Author: Steketee PC, Dickie EA, Iremonger J, Crouch K, Paxton E
About this Publication:
Grant: Tryps 3 Country/Region: Multiple countries, Sub-Saharan Africa Trypanosomiasis is a debilitating livestock disease in sub-Saharan Africa and a major cause is Trypanosoma congolense. Omics technologies and novel genetic tools are used to characterise the core metabolism of mammalian-infective and bloodstream-stage T. congolense, and test whether metabolic differences compared with T. brucei affect sensitivity to metabolic inhibition. Like the bloodstream-stage of T. brucei, glycolysis is important for T. congolense energy metabolism. The rate of glucose uptake is significantly lower in bloodstream-stage T. congolense; cultured cells remain viable in concentrations as low as 2 mM. Instead of pyruvate, 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 with T. brucei. Stable-isotope labelling of glucose allowed comparison of carbon usage between T. brucei and T. congolense, highlighting differences in nucleotide and saturated fatty acid metabolism. To validate the metabolic similarities and differences, both species were treated with metabolic inhibitors, confirming that electron transport chain activity is not essential in T. congolense but it exhibits increased sensitivity to inhibition of mitochondrial pyruvate import compared with T. brucei. 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 with T. brucei. These data highlight that bloodstream-stage T. congolense diverges from T. brucei in key areas of metabolism, with several features that are intermediate between bloodstream- and insect-stage T. brucei.
Subject Areas: Research and Development