Inter-host diversity associated with age, sex, and menstrual cycle modulates clinical manifestations in DENV-2 patients.

Dengue virus (DENV-2) remains a global threat, yet the influence of age, sex, and menstrual status on its epidemiology and genetic diversity is underexplored. We analyzed 2136 hospitalized DENV-2 patients (ages 0-86) using whole-genome sequencing (WGS) to examine how these host factors shape interhost viral diversity and clinical manifestations. Young adult males (19-35 years) had the highest prevalence with sex-based clinical differences where females exhibited severe hematological changes, while males showed increased hepatic injury. Premenopausal females harbored more diverse viral populations, whereas postmenopausal women experienced pronounced platelet depletion. Dengue virus WGS identified 1100336 single nucleotide variants (SNVs) across 2932 genomic positions, with greater viral diversity in adults and females. Significant SNV burdens were observed in the E, NS3, and NS5 genes of the virus. These interconnected findings underscore the profound impact of age, sex, and menstrual status on DENV-2 epidemiology which merits inclusion into the disease pathophysiology.