Targeting steroid hormone signaling in Anopheles mosquitoes for malaria control

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 DESCRIPTION (provided by applicant): To transmit malaria, not only must the mosquito vector mate, feed and reproduce successfully, but it must also be able to sustain the Plasmodium parasite through its sexual life-stages and several rounds of multiplicative division. In this project we will study the role of the steroid hormone 20-hydroxyecdysone (20E) in regulating entomological parameters critical for continued disease transmission in the major Afro-tropical malaria vector Anopheles gambiae. In adult An. gambiae, like in other hematophagous mosquitoes, 20E is synthesized by females in their ovaries in response to a vertebrate blood meal. Moreover, An. gambiae males also synthesize significant quantities of 20E in their ejaculate and transfer this steroid hormone during copulation, initiating signaling cascades critical for female reproductive fitness. Increasing preliminary data from our research group indicates that sexually transferred 20E plays a far more pervasive role in mediating components of adult mosquito physiology and behavior that are also relevant to Plasmodium transmission. We have determined that females actively choose to mate with males with significantly higher levels of 20E in their male reproductive accessory glands (MAGs); that the sexual transfer of male 20E activates female pathways that impact Plasmodium development; and that application of synthetic non-steroidal 20E agonists triggers a potent life-shortening and sterilizing effect in female An. gambiae and disrupts Plasmodium development. Here we will considerably expand on these preliminary studies to unravel the role of male 20E in modulating chemical and acoustic processes critical for male mating success (Aim 1), determine the contribution of male 20E to molecular pathways regulating the development of the human malaria parasite Plasmodium falciparum (Aim 2), and validate the use of 20E agonists as mosquito and malaria control agents (Aim 3). By combining behavioral, molecular and genomic tools, our project will fill in critical knowledge gaps in mosquito biology and will produce new tools that can be exploited in mosquito control strategies aimed at the elimination of malaria.