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

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.

doi:10.1101/2024.09.06.611687

bioRxiv · 10.1101/2024.09.06.611687

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

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.

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Abstract

Dengue is a mosquito-borne virus infection affecting half of the worlds 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.

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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.. 2024-09-11. Early NK-cell and T-cell dysfunction marks progression to severe dengue in patients with obesity and healthy weight. https://doi.org/10.1101/2024.09.06.611687

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