Killing Plasmodium parasites in the mosquito: target identification and feasibility testing for a novel malaria control strategy

Abstract

Malaria is a devastating disease that affects hundreds of millions of people worldwide, leading to nearly 600,000 deaths in 2023. Plasmodium falciparum parasites are the causative agent of over 90% of malaria cases and are transmitted to people by the bite of an infectious Anopheles female mosquito. Vector control strategies that target these mosquitoes have been instrumental to control efforts, and the extensive rollout of insecticide treated bed nets has contributed to substantial reductions in malaria prevalence and mortality since the turn of the century. However, high levels of insecticide resistance have emerged in anophelines, and to-date, insecticide-resistant mosquitoes have been identified in over 80% of malaria endemic countries. This widespread resistance jeopardizes the efficacy of current vector control tools and has contributed to the recent plateau in malaria cases worldwide. New interventions are thus urgently needed. In this dissertation, I describe our efforts to develop a novel transmission blocking strategy that circumvents insecticide resistance by targeting parasites directly with antimalarial compounds during their development in the mosquito. In Chapter 1, I review the current state of malaria control and promising new tools, with an emphasis on vector control. I introduce the concept of mosquito-targeted antiplasmodials and outline key features for their successful implementation. In Chapter 2, I identify suitable targets for this strategy by performing an in vivo screen of antiplasmodial compounds in mosquitoes, optimize key inhibitors for improved uptake and activity, and assess their resistance propensity and transmissibility. In Chapter 3, I test the feasibility of incorporating hit compounds in bed net-like materials, determine their antiplasmodial activity in insecticide-resistant mosquitoes, and assess their activity across sporogonic development. Finally, in Chapter 4 I discuss implications of this work and directions for further development of this strategy. Altogether, this dissertation significantly expands our understanding of mosquito-targeted antiplasmodials and demonstrates their potential for malaria control in the context of widespread insecticide resistance.