From Global to Local—New Insights into Features of Pyrethroid Detoxification in Vector Mosquitoes

SIMPLE SUMMARY: Insecticides are used to reduce the nuisance of biting insects, and, importantly, also to reduce the spread of insect-borne diseases. Over the years, mosquitoes have developed resistance to these insecticides. The most commonly used class of insecticides are the pyrethroids, synthetic versions of plant-derived compounds; they are less toxic to mammals and other animals than some other classes. One problem with all insecticides, though, is the development of resistance by the insect groups they are applied to combat. This review describes new insights into the ways in which mosquitoes have evolved resistance to pyrethroids. For example, before pyrethroids bind to their targets on motoneurons to paralyze mosquitoes, they must first pass through the outer exoskeleton to inner tissues. Resistant mosquitoes have evolved the ability to break down pyrethroids into nontoxic products that are then excreted. This metabolism prevents toxic buildup of the insecticide, which would otherwise be lethal to the mosquitoes. Scientists have identified a variety of changes to mosquito genes that are responsible for insecticide degradation and excretion. In this review, we outline the genes and pathways involved in the breakdown of pyrethroids and the key gene categories that are involved. ABSTRACT: The threat of mosquito-borne diseases continues to be a problem for public health in subtropical and tropical regions of the world; in response, there has been increased use of adulticidal insecticides, such as pyrethroids, in human habitation areas over the last thirty years. As a result, the prevalence of pyrethroid-resistant genetic markers in natural mosquito populations has increased at an alarming rate. This review details recent advances in the understanding of specific mechanisms associated with pyrethroid resistance, with emphasis on features of insecticide detoxification and the interdependence of multiple cellular pathways. Together, these advances add important context to the understanding of the processes that are selected in resistant mosquitoes. Specifically, before pyrethroids bind to their targets on motoneurons, they must first permeate the outer cuticle and diffuse to inner tissues. Resistant mosquitoes have evolved detoxification mechanisms that rely on cytochrome P450s (CYP), esterases, carboxyesterases, and other oxidation/reduction (redox) components to effectively detoxify pyrethroids to nontoxic breakdown products that are then excreted. Enhanced resistance mechanisms have evolved to include alteration of gene copy number, transcriptional and post-transcriptional regulation of gene expression, as well as changes to cellular signaling mechanisms. Here, we outline the variety of ways in which detoxification has been selected in various mosquito populations, as well as key gene categories involved. Pathways associated with potential new genes of interest are proposed. Consideration of multiple cellular pathways could provide opportunities for development of new insecticides.