Dataset Information

Glycans on Non-Structural Protein 1 Prevent Premature T-cell Mediated Dengue Virus Clearance

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 wildtype 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 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-deglycosylated 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.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Corrine Wan

LAB HEAD: Ian Walah

PROVIDER: PXD065422 | Pride | 2025-11-17

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	NS1_T209L_HEK_SM_mz500_2000_145min.msf	Msf
	NS1_T209L_HEK_SM_mz500_2000_145min.raw	Raw
	NS1_WT_HEK_SM_mz500_2000_145min.msf	Msf
	NS1_WT_HEK_SM_mz500_2000_145min.raw	Raw

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

Idris Fakhriedzwan F Ooi Justin Seng Geap JSG Ting Donald Heng Rong DHR Tan Eunice Tze Xin ETX Wan Corrine C Benke Peter I PI Marzinek Jan K JK Copping Jack M JM Li Qin Hui QH Ng Lu Yi LY Lim Sheau Yng SY Walsh Ian I Allison Jane R JR Bond Peter J PJ Torta Federico F Nguyen-Khuong Terry T Chan Kuan Rong KR Alonso Sylvie S

EMBO molecular medicine 20250917 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< ...[more]

PMID: 40962941

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Project description:Dengue virus (DENV) infects hundreds of millions of people annually, yet there is only a limited knowledge of the host immune response to dengue. Here, we used a systems biological approach to perform a detailed analysis of the innate immune response to DENV infection in the whole blood samples of acutely infected humans in Bangkok, Thailand. Transcriptomic analysis revealed that genes encoding pro-inflammatory mediators and type I IFN related proteins, were associated with high levels of virus during the first few days of infection. Individuals with low or negative viremia at the late stage of fever were enriched with genes associated with pathways involved in cell cycle, proliferation, cell metabolism and translational control. Meta-analysis showed significant enrichment in genes specific for innate cells (monocytes, macrophages and DCs) in the specimens with high VL and enrichment in genes specific for NK cells, CD4+ and CD8+ T cells as well as B cells in specimens with low VL. Furthermore, flow cytometric analysis revealed an expansion in the numbers of CD14+CD16+ monocytes and depletion of CD14dimCD16++ cells and BDCA-1+ myeloid DC in blood. Consistent with this, in a non-human primate model, infection with DENV boosted the numbers of CD14+CD16+ monocytes in the blood and in secondary lymphoid organs. In vitro, freshly isolated blood monocytes infected with DENV up regulated CD16 and mediated robust differentiation of resting B cells to CD27++CD38++ plasmablasts and IgG and IgM secretion. Taken together, these data provide a detailed picture of the innate response to dengue infection in humans, and highlight an unappreciated role for CD14+CD16+ monocytes in promoting the differentiation of plasmablasts and mediating antibody response to DENV. We analyzed whole blood samples from 28 dengue patients (DF n=18, DHF=10) hospitalized at the Siriraj Hospital in Bangkok, Thailand during the season of 2009 The specimens were acquired between days 2 and 9 after onset of symptoms (acute illness), and for 19 patients (DF n=13, DHF=6) also at the convalescence at 4 weeks or later after discharge. Additionally, blood was sampled from 9 healthy, non-infected donors to provide controls for transcriptomic and immunological analysis.