20-Hydroxyecdysone (20E) signaling as a promising target for the chemical control of malaria vectors.

With the rapid development and spread of resistance to insecticides among anopheline malaria vectors, the efficacy of current World Health Organization (WHO)-approved insecticides targeting these vectors is under threat. This has led to the development of novel interventions, including improved and enhanced insecticide formulations with new targets or synergists or with added sterilants and/or antimalarials, among others. To date, several studies in mosquitoes have revealed that the 20-hydroxyecdysone (20E) signaling pathway regulates both vector abundance and competence, two parameters that influence malaria transmission. Therefore, insecticides which target 20E signaling (e.g. methoxyfenozide and halofenozide) may be an asset for malaria vector control. While such insecticides are already commercially available for lepidopteran and coleopteran pests, they still need to be approved by the WHO for malaria vector control programs. Until recently, chemicals targeting 20E signaling were considered to be insect growth regulators, and their effect was mostly studied against immature mosquito stages. However, in the last few years, promising results have been obtained by applying methoxyfenozide or halofenozide (two compounds that boost 20E signaling) to Anopheles populations at different phases of their life-cycle. In addition, preliminary studies suggest that methoxyfenozide resistance is unstable, causing the insects substantial fitness costs, thereby potentially circumventing one of the biggest challenges faced by current vector control efforts. In this review, we first describe the 20E signaling pathway in mosquitoes and then summarize the mechanisms whereby 20E signaling regulates the physiological processes associated with vector competence and vector abundance. Finally, we discuss the potential of using chemicals targeting 20E signaling to control malaria vectors.