University of Dundee Ornithine uptake and the modulation of drug sensitivity in Trypanosoma brucei

Trypanosoma brucei, protozoan parasites that cause human African trypanosomiasis (HAT), depend on ornithine uptake and metabolism by ornithine decarboxylase (ODC) for survival. Indeed, ODC is the target of the WHO “essential medicine” eflornithine, which is antagonistic to another anti-HAT drug, suramin. Thus, ornithine uptake has important consequences in T. brucei, but the transporters have not been identified. We describe these aminoacid transporters (AATs). In aheterologous expression system,TbAAT10-1 is selective for ornithine,whereas TbAAT2-4 transports both ornithine and histidine. These AATs are also necessary to maintain intracellular ornithine and polyamine levels in T. brucei, thereby decreasing sensitivity to eflornithine and increasing sensitivity to suramin. Consistent with competition for histidine, high extracellular concentrations of this amino acid phenocopied aTbAAT2-4 genetic defect.Our findings establishedTbAAT10-1 andTbAAT2-4 as the parasite ornithine transporters, oneofwhich canbemodulatedbyhistidine,butbothofwhichaffect sensitivity to important anti-HAT drugs.—Macedo, J. P., Currier, R. B., Wirdnam, C., Horn, D., Alsford, S., Rentsch, D. Ornithine uptake and the modulation of drug sensitivity in Trypanosoma brucei. FASEB J. 31, 4649–4660 (2017). www.fasebj.org