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A 6.5kb intergenic structural variation enhances P450-mediated resistance to pyrethroids in malaria vectors lowering bed net efficacy

Article scientifique 2020 Anglais

Résumé

Abstract Elucidating the complex evolutionary armory that mosquitoes deploy against insecticides is crucial to maintain the effectiveness of insecticide-based interventions. Here, we deciphered the role of a 6.5kb structural variation (SV) in driving cytochrome P450-mediated pyrethroid resistance in the malaria vector, Anopheles funestus . Whole genome pooled sequencing detected an intergenic 6.5kb SV between duplicated CYP6P9a/b P450s in pyrethroid resistant mosquitoes through a translocation event. Promoter analysis revealed a 17.5-fold higher activity (P<0.0001) for the SV-carrying fragment than the SV-free one. qRT-PCR expression profiling of CYP6P9a/b for each SV genotype supported its role as an enhancer since SV+/SV+ homozygote mosquitoes had significantly greater expression for both genes than heterozygotes SV+/SV- (1.7-2-fold) and homozygotes SV-/SV- (4-5-fold). Designing a PCR assay revealed a strong association between this SV and pyrethroid resistance (SV+/SV+ vs SV-/SV-; OR=2079.4, P =<0.001). The 6.5kb SV is present at high frequency in southern Africa (80-100%) but absent in East/Central/West Africa. Experimental hut trials revealed that homozygote SV mosquitoes had significantly greater chance to survive exposure to pyrethroid-treated Nets (OR 27.7; P < 0.0001) and to blood feed than susceptible. Furthermore, triple homozygote resistant (SV+/CYP6P9a_R/CYP6P9b_R) exhibit a higher resistance level leading to a far superior ability to survive exposure to nets than triple susceptible mosquitoes, revealing a strong additive effect. This study highlights the important role of structural variations in the development of insecticide resistance in malaria vectors and their detrimental impact on the effectiveness of pyrethroid-based nets.

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Mugenzi, L., Menze, B., Tchouakui, M., Wondji, M., Irving, H., Tchoupo, M., Hearn, J., Weedall, G., Riveron, J., Cho‐Ngwa, F., Wondji, C. (2020). A 6.5kb intergenic structural variation enhances P450-mediated resistance to pyrethroids in malaria vectors lowering bed net efficacy. https://doi.org/10.1101/2020.05.05.078600

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Auteur(s)

Leon M. J. Mugenzi Benjamin D. Menze Magellan Tchouakui Murielle J. Wondji Helen Irving Micareme Tchoupo Jack Hearn Gareth D. Weedall Jacob M. Riveron Fidelis Cho‐Ngwa Charles S. Wondji

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