Dissertation
Lipid homeostasis and antimalarials in Plasmodium falciparum
Doctor of Philosophy (Ph.D.), Drexel University
May 2022
DOI:
https://doi.org/10.17918/00001173
Abstract
During its dynamic intra-erythrocytic lifecycle in the human host, Plasmodium falciparum, a protozoan parasite is exposed to varied environment. In addition, the parasite also undergoes unique morphological changes during its lifetime. It introduces various membranous organelles in the infected erythrocyte cytoplasm that establish pathogenesis. P. falciparum heavily relies on host derived nutrients and lipids to survive. A very unique feature of the P. falciparum infected host erythrocyte is the distribution of cholesterol in various membranes. The infected erythrocyte plasma membrane has the highest amount of cholesterol. The amount of cholesterol in the parasite plasma membrane (PPM) is maintained at low levels through the activity of a cholesterol pump, PfNCR1. Short term exposure to novel antimalarials that target PfNCR1, leads to the accumulation of cholesterol in the PPM. These results highlight the presence of an active process that maintains cholesterol in membranes. The exact mechanism by which P. falciparum maintains the cholesterol gradient and the importance of erythrocyte membrane cholesterol in the development of the parasite remains unknown. Here, we looked at the effects of modifying erythrocyte membrane cholesterol on the growth and development of P. falciparum. Using live fluorescent video microscopy, we report that treatment with M[beta]CD resulted in dramatic expulsion of the trophozoite from the erythrocyte without causing cell lysis. This expulsion happens under ~10s. Using live fluorescent microscopy and flow cytometry, we show that infection with P. falciparum dramatically alters the distribution of accessible pool of cholesterol in the erythrocyte plasma membrane This was assessed by binding of domain 4 of anthrolysin O (ALOD4) and treatment with sphingomyelinase. Our studies also highlight the unrecognized role of parasite heat shock protein complex; J-dots, as potential transporters of lipids. Upon treatment with antimalarials, we show that the uptake of an essential fatty acid is not altered but there is a significant reduction in the number of neutral lipid bodies in the parasites These findings uncover the dynamic modifications that occur in the erythrocyte membrane cholesterol upon infection with P. falciparum, the essential nature of erythrocyte membrane cholesterol and mechanism by which lipids are transported in the infected erythrocyte.
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Details
- Title
- Lipid homeostasis and antimalarials in Plasmodium falciparum
- Creators
- Avantika I. Ahiya
- Contributors
- Akhil B. Vaidya (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- xvi, 201 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Microbiology and Immunology; College of Medicine; Drexel University
- Other Identifier
- 991018018928204721