Exploring interactions between the parasite plasma membrane and the parasite vacuolar membrane of Plasmodium falciparum

Abstract

Malaria poses a large health and economical threat to 40% of the world’s population. Treatment and prophylaxis with antimalarials remain a mainstay to control malaria. However, drug resistance remains a constant threat to these efforts. It is hoped that with the approval of new antimalarials and their proper distribution to endemic populations, the disease will stay contained and resistance to currently implemented drugs can be suppressed. Understanding the biology of the Plasmodium parasites that cause malaria infection will greatly aid in the hunt for potential antimalarials. Here, we study a series of compounds from the Medicines for Malaria Venture by monitoring their ability to induce lipid dysregulation within the parasites’ plasma membranes (PPM). Saponin sensitivity was measured in this newly developed assay via release of parasite cytosolic proteins after their exposure to drug. Proteins that contribute to lipid dynamic movement in P. falciparum are under investigation in our laboratory. Specifically, Niemann-Pick type C1-related protein (PfNCR1) and oxysterol-binding protein (PfOSBP) influence lipid movement across the PPM within an infected red blood cell. Though, we have shown PfOSBP not to be essential for asexual blood stage growth, this protein plays a notable role in sexual stage development and functionality. Additionally, [delta]PfOSBP transgenic parasites display altered PPM composition, which may link PfOSBP’s function with the lipid transfer pathway in P. falciparum as was shown with PfNCR1. We have proposed cholesterol to transfer from the parasite vacuolar membrane (PVM) inward, to the PPM upon drug exposure. The PPM and PVM are in proximity to one another, especially at the parasite’s cytostome which forms a site for lipid movement between membranes. To investigate proteins involved in cytostome development, we looked to analogous proteins found in a ciliate, Tetrahymena. A citrate synthase protein is involved in this ciliate’s oral apparatus formation. We show P. falciparum citrate synthase-like protein (PfCSL) to be an essential protein. In analogy with citrate synthase in Tetrahymena, we propose PfCSL to contribute to parasite cytostome function.Ph.D., Microbiology and Immunology -- Drexel University, 201