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

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

doi: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

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

^*Corresponding author for this work

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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.

Original language	English
Article number	5569
Number of pages	17
Journal	Nature Communications
Volume	16
Issue number	1
DOIs	https://doi.org/10.1101/2024.09.06.611687 https://doi.org/10.1038/s41467-025-60941-9
Publication status	Published - 1 Jul 2025

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© The Author(s) 2025.

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Gregorova, M., Santopaolo, M., Garner, L., Hayati, R. F., Diamond, D., Ramamurthy, N., Thuy Vi, T., Heesom, K. J., Lam Vuong, N., Jones, E., Nsubuga, M., Luscombe, C. T., Vo Thi My, H., Quang Chanh, H., Thi Xuan Chau, N., Thi Hoai Tam, D., Le Huynh, D. T., Thi Tam, C., Davidson, A. D., ... Rivino, L. (2025). Early NK-cell and T-cell dysfunction marks progression to severe dengue in patients with obesity and healthy weight. Nature Communications, 16(1), Article 5569. https://doi.org/10.1101/2024.09.06.611687, https://doi.org/10.1038/s41467-025-60941-9

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

abstract = "Dengue is a mosquito-borne virus infection affecting half of the world{\textquoteright}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.",

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

note = "Publisher Copyright: {\textcopyright} The Author(s) 2025.",

year = "2025",

month = jul,

day = "1",

doi = "10.1101/2024.09.06.611687",

language = "English",

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Gregorova, M, Santopaolo, M, Garner, L, Hayati, RF, Diamond, D, Ramamurthy, N, Thuy Vi, T, Heesom, KJ, Lam Vuong, N, Jones, E, Nsubuga, M, Luscombe, CT, Vo Thi My, H, Quang Chanh, H, Thi Xuan Chau, N, Thi Hoai Tam, D, Le Huynh, DT, Thi Tam, C, Davidson, AD, Klenerman, P, Yacoub, S & Rivino, L 2025, 'Early NK-cell and T-cell dysfunction marks progression to severe dengue in patients with obesity and healthy weight', Nature Communications, vol. 16, no. 1, 5569. https://doi.org/10.1101/2024.09.06.611687, https://doi.org/10.1038/s41467-025-60941-9

TY - JOUR

T1 - Early NK-cell and T-cell dysfunction marks progression to severe dengue in patients with obesity and healthy weight

AU - Gregorova, Michaela

AU - Santopaolo, Marianna

AU - Garner, Lucy

AU - Hayati, Rahma F

AU - Diamond, Divya

AU - Ramamurthy, Narayan

AU - Thuy Vi, Tran

AU - Heesom, Kate J

AU - Lam Vuong, Nguyem

AU - Jones, Eben

AU - Nsubuga, Mike

AU - Luscombe, Curtis T

AU - Vo Thi My, Hoa

AU - Quang Chanh, Ho

AU - Thi Xuan Chau, Nguyen

AU - Thi Hoai Tam, Dong

AU - Le Huynh, Duyen Thi

AU - Thi Tam, Cao

AU - Davidson, Andrew D

AU - Klenerman, Paul

AU - Yacoub, Sophie

AU - Rivino, Laura

PY - 2025/7/1

Y1 - 2025/7/1

N2 - 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.

AB - 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.

U2 - 10.1101/2024.09.06.611687

DO - 10.1101/2024.09.06.611687

M3 - Article (Academic Journal)

C2 - 40595657

SN - 2041-1723

VL - 16

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 5569

ER -

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

Abstract

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