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 and Laura Rivino ()
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Michaela Gregorova: University of Bristol
Marianna Santopaolo: University of Bristol
Lucy C. Garner: University of Oxford
Rahma F. Hayati: University of Bristol
Divya Diamond: University of Bristol
Narayan Ramamurthy: University of Oxford
Vi Thuy Tran: Oxford University Clinical Research Unit
Nguyet Minh Nguyen: Oxford University Clinical Research Unit
Kate J. Heesom: University of Bristol
Vuong Lam Nguyen: Oxford University Clinical Research Unit
Eben Jones: University of Bristol
Mike Nsubuga: University of Bristol
Curtis Luscombe: University of Bristol
Hoa Thi My Vo: Oxford University Clinical Research Unit
Chanh Quang Ho: Oxford University Clinical Research Unit
Chau Thi Xuan Nguyen: Oxford University Clinical Research Unit
Tam Thi Hoai Dong: Oxford University Clinical Research Unit
Duyen Thi Le Huynh: Oxford University Clinical Research Unit
Tam Thi Cao: Hospital for Tropical Diseases
Andrew D. Davidson: University of Bristol
Paul Klenerman: University of Oxford
Sophie Yacoub: Oxford University Clinical Research Unit
Laura Rivino: University of Bristol

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-60941-9

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