Author's School

Graduate School of Arts & Sciences

Author's Department/Program

Biology and Biomedical Sciences: Biochemistry

Language

English (en)

Date of Award

Spring 4-25-2014

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Chair and Committee

Daniel E Goldberg

Abstract

Malaria is the world's second biggest infectious killer after tuberculosis. It accounts for 219 million cases each year, with an estimated 660,000 deaths. The majority of these deaths occur in sub-Saharan Africa, in children under 5 years old. In addition to Africa, malaria is endemic to Asia, Central and South America, the Caribbean and the Middle East.

Plasmodium falciparum (P. falciparum) is the protozoan parasite that is responsible for the deadliest form of human malaria. Plasmodia are carried by the female Anopheles mosquito and infected into humans during a blood meal. The parasites invade liver cells and form merozoites which erupt from liver cells to invade red blood cells. The intraerythrocytic cycle of infection is responsible for the clinical manifestations of malaria, namely fever and chills. The intraerythrocytic cycle is also the stage of disease that is most studied and targeted for treatment.

Although treatment for malaria is available, drug-resistant forms of the parasite are increasingly rampant. For this reason, new, more effective treatments for malaria are necessary. To develop these treatments, we must have a better understanding of the biological processes that the parasite employs to survive in the host to cause disease.

In 1996, an international effort was launched to sequence the genome of P. falciparum with the expectation that the genome sequence could be exploited in the search for new drugs and vaccines to fight malaria. In 2002, the genome sequence was published with gaps in some chromosomes. Approximately 5,300 protein-encoding genes were identified; of these about 60% were labeled as hypothetical proteins.

Our studies focus on determining the function of one hypothetical protein, PFB0923c, that we now call Glucose Uptake Restoration Protein (GURP). We show that GURP localizes to novel double membrane vesicles in the RBC cytosol and is essential during P. falciparum intraerythrocytic infection. GURP interacts with and sequesters the host protein stomatin, which is known to depress glucose uptake in mammalian cells. Knockdown of GURP decreases glucose uptake and impairs parasite growth in RBCs. This phenotype can be rescued with antioxidants, suggesting that hexose monophosphate/pentose phosphate pathway impairment is lethal in the knockdown parasites. GURP C183 is essential to parasite viability and trafficking of GURP vesicles to the RBC cytosol. Together, these data demonstrate that GURP is essential to P. falciparum viability and glucose uptake during infection of red blood cells.

Comments

This work is not available online per the author’s request. For access information, please contact digital@wumail.wustl.edu or visit http://digital.wustl.edu/publish/etd-search.html.

Permanent URL: http://dx.doi.org/10.7936/K72F7KFV

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