Abstract
A recurring target-site mutation identified in various pests and disease vectors alters the voltage gated sodium channel (vgsc) gene (often referred to as knockdown resistance or kdr) to confer resistance to commonly used insecticides, pyrethroids and DDT. The ubiquity of kdr mutations poses a major global threat to the continued use of insecticides as a means for vector control. In this study, we generate common kdr mutations in isogenic laboratory Drosophila strains using CRISPR/Cas9 editing. We identify differential sensitivities to permethrin and DDT versus deltamethrin among these mutants as well as contrasting physiological consequences of two different kdr mutations. Importantly, we apply a CRISPR-based allelic-drive to replace a resistant kdr mutation with a susceptible wild-type counterpart in population cages. This successful proof-of-principle opens-up numerous possibilities including targeted reversion of insecticide-resistant populations to a native susceptible state or replacement of malaria transmitting mosquitoes with those bearing naturally occurring parasite resistant alleles.
Highlights
IntroductionA recurring target-site mutation identified in various pests and disease vectors alters the voltage gated sodium channel (vgsc) gene (often referred to as knockdown resistance or kdr) to confer resistance to commonly used insecticides, pyrethroids and DDT
A recurring target-site mutation identified in various pests and disease vectors alters the voltage gated sodium channel gene to confer resistance to commonly used insecticides, pyrethroids and DDT
Common vector control practices include indoor residual spraying with pyrethroids, or a few other insecticides recommended by the WHO and use of long-lasting insecticide-treated mosquito nets (LLINs), all of which incorporate a pyrethroid
Summary
A recurring target-site mutation identified in various pests and disease vectors alters the voltage gated sodium channel (vgsc) gene (often referred to as knockdown resistance or kdr) to confer resistance to commonly used insecticides, pyrethroids and DDT. A complementary approach is to piggyback on newly developed gene-drive technologies designed to disseminate gene cassettes through insect populations that either reduce the number of individuals (suppression drives) or modify populations so that they no longer present a threat to public health (e.g., by expressing anti-malarial effectors preventing pathogen transmission by anopheline mosquitoes)[4] In this current study, we employ the powerful genetic tools available in the fruit fly Drosophila melanogaster to provide proof-of-principle for allelicdrive wherein we endow a gene-drive element with an additional functionality to bias inheritance of a preferred allelic variant (the wild-type insecticide susceptible vgsc allele) over a IR allele prevalent in many insects (L1014F)
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