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The factors that drive dengue virus (DENV) evolution, and selection of virulent variants are yet not clear. Higher environmental temperature shortens DENV extrinsic incubation period in mosquitoes, increases human transmission, and plays a critical role in outbreak dynamics. In the present study, we looked at the effect of temperature in altering the virus virulence. We found that DENV cultured at a higher temperature in C6/36 mosquito cells was significantly more virulent than the virus grown at a lower temperature. In a mouse model, the virulent strain induced enhanced viremia and aggressive disease with a short course, hemorrhage, severe vascular permeability, and death. Higher inflammatory cytokine response, thrombocytopenia, and severe histopathological changes in vital organs such as heart, liver, and kidney were hallmarks of the disease. Importantly, it required only a few passages for the virus to acquire a quasi‐species population harboring virulence‐imparting mutations. Whole genome comparison with a lower temperature passaged strain identified key genomic changes in the structural protein‐coding regions as well as in the 3′UTR of the viral genome. Our results point out that virulence‐enhancing genetic changes could occur in the dengue virus genome under enhanced growth temperature conditions in mosquito cells.

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