Dengue virus rapidly reshapes the transcriptional landscape of human neutrophils toward cytokine storm–associated inflammation

<title>Abstract</title> <p> Dengue virus (DENV) remains a major global health threat, and severe disease outcomes are associated with dysregulated immune responses. Although immunological studies have been extensively performed, the transcriptomic response of neutrophils to DENV infection remains poorly defined, partly owing to technical challenges in profiling neutrophil gene expression during infection. Here, we performed bulk RNA sequencing of primary human neutrophils coincubated with DENV to characterize the transcriptional changes induced by viral exposure. We identified 673 genes associated with dengue virus exposure, including 527 upregulated genes in the KEGG pathway related to cytokine signaling, immune activation, and host defense. Protein–protein interaction network analysis revealed a highly interconnected network comprising 385 nodes and 1,774 edges, with key hub mediators, including <italic>Tnf-α, Il-1β, Il-6, Il-8, and Ccl2.</italic> Pathway analysis (IPA) predicted that DENV-stimulated neutrophils are potential contributors to cytokine release capable of influencing both immune and nonimmune cells. Importantly, these transcriptomic signatures correlated with dengue patient transcriptomes during the acute phase (Pearson r = 0.62, <italic>p</italic> &lt; 0.01). Collectively, these findings demonstrate that DENV rapidly induces a proinflammatory transcriptional program in human neutrophils, providing new mechanistic insight into neutrophil-driven inflammatory responses and their potential contribution to dengue-associated immunopathology. </p>