Early NK-cell and T-cell dysfunction marks progression to severe dengue in patients with obesity and healthy weight
- 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
2025-07-01
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.