Early NK-cell and T-cell dysfunction marks progression to severe dengue in patients with obesity and healthy weight
Gregorova M., Santopaolo M., Garner LC., Hayati RF., Diamond D., Ramamurthy N., Tran VT., Nguyen NM., Heesom KJ., Nguyen VL., Jones E., Nsubuga M., Luscombe C., Vo HTM., Ho CQ., Nguyen CTX., Dong TTH., Huynh DTL., Cao TT., Davidson AD., Klenerman P., Yacoub S., Rivino L.
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.