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Divergent metabolism between Trypanosoma congolense and Trypanosoma brucei results in differential sensitivity to metabolic inhibition

Steketee, Pieter C.; Dickie, Emily A.; Iremonger, James; Crouch, Kathryn; Paxton, Edith; Jayaraman, Siddharth; Alfituri, Omar A.; Awuah-Mensah, Georgina; Ritchie, Ryan; Schnaufer, Achim; Rowan, Tim; de Koning, Harry P.; Gadelha, Catarina; Wickstead, Bill; Barrett, Michael P.; Morrison, Liam J.

Divergent metabolism between Trypanosoma congolense and Trypanosoma brucei results in differential sensitivity to metabolic inhibition Thumbnail


Authors

Pieter C. Steketee

Emily A. Dickie

James Iremonger

Kathryn Crouch

Edith Paxton

Siddharth Jayaraman

Omar A. Alfituri

Ryan Ritchie

Achim Schnaufer

Tim Rowan

Harry P. de Koning

Michael P. Barrett

Liam J. Morrison



Abstract

Animal African Trypanosomiasis (AAT) is a debilitating livestock disease prevalent across sub-Saharan Africa, a main cause of which is the protozoan parasite Trypanosoma congolense. In comparison to the well-studied T. brucei, there is a major paucity of knowledge regarding the biology of T. congolense. Here, we use a combination of omics technologies and novel genetic tools to characterise core metabolism in T. congolense mammalian-infective bloodstream-form parasites, and test 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, with cells remaining viable when cultured 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 to T. brucei. Stable-isotope labelling of glucose enabled the 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. However, the parasite exhibits increased sensitivity to inhibition of mitochondrial pyruvate import, compared to T. brucei. 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.

Citation

Steketee, P. C., Dickie, E. A., Iremonger, J., Crouch, K., Paxton, E., Jayaraman, S., …Morrison, L. J. (2021). Divergent metabolism between Trypanosoma congolense and Trypanosoma brucei results in differential sensitivity to metabolic inhibition. PLoS Pathogens, 17(7), Article e1009734. https://doi.org/10.1371/journal.ppat.1009734

Journal Article Type Article
Acceptance Date Jun 21, 2021
Online Publication Date Jul 26, 2021
Publication Date Jul 1, 2021
Deposit Date Feb 5, 2023
Publicly Available Date Mar 28, 2024
Print ISSN 1553-7366
Electronic ISSN 1553-7374
Peer Reviewed Peer Reviewed
Volume 17
Issue 7
Article Number e1009734
DOI https://doi.org/10.1371/journal.ppat.1009734
Keywords Virology; Genetics; Molecular Biology; Immunology; Microbiology; Parasitology
Public URL https://nottingham-repository.worktribe.com/output/6016355
Publisher URL https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1009734

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