Dengue virus susceptibility in Aedes aegypti linked to natural cytochrome P450 promoter variants
The mosquito Aedes aegypti is the primary vector for dengue virus (DENV), which infects millions of people annually. Variability in DENV susceptibility among wild Ae. aegypti populations is governed by genetic factors, but specific causal variants are unknown. Here, we identify a cytochrome P450-encoding gene (CYP4G15) whose genetic variants drive differences in DENV susceptibility in a natural Ae. aegypti population. CYP4G15 is transiently upregulated in DENV-resistant midguts, while knockdown increases susceptibility, and transgenic overexpression enhances resistance. A naturally occurring 18-base-pair promoter deletion reduces CYP4G15 expression and confers higher DENV susceptibility. The unexpected role of a cytochrome P450 in DENV susceptibility challenges the long-standing focus on canonical immune pathways and opens new avenues for understanding antiviral defense and DENV transmission in mosquitoes.
Authors
- Josquin Daron (ORCID: https://orcid.org/0000-0003-3914-5998)
- Hugo Varet (ORCID: https://orcid.org/0000-0003-3980-4463)
- Adrien Pain (ORCID: https://orcid.org/0000-0003-0467-1357)
- Rachel Legendre (ORCID: https://orcid.org/0000-0002-5196-9431)
- Éric Marois (ORCID: https://orcid.org/0000-0003-4147-3747)
- Diégo Ayala (ORCID: https://orcid.org/0000-0003-4726-580X)
- Christophe Paupy (ORCID: https://orcid.org/0000-0002-7122-2079)
- Natapong Jupatanakul (ORCID: https://orcid.org/0000-0003-2326-4255)
- Stéphanie Dabo (ORCID: https://orcid.org/0000-0002-6275-0128)
- Odile Sismeiro (ORCID: https://orcid.org/0000-0003-4113-4606)
- Anna B. Crist (ORCID: https://orcid.org/0000-0002-8000-7020)
- Sarah H. Merkling (ORCID: https://orcid.org/0000-0002-6823-4474)
- Myriam Burckbuchler (ORCID: https://orcid.org/0000-0002-5865-1987)
- Élodie Couderc (ORCID: https://orcid.org/0000-0001-7508-8439)
- Louis Lambrechts (ORCID: https://orcid.org/0000-0001-5958-2138)
- Davy Jiolle (ORCID: https://orcid.org/0000-0002-7420-5768)
- Thomas Vial (ORCID: https://orcid.org/0000-0003-3347-7342)
Institutions
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Institut Pasteur (FR)
- Université Sorbonne Nouvelle (FR)
- Université de Montpellier (FR)
- Université Paris Cité (FR)
- Sorbonne Université (FR)
- Maladies Infectieuses et Vecteurs: Écologie, Génétique, Évolution et Contrôle (FR)
- Centre International de Recherches Médicales de Franceville (GA)
- Institut de Recherche pour le Développement (FR)
- Université de Strasbourg (FR)
- National Center for Genetic Engineering and Biotechnology (TH)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-08-12
- DOI
- https://doi.org/10.1038/s41467-025-62693-y
- Citations
- 1
- Primary Topic
- Mosquito-borne diseases and control
- Type
- article
- Field-Weighted Citation Impact
- 1.88
Funders
- International Business Machines Corporation
- Agence Nationale de la Recherche
- Centre National de la Recherche Scientifique