Szempruch, Anthony James
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Trypanosomes are protozoan parasites, which are characterized by their large single mitochondrial genome termed the kinetoplast. Trypanosoma brucei cycles between an insect vector, the tsetse fly, and a mammalian host where it causes human African sleeping sickness and the cattle wasting disease Nagana. Though T. brucei undergoes a complex life cycle, with extensive developmental regulation, these organisms lack intron splicing the most common mechanism for expanding functional diversity at the transcript level. Instead, these parasites may rely on their unique mitochondrial process of RNA editing for the generation of novel open reading frames and the process of moonlighting to expand the functional repertoire of protein products. By developing new methods to investigate mitochondrial RNA function in vivo and analyzing mitochondrial protein moonlighting functions this work sets out to expand out understanding of mitochondrial protein diversity in T. brucei. Disruption of a critical mitochondrial moonlighting protein within T. brucei revealed that these parasites undergo a process of extracellular vesicle (EVs) mediated cellular communication. Bloodstream form T. brucei generate membrane nanotubes originate from the flagellar membrane and disassociate into free EVs. These EVs contain virulence factor proteins including the T. b. rhodesiense specific serum resistance-associated protein (SRA) necessary for human infectivity. T. b. rhodesiense EVs transfer SRA to non-human infectious trypanosomes allowing evasion of human innate immunity. These EVs are also able to fuse with host erythrocytes resulting in anemia. studying the complex biological processes employed by these parasites to generate protein diversity allowed for the identified of a novel mechanism of T. brucei virulence.