All ETDs from UAB

Advisory Committee Chair

Julian C Rayner

Advisory Committee Members

David M Bedwell

Louis B Justment

Elizabeth S Sztul

Thomas R Unnasch

Document Type

Dissertation

Date of Award

2009

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Malaria is a mosquito-borne infectious disease that is caused by parasites in the genus Plasmodium. There are four species of malaria that routinely infect humans, but it is P. falciparum that is responsible for the majority of the severe and fatal cases of malaria. P. falciparum has a complex life cycle involving a mosquito vector and intracellular stages in both hepatocytes and erythrocytes; however, it is only the intraerythrocytic stages that are the cause of the pathology associated with malaria. This pathology is largely due to the ability of infected erythrocytes to cytoadhere to host microvasculature. After invasion, the parasite begins to traffic and export proteins into the host erythrocyte that induce substantial changes in the erythrocyte shape, membrane, and cytoskeleton, which enable infected erythrocytes to cytoadhere. Therefore, we sought to characterize components of the P. falciparum secretory pathway that are needed for this unique intracellular parasite to interact with the host erythrocyte, including components necessary for trafficking exported P. falciparum proteins in the erythrocyte cytosol. We identified seven P. falciparum Qa-SNAREs and characterized four of them: PfStx1, PfStx2, PfStx3, and PfStx5. Secondly, we sought to characterize changes in the cytoskeleton of infected erythrocytes. We show that a population of the erythrocyte cytoskeleton-associated protein 4.1R relocalizes to the parasitophorous vacuole membrane (PVM), and through a yeast two-hybrid screen, we identified a P. falciparum protein, PfFRIP (FouR point one Interacting Protein), which interacts with 4.1R. We characterized PfFRIP and mapped iii the region of PfFRIP that interacts with 4.1R. Additionally, we determined that 4.1R still relocalized to the PVM in a PfFRIP knockout strain of P. falciparum, indicating that other unknown P. falciparum proteins likely interact with 4.1R at the PVM. Overall, this dissertation provides insight into the secretory pathway of the intracellular parasite P. falciparum and changes in the host erythrocyte cytoskeleton induced by the parasite.

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