Date of Award

2018

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Cell & Molecular Biology

First Advisor

Beatrice H. Hahn

Abstract

Plasmodium falciparum and Plasmodium vivax cause over 95% of all human malaria infections. To control and potentially eliminate these pathogens, it is important to understand their origins and evolutionary history. The recent discovery of a multitude of Plasmodium species in apes revealed that P. vivax and P. falciparum evolved from parasites infecting African apes, but the zoonotic threat posed by ape parasites and the precise circumstances surrounding the emergence of Plasmodium in humans remain unknown. Thus, in this thesis, I asked two questions: Are humans exposed to ape parasites and what can be learned about the history of human P. vivax through analyses of related ape parasites. To address the first question, I asked whether humans living near Plasmodium-infected apes develop pre-erythrocytic infections in the absence of blood stage infections. Screening 504 Cameroonian fecal samples for ape Plasmodium species, I found no evidence of abortive liver infection. Next, to facilitate genome sequencing of ape P. vivax, I adapted selective whole genome amplification (SWGA) to P. vivax, achieving a dramatic increase in the proportion of P. vivax DNA in human samples without introducing systemic sequence errors. I then generated partial P. vivax genome sequences from six chimpanzees and one gorilla, which revealed that human strains of P. vivax exhibit ~10-fold less diversity and have a unique excess of nonsynonymous nucleotide polymorphisms. This suggests a recent bottleneck and greatly relaxed purifying selection in the human parasite lineage. Investigating potential host specificity determinants, I found that ape P. vivax parasites encode three reticulocyte binding protein genes (rbp2d, rbp2e, and rbp3) whose orthologs are pseudogenes in human P. vivax strains. However, recombinant RBP2e and RBP3 proteins bound human, chimpanzee, and gorilla erythrocytes with similar efficiency. These results suggest that the P. vivax ancestor infected humans and apes in Africa, and that modern human P. vivax is derived from parasites that escaped Africa. Although many questions remain concerning the biology and zoonotic potential of ape malaria parasites, my studies show that comparative genomics, coupled with functional parasite studies, can yield new insights that are relevant to the prevention and eradication of human malaria.

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