Metabolism and drug resistance probed with new genetic tools in the neglected animal pathogen Trypanosoma vivax.

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Trypanosoma vivax is one of the main causes of Animal African Trypanosomiasis, but is sorely neglected despite its substantial impact. This project will bridge the critical knowledge and capability gaps in order to shift paradigms for basic and applied research on this important pathogen. The project will build on the experience of the applicants, and the industrial partner, the Global Alliance for Livestock Veterinary Medicines (GALVmed), to generate new knowledge on key areas of T. vivax biology and develop a laboratory toolkit for in vitro culture and genetic transformation, through a series of integrated aims. We will comprehensively characterise the metabolism of bloodstream-form T. vivax using RNAseq and LC-MS/GC-MS, enabling the production of a genome-scale model of metabolism. Predictions will be validated in genetic mutants or chemical inhibition of key metabolic steps. In parallel, the T. vivax surface proteome will be defined to identify proteins expected to be involved in metabolite and drug transport. Resistance induced both in vivo and in vitro to three drugs - the widely used diminazene aceturate and isometamidium chloride, and a benzoxaborole in clinical development - will be used in combination with data on parasite metabolism and surface proteome to identify mechanisms of drug uptake and resistance. These outputs will provide novel and foundational information on how T. vivax interacts with its environment, and particularly how it responds to exposure to drugs. Finally, we will generate laboratory capabilities to transform the ability to work meaningfully with T. vivax. Building upon the applicants' expertise with related trypanosomes, we will use the data generated to design culture medium that will support the growth of bloodstream-form T. vivax, and will generate a toolkit for functional genetics in this important parasite.