Genetically Modifying Mosquitoes Without Compromising Fitness: Can It Be Done?

Abstract

Malaria is a mosquito-borne disease caused by parasites belonging to the genus Plasmodium. Malaria remains one of the most devastating infectious diseases, killing nearly half a million people each year (WHO 2015). 1,2 With the current increase in drug and insecticide resistance, there is an urgent need to develop novel strategies for malaria control. One such strategy to genetically engineer mosquito vectors to make them resistant to infection by malaria parasites in order to replace the wild population with malaria refractory mosquitoes. The insulin/IGF-like signaling (IIS) pathway is one potential target for a population replacement strategy since it regulates metabolism, immunity, lifespan and reproduction in mosquitoes. We previously generated a transgenic Anopheles stephensi line with increased insulin signaling in the fat body. Surprisingly, these transgenic mosquitoes survived significantly longer than their non-transgenic siblings, while in nearly every other organism increased IIS resulted in a decrease in lifespan. In this work, we sought to define how the fat body IIS controls lifespan, and also to determine the impact of the fat body IIS on reproduction, metabolism, and Plasmodium resistance. We found that overexpression of the molecule Akt, a key IIS nexus molecule, resulted in an increased overall fitness and enhanced Plasmodium falciparum parasite resistance in transgenic Anopheles stephensi, as compared to their non-transgenic siblings. Overall results from these studies highlight the important role of IIS in the mosquito fat body in controlling lifespan, reproduction, metabolism and immunity.