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.

Public Health Relevance

Plasmodium falciparum is a protozoan parasite that causes the most virulent form of human malaria. Artemisinin combination therapies have contributed significantly to the reducing the global burden of malaria. Artemisinins are also the most effective drugs at treating severe malaria disease. However resistance to artemsinins threatens malaria control and eradication. This research project proposes to study the mechanisms of artemisinin resistance in order to rationally design strategies to circumvent it and thereby continue to effectively treat both acute infection and severe disease in malaria, a major global health problem.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL130330-03
Application #
9418102
Study Section
Drug Discovery and Mechanisms of Antimicrobial Resistance Study Section (DDR)
Program Officer
Klauzinska, Malgorzata
Project Start
2016-02-01
Project End
2020-01-31
Budget Start
2018-02-01
Budget End
2019-01-31
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Notre Dame
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
824910376
City
Notre Dame
State
IN
Country
United States
Zip Code
46556