Gregorova Michaela, Santopaolo Marianna, Garner Lucy C, Hayati Rahma F, Diamond Divya, Ramamurthy Narayan, Tran Vi Thuy, Nguyen Nguyet Minh, Heesom Kate J, Nguyen Vuong Lam, Jones Eben, Nsubuga Mike, Luscombe Curtis, Vo Hoa Thi My, Ho Chanh Quang, Nguyen Chau Thi Xuan, Dong Tam Thi Hoai, Huynh Duyen Thi Le, Cao Tam Thi, Davidson Andrew D, Klenerman Paul, Yacoub Sophie, Rivino Laura
School of Cellular and Molecular Medicine, University of Bristol, Bristol, UK.
Translational Gastroenterology and Liver Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
Nat Commun. 2025 Jul 1;16(1):5569. doi: 10.1038/s41467-025-60941-9.
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.
登革热是一种由蚊子传播的病毒感染，影响着世界一半的人口，目前缺乏相应的治疗方法。对于登革热而言，T细胞和自然杀伤细胞（NK细胞）在保护/免疫发病机制中的作用仍不清楚。我们使用流式细胞术和单细胞RNA测序对124例登革热患者的T细胞和NK细胞进行了纵向表型、功能和转录分析。我们发现，感染早期的T/NK细胞特征可区分出发生重症登革热（SD）的患者和未发生的患者。与健康体重的患者相比，超重/肥胖患者的这些特征更为明显，这表明他们对SD的易感性增加。在SD患者中，与非SD患者相比，CD4/CD8 T细胞和NK细胞显示出共抑制受体表达增加，细胞毒性潜力降低。通过转录组学和蛋白质组学方法，我们发现SD患者中I型干扰素反应降低，提示先天性免疫缺陷可能是NK/T细胞功能障碍的基础。我们认为，功能失调的T细胞和NK细胞特征是登革热发病机制的基础，可能代表登革热免疫调节治疗的新靶点。
