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Dengue virus susceptibility in Aedes aegypti tied to natural cytochrome P450 variants

ABSTRACT: The mosquito Aedes aegypti serves as the primary vector for dengue virus (DENV), a human pathogen responsible for infecting hundreds of millions of people globally each year. Natural populations of Ae. aegypti show significant variability in their ability to become infected with DENV, which is largely governed by mosquito genetic factors. Previous studies suggest that genes encoding digestive enzymes, such as trypsins, and canonical antiviral immune genes may contribute to this variation 5-10. However, the specific causal gene variants underlying DENV susceptibility in Ae. aegypti are unknown. Here, we identify a gene encoding a cytochrome P450 (CYP4G15) whose genetic variants drive differences in DENV susceptibility in a natural Ae. aegypti population. CYP4G15 is transiently overexpressed in the midguts of DENV-resistant mosquitoes early in infection. Knockdown of CYP4G15 expression increases DENV susceptibility, while transgenic overexpression enhances resistance. A naturally occurring CYP4G15 variant with an 18-base-pair deletion in its promoter shows reduced expression and confers higher DENV susceptibility. The identification of CYP4G15 as a factor underlying DENV susceptibility in Ae. aegypti is unexpected because cytochrome P450 enzymes are typically associated with metabolism. Our finding challenges the long-standing focus on canonical immune pathways and opens new avenues for understanding antiviral defense and DENV transmission in mosquitoes.

ORGANISM(S): Aedes aegypti

PROVIDER: GSE279387 | GEO | 2025/07/22

REPOSITORIES: GEO

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