Högskolan i Skövde

Dengue virus infection is a major global health problem that can cause a wide range of clinical outcomes, from mild febrile illness to severe dengue associated with plasma leakage, haemorrhage, and organ dysfunction. The mechanisms underlying disease severity are not fully understood, particularly regarding immune and metabolic responses in different immune cell populations. Therefore, the aim of this study was to investigate transcriptional and metabolic alterations in monocytes and NK cells during dengue infection using a systems biology approach. Publicly available single-cell type RNA sequencing data from dengue patients were analyzed. A total of 2449 monocytes and 802 NK cells were included in the study. Differential gene expression analysis, pathway enrichment analysis, genome-scale metabolic modelling and flux balance analysis were performed to compare control, mild, and severe dengue conditions. Context-specific metabolic models were generated using transcriptomic profiles of the cells and analyzed using flux balance analysis. The results showed substantial transcriptional and metabolic alterations associated with dengue infection, particularly in monocytes. Severe dengue conditions showed a higher number of differentially expressed genes and stronger pathway dysregulation compared with mild infection. Several immune-related and metabolic pathways, including oxidative phosphorylation, cytokine signalling, NOD-like receptor signalling, and lipid metabolism, were significantly altered. Metabolic modelling further revealed major changes in transport reactions and lipid metabolic pathways, especially in severe monocytes. Compared with monocytes, NK cells showed more moderate transcriptional and metabolic alterations. In conclusion, this study demonstrates that dengue infection induces significant immunometabolic changes in immune cells, with monocytes showing stronger metabolic reprogramming during severe disease. The integration of transcriptomics with genome-scale metabolic modelling provided systems-level insight into host–virus interactions and highlighted potential metabolic pathways associated with dengue severity. These findings contribute to the understanding of dengue pathogenesis and may support future research into therapeutic strategies targeting host metabolism.