Proteostatic Mechanisms of Resistance in Malaria

University Of Notre Dame, Notre Dame IN

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Abstract

? DESCRIPTION (provided by applicant): The long-term objective of our project is to develop a comprehensive, mechanistic understanding of artemisinin resistance and action in malarial parasites. This is critical because artemisinin based therapies are most effective treatments for both uncomplicated malaria as well as severe disease. The onset of artemisinin resistance threatens malaria control and eradication. Plasmodium falciparum causes the most virulent of human malaria. Mutations in a P. falciparum protein PF3D7_1343700 (also known as PfKelch13) have been shown to associate with artemisinin resistance both in laboratory parasites as well as in clinical isolates. However, the mechanistic basis of resistance, cellular functions of Kelch13 and the major pathways of artemisinin action in parasites are unknown. Our work from the fundamental studies of Kelch13 suggests that it plays a central role in lipid-protein homeostasis, whose disruption leads to resistance. We have two aims. In the first aim, we will undertake molecular, biochemical and genetic approaches to identify Kelch13 function in regulating a lipid pool that is active in signaling in subcellular membranes in the parasite. In th second we will prove that this pool is perturbed in clinically resistant strains and laboratory strains. Moreover its perturbation in genetically engineered renders resistance to artemisinins. Our studies will establish that PfKelch13 acts in a major pathway of artemisinin action. The work will help devise strategies to extend the use of life saving artemisinins as well as identify novel targets and rational strategies to develop drugs that circumvent resistance.