediated T-cell apoptosis. Our study uncovers a novel immune evasion strategy and identifies PD-L1/PD-1 as a novel mechanism of dengue immunopathogenesis.

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Publication Details

Journal
EMBO Molecular Medicine
Published
2025-09-17
DOI
https://doi.org/10.1038/s44321-025-00311-6
Citations
1
Primary Topic
Mosquito-borne diseases and control
Type
article
Field-Weighted Citation Impact
1.88
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article

Glycans on non-structural protein 1 prevent premature T-cell mediated dengue virus clearance

Peter John Bond, Kuan Rong Chan, Peter I. Benke, Jane R. Allison et al.
1 citations
EMBO Molecular Medicine
Mosquito-borne diseases and control
1.88
article

Glycans on non-structural protein 1 prevent premature T-cell mediated dengue virus clearance

Peter John Bond, Kuan Rong Chan, Peter I. Benke, Jane R. Allison, Sylvie Alonso, Justin S. G. Ooi, Qin Hui Li, Corrine Wan, Ian Walsh, Terry Nguyen‐Khuong, Jan K. Marzinek, Federico Torta, Heng Rong Donald Ting, Lu Yi Ng, Eunice Tze Xin Tan, Fakhriedzwan Idris, Jack M. Copping, Sheau Yng Lim
article en
1 citations

Abstract

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<sup>+</sup> 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<sup>+</sup> T-cells in mice infected with de-glycosylated DENV. PD-1 blockade demonstrated the involvement of premature T-cell apoptosis through the PD-L1/PD-1 axis in DENV pathogenesis. Collectively, our findings support that N207-de-glycosylated NS1 inhibits early inflammatory responses, which restricts PD-L1 upregulation on innate immune cells, which in turn limits PD-L1/PD-1 mediated T-cell apoptosis. Our study uncovers a novel immune evasion strategy and identifies PD-L1/PD-1 as a novel mechanism of dengue immunopathogenesis.

EMBO Molecular MedicineVol. 17(11)
Agency for Science, Technology and Research (SG), University of Auckland (NZ), National University of Singapore (SG), Duke-NUS Medical School (SG), Maurice Wilkins Centre (NZ), Bioprocessing Technology Institute (SG), Bioinformatics Institute (SG), National Centre for Infectious Diseases (SG), Signature Research (United States) (US)
Openalex Percentile: Top 12%
Mosquito-borne diseases and control
1.88
DOIOpen Access PDFOpenAlex
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