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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 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 will progressdevelop to severe dengue (SD) from those who do not. These signatures are exacerbated in In patients with overweight/obesity these signatures are exacerbated 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 capacity potential compared to non-SD. Using transcriptional and proteomics approaches we demonstrate decreased Furthermore, type-I Interferon signalling is downregulatedresponses in SD, suggesting defective innate immunity virus-sensing mechanisms may underlie NK/T-cell dysfunction.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Peripheral Blood Mononuclear Cell, Blood

DISEASE(S): Dengue Hemorrhagic Fever,Susceptibility To Dengue Virus,Dengue Disease,Dengue Shock Syndrome

SUBMITTER: Andrew Davidson

LAB HEAD: Laura Rivino

PROVIDER: PXD061694 | Pride | 2025-05-21

REPOSITORIES: Pride

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Project description:Background: We report the detailed development of biomarkers to predict the clinical outcome under dengue infection. Transcriptional signatures from purified peripheral blood mononuclear cells were derived from whole-genome gene-expression microarray data and validated by quantitative PCR and tested in independent samples. Methodology/Principal Findings: The study was performed on patients of a well-characterized dengue cohort from Recife, Brazil. The samples analyzed were collected prospectively from acute febrile dengue patients who evolved with different degrees of disease severity, classic dengue fever or dengue hemorrhagic fever (DHF) and compared with similar samples from other non-dengue febrile illnesses. The DHF samples were collected 2-3 days before the presentation of the plasma leakage symptoms. Differentially-expressed genes were selected by univariate statistical tests as well as multivariate classification techniques. The results showed that at early stages of dengue infection, the genes involved in effector mechanisms of innate immune response presented a weaker activation on patients who later developed hemorrhagic fever, whereas the genes involved in apoptosis were expressed in higher levels. Conclusions/Significance: Some of the gene expression signatures displayed estimated accuracy rates of more than 95%, indicating that expression profiling with these signatures may provide a useful means of DHF prognosis at early stages of infection The samples correspond to blood samples from 26 patients from a cohort in Brazil, divided into three classes, DHF, DF, ND, as follows: 18 were confirmed dengue 3, genotype III cases, among which 10 were diagnosed as dengue hemorrhagic fever (DHF) and 8 as classical dengue fever (DF), and 8 control samples (ND) from febrile patients confirmed to be not infected with dengue. None of the DHF patients presented vasculopathy signs and symptoms at the time the samples used in the functional genomic characterization were collected. At the time of collection the patients referred approximately 5 days of disease and the absence of fever was reported two to three days after enrollment. The samples from the DF, DHF and ND patients were matched to avoid significant differences regarding patient age, gender, dengue infection history and days of symptoms among the groups.

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

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