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’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 a...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-07-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-60941-9 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Michaela Gregorova |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-1510535edf5f45f3a18c8fc9883d39e8 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-1510535edf5f45f3a18c8fc9883d39e82025-08-20T03:45:34ZengNature PortfolioNature Communications2041-17232025-07-0116111710.1038/s41467-025-60941-9Early NK-cell and T-cell dysfunction marks progression to severe dengue in patients with obesity and healthy weightMichaela Gregorova0Marianna Santopaolo1Lucy C. Garner2Rahma F. Hayati3Divya Diamond4Narayan Ramamurthy5Vi Thuy Tran6Nguyet Minh Nguyen7Kate J. Heesom8Vuong Lam Nguyen9Eben Jones10Mike Nsubuga11Curtis Luscombe12Hoa Thi My Vo13Chanh Quang Ho14Chau Thi Xuan Nguyen15Tam Thi Hoai Dong16Duyen Thi Le Huynh17Tam Thi Cao18Andrew D. Davidson19Paul Klenerman20Sophie Yacoub21Laura Rivino22School of Cellular and Molecular Medicine, University of BristolSchool of Cellular and Molecular Medicine, University of BristolTranslational Gastroenterology and Liver Unit, Nuffield Department of Medicine, University of OxfordSchool of Cellular and Molecular Medicine, University of BristolSchool of Cellular and Molecular Medicine, University of BristolTranslational Gastroenterology and Liver Unit, Nuffield Department of Medicine, University of OxfordOxford University Clinical Research UnitOxford University Clinical Research UnitBristol Proteomics Facility, School of Biochemistry, University of BristolOxford University Clinical Research UnitSchool of Cellular and Molecular Medicine, University of BristolJean Golding Institute, University of BristolSchool of Cellular and Molecular Medicine, University of BristolOxford University Clinical Research UnitOxford University Clinical Research UnitOxford University Clinical Research UnitOxford University Clinical Research UnitOxford University Clinical Research UnitHospital for Tropical DiseasesSchool of Cellular and Molecular Medicine, University of BristolTranslational Gastroenterology and Liver Unit, Nuffield Department of Medicine, University of OxfordOxford University Clinical Research UnitSchool of Cellular and Molecular Medicine, University of BristolAbstract 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.https://doi.org/10.1038/s41467-025-60941-9 |
| spellingShingle | 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 Early NK-cell and T-cell dysfunction marks progression to severe dengue in patients with obesity and healthy weight Nature Communications |
| title | Early NK-cell and T-cell dysfunction marks progression to severe dengue in patients with obesity and healthy weight |
| title_full | Early NK-cell and T-cell dysfunction marks progression to severe dengue in patients with obesity and healthy weight |
| title_fullStr | Early NK-cell and T-cell dysfunction marks progression to severe dengue in patients with obesity and healthy weight |
| title_full_unstemmed | Early NK-cell and T-cell dysfunction marks progression to severe dengue in patients with obesity and healthy weight |
| title_short | Early NK-cell and T-cell dysfunction marks progression to severe dengue in patients with obesity and healthy weight |
| title_sort | early nk cell and t cell dysfunction marks progression to severe dengue in patients with obesity and healthy weight |
| url | https://doi.org/10.1038/s41467-025-60941-9 |
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