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<p>Dengue is a mosquito-borne virus infection affecting half of the world’s population for which therapies are lacking. The role of T and NK-cells in protection/immunopathogenesis remains unclear for dengue. We performed a longitudinal phenotypic, functional and transcriptional analyses of T and NK-cells in 124 dengue patients using flow cytometry and single-cell RNA-sequencing. We show that T/NK-cell signatures early in infection discriminate patients who develop severe dengue (SD) from those who do not. These signatures are exacerbated in patients with overweight/obesity compared to healthy weight patients, supporting their increased susceptibility to SD. In SD, CD4<sup>+</sup>/CD8<sup>+</sup> T-cells and NK-cells display increased co-inhibitory receptor expression and decreased cytotoxic potential compared to non-SD. Using transcriptional and proteomics approaches we show decreased type-I Interferon responses in SD, suggesting defective innate immunity may underlie NK/T-cell dysfunction. We propose that dysfunctional T and NK-cell signatures underpin dengue pathogenesis and may represent novel targets for immunomodulatory therapy in dengue.</p>

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Early NK-cell and T-cell dysfunction marks progression to severe dengue in patients with obesity and healthy weight

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月1日

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  • Michaela Gregorova,
  • Marianna Santopaolo,
  • Lucy C. Garner,
  • Rahma F. Hayati,
  • Divya Diamond,
  • Narayan Ramamurthy,
  • Vi Thuy Tran,
  • Nguyet Minh Nguyen,
  • Kate J. Heesom,
  • Vuong Lam Nguyen,
  • Eben Jones,
  • Mike Nsubuga,
  • Curtis Luscombe,
  • Hoa Thi My Vo,
  • Chanh Quang Ho,
  • Chau Thi Xuan Nguyen,
  • Tam Thi Hoai Dong,
  • Duyen Thi Le Huynh,
  • Tam Thi Cao,
  • Andrew D. Davidson,
  • Paul Klenerman,
  • Sophie Yacoub,
  • Laura Rivino

摘要

Dengue is a mosquito-borne virus infection affecting half of the world’s population for which therapies are lacking. The role of T and NK-cells in protection/immunopathogenesis remains unclear for dengue. We performed a longitudinal phenotypic, functional and transcriptional analyses of T and NK-cells in 124 dengue patients using flow cytometry and single-cell RNA-sequencing. We show that T/NK-cell signatures early in infection discriminate patients who develop severe dengue (SD) from those who do not. These signatures are exacerbated in patients with overweight/obesity compared to healthy weight patients, supporting their increased susceptibility to SD. In SD, CD4+/CD8+ T-cells and NK-cells display increased co-inhibitory receptor expression and decreased cytotoxic potential compared to non-SD. Using transcriptional and proteomics approaches we show decreased type-I Interferon responses in SD, suggesting defective innate immunity may underlie NK/T-cell dysfunction. We propose that dysfunctional T and NK-cell signatures underpin dengue pathogenesis and may represent novel targets for immunomodulatory therapy in dengue.