Bulk transcriptomics of peripheral blood mononuclear cells delineates systems-level immune dysregulation in pediatric dengue infection

Abstract Children are disproportionately at a greater risk of developing severe dengue disease, yet the molecular mechanisms driving the heightened susceptibility remains poorly understood. To elucidate the immune determinants of pediatric dengue pathogenesis, we profiled the transcriptomic landscape by performing RNA sequencing (RNA-Seq) on peripheral blood mononuclear cells (PBMCs) from laboratory-confirmed cases of primary and secondary pediatric dengue, as well as pediatric healthy controls. Differential gene expression (DEG) and pathway analyses were performed to delineate the transcriptional alterations. Pediatric dengue was marked by extensive transcriptional changes with altered expression of genes associated with the complement cascade macrophage-associated genes as well as immune checkpoint molecules. Notably, secondary infection had significant alterations in immune checkpoint molecules and genes associated with macrophage activation, suggesting the onset of immune exhaustion during reinfection. Differences between the primary and secondary dengue cohorts were modest relative to the transcriptional differences observed between either of the groups and healthy controls, with immune checkpoint genes showing the most consistent divergence between the two dengue cohorts. While our initial findings provide early insights into the transcriptional patterns potentially associated with disease outcomes, the dysregulated transcriptomic signatures reported here are preliminary requiring systemic functional validation to determine their biologic role in the immunopathogenesis of pediatric dengue infection.