The Evolution of Knockdown Resistance: Genotypic and Phenotypic Insights Into Aedes aegypti Insecticide Resistance

Insecticide resistance is a significant challenge for mosquito population control and disease prevention. This research investigated knockdown resistance (kdr) mutations V410L, V1016I, and F1534C in Aedes aegypti mosquitoes to address crucial gaps in understanding insecticide resistance evolution and management. Six common kdr genotypes were obtained through genetic crosses of three unique parental strains from the same location in Florida, USA. Through topical application of deltamethrin on both males and females, we quantified the resistance profiles of each genotype and sex. Triple homozygous mutants were over 52 times more resistant than the susceptible Rockefeller lab strain, with resistance ratios of the five other genotypes ranging from 8 to 19. We demonstrated that the resistant haplotypes I ¹⁰¹⁶-C ¹⁵³⁴ (on V410L mutant background) and L ⁴¹⁰-I ¹⁰¹⁶ (on F1534C mutant background) were incompletely recessive. Using these data in a simulation model, we show that the selective advantage is not constant but fluctuates within the window of selection. Selective advantage depended on the frequency of the resistance haplotype at the time of treatment, and both the level and dose of exposure. Finally, resistance profiles revealed that male mosquitoes had similar resistance profiles to females when sex and weight differences were accounted for, indicating that males could be used for resistance surveillance, which could enhance surveillance efforts. Overall, this study provides the first detailed quantification of dose-response curves and selection advantages for both sexes across multiple kdr genotypes. These results offer critical insights into the evolutionary dynamics of insecticide resistance and support the development of evidence-based strategies for more sustainable mosquito control.