. Trypanosomatids are parasites that cause debilitating and often fatal diseases in humans and livestock. A particularly serious problem in sub-Saharan Africa is caused by Trypanosoma brucei, a parasite spread by the bite of an infected Tsetse fly. T. brucei causes disease by proliferating in the blood, tissue spaces, and eventually the central nervous system of its mammalian host. Related parasites are equally important to human populations in other parts of the world, including South and Central America, Southeastern Asia and the Middle East. Our long-term goal is to understand, in biochemical and genetic detail, the mechanisms that coordinate gene expression in trypanosomatids. To achieve this goal, we are specifically investigating the mechanism used by the parasites to regulate their mRNA expression pattern. mRNA expression gives rise to a characteristic and essential proteome and determines the metabolic capabilities of the parasites. As a pathway into understanding mRNA expression control, we are studying a novel RNA-binding protein, RBP42, which was chosen for investigation because it (1) is essential for parasite proliferation and (2) binds to polysome-associated, translating mRNAs that encode a variety of enzymes and proteins within the cell's energy metabolic pathways and (3) is up-regulated in adipose tissue-dwelling parasites compared to bloodstream-dwelling parasites in the mouse model of infection. These data suggest that RBP42 is a key regulator of the parasite's nutritional homeostasis by influencing mRNA translation/ stability/sequestration as parasites flourish in the bloodstream, interstitial regions and central nervous system of their mammalian host. This exploratory, two-year project is grounded in preliminary and published data, and is strengthened by the complementary expertise of our group, revealing RBP42's role in parasite energy metabolism in the tissue culture model, and the Nagajyothi group, revealing parasite-host metabolic homeostasis in adipose tissue in the mouse model of infection.
Our aims are to explore the spatiotemporal expression of RBP42, and determine its mRNA targeting function, in T. brucei during the dynamics of host infection.
Human health is undermined by parasitic infections caused by the arthropod?borne protists, Trypanosoma sp. and Leishmanial sp. Infection?related deaths, as well as the overall burden of disease (measured in disability?adjusted life years, DALYs) are unacceptably high in our medically advanced world. During their life cycle, African trypanosomes must successfully adapt to the very different environments of their mammalian host and their insect vector. This requires dynamic and rapid regulation of gene expression. Our goal is to uncover the mechanism by which trypanosomes accomplish this regulatory feat. By determining the biological differences between the African trypanosomes and their mammalian hosts, we will identify new biochemical approaches and drug targets to replace the inadequate therapies currently in place.