Authors

PC Steketee⁶; E Dickie⁴; K CrouchG Awuah-Mensah²; E Paxton⁶; HP De KoningC Gadelha³; B Wickstead⁵; MP Barrett⁷; LJ Morrison⁶;  ¹ University of Glasgow , UK;  ² University of Nottingham, UK;  ³ Queen's Medical Centre, University of Nottingham, Nottingham, UK;  ⁴ Wellcome Centre for Molecular Parasitology, Institute of Infection, Immunity and Inflammation, University of Glasgow, UK;  ⁵ Queen's Medical Centre, University of Nottingham, UK;  ⁶ The Roslin Institute, University of Edinburgh, UK;  ⁷ Wellcome Centre for Integrative Parasitology, Institute of Infection, Immunity and Inflammation, University of Glasgow, UK

Discussion

Animal African Trypanosomiasis (AAT) is a debilitating livestock disease prevalent across sub-Saharan Africa. One of the main causes is the protozoan parasite Trypanosoma congolense. Whilst the closely related T. brucei has been studied for decades, there is a major paucity of knowledge regarding the biology of T. congolense. In this study, we have used a combination of omics technologies and novel genetic tools to characterise core metabolism in T. congolense mammalian-infective bloodstream-form parasites. In addition, we have tested whether metabolic differences compared to T. brucei impact upon sensitivity to metabolic inhibition. Like the bloodstream stage of T. brucei, glycolysis plays a major part in T. congolense energy metabolism. However, the rate of glucose uptake is significantly lower in bloodstream stage T. congolense. Furthermore, the primary glycolytic endpoints are succinate, malate and acetate. Transcriptomics analysis showed higher levels of transcripts associated with the mitochondrial pyruvate dehydrogenase complex, acetate generation, and the glycosomal succinate shunt in T. congolense, compared to T. brucei. To validate the metabolic similarities and differences, both species were treated with metabolic inhibitors, Strikingly, T. congolense exhibited significant resistance to inhibitors of fatty acid synthesis, including a 780-fold higher EC₅₀ for the lipase and fatty acid synthase inhibitor Orlistat, compared to T. brucei. These data highlight that bloodstream form T. congolense diverges from T. brucei in key areas of metabolism, with several features that are intermediate between bloodstream- and insect-stage T. brucei. These results have implications for drug development, mechanisms of drug resistance and host-pathogen interactions.