Gregorova, M.; Santopaolo, M.; Garner, L. C.; Diamond, D.; Ramamurthy, N.; Tran, V.; Nguyen Minh, N.; Jones, E.; Nsubuga, M.; Luscombe, C.; Vo Thi My, H.; Quang Chanh, H.; Thi Xuan Chau, N.; Thi Hoai Tam, D.; Huynh Thi Le, D.; Thi Tam, C.; Klenerman, P.; Yacoub, S.; Rivino, L.

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 will progress to severe dengue (SD) from those who do not. In patients with overweight/obesity these signatures are exacerbated 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 capacity compared to non-SD. Furthermore, type-I Interferon signalling is downregulated in SD, suggesting defective virus-sensing mechanisms may underlie NK/T-cell dysfunction. We propose that dysfunctional \"professional killer\" T/NK-cells underpin dengue pathogenesis. Our findings pave the way for the evaluation of immunomodulatory therapies for dengue.