Increased insulin signaling in the mosquito midgut blocks malaria parasite development and reduces lifespan

The insulin/insulin growth factor 1 signaling (IIS) cascade is a key regulator of lifespan, reproduction and immunity in numerous organisms, including mosquitoes. To assess the roles of IIS in the mosquito’s midgut we genetically engineered an active form of the IIS molecule Akt into Anopheles stephensi mosquitoes. Expression was controlled by the midgut specific carboxypeptidase promoter. The myrAsteAkt transgene localized to the cell membrane of midgut epithelial cells where it was activated. Once activated it was capable of phosphorylating and activating FOXO, a downstream signaling molecule of the IIS cascade. To assess what impact this increased midgut IIS had on mosquito lifespan and immunity, mortality studies and malaria parasite challenges were performed. Increased IIS in the midgut of transgenic mosquitoes dramatically reduced the number of Plasmodium falciparum oocysts developing on the midgut. The prevalence of infection was reduced by 60-99% in heterozygous transgenic mosquitoes and the oocyst load decreased by 75-99%. In homozygous mosquitoes parasite infection was completely blocked. In addition, transgenic mosquitoes given weekly bloodmeals had a 20% reduction in lifespan compared with non-transgenic sibling mosquitoes. A similar increase in mortality was observed in transgenic mosquitoes fed only sugar. In summary, activation of Akt signaling offers a powerful and novel approach to controlling malaria transmission by reducing the number of mosquitoes infected, the number of parasites per infected mosquito, and the duration of mosquito infectivity.