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

Steketee, P. C. et al. (2021) Divergent metabolism between Trypanosoma congolense and Trypanosoma brucei results in differential sensitivity to metabolic inhibition. PLoS Pathogens, 17(7), e1009734. (doi: 10.1371/journal.ppat.1009734) (PMID:34310651) (PMCID:PMC8384185)

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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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:De Koning, Professor Harry and Crouch, Dr Kathryn and Ritchie, Mr Ryan and Morrison, Dr Liam and Barrett, Professor Michael and Dickie, Dr Emily
Creator Roles:
Dickie, E. A.Data curation, Formal analysis, Investigation, Writing – original draft, Writing – review and editing
Crouch, K.Conceptualization, Formal analysis, Methodology
Ritchie, R.Data curation, Formal analysis
de Koning, H. P.Conceptualization, Funding acquisition, Investigation, Writing – review and editing
Barrett, M. P.Conceptualization, Funding acquisition, Investigation, Methodology, Project administration, Resources, Validation, Writing – review and editing
Morrison, L. J.Conceptualization, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Supervision, Writing – original draft, Writing – review and editing
Authors: Steketee, P. C., Dickie, E. A., Iremonger, J., Crouch, K., Paxton, E., Jayaraman, S., Alfituri, O. A., Awuah-Mensah, G., Ritchie, R., Schnaufer, A., Rowan, T., de Koning, H. P., Gadelha, C., Wickstead, B., Barrett, M. P., and Morrison, L. J.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:PLoS Pathogens
Publisher:Public Library of Science
ISSN:1553-7366
ISSN (Online):1553-7374
Published Online:26 July 2021
Copyright Holders:Copyright © 2021 Steketee et al.
First Published:First published in PLoS Pathogens 17(7): e1009734
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
172474A new drug discovery pipeline for animal African trypanosomiasisMichael BarrettBiotechnology and Biological Sciences Research Council (BBSRC)BB/N007999/1III - Parasitology
302761Tracking isometamidium resistance in livestock trypanaosomesMichael BarrettBiotechnology and Biological Sciences Research Council (BBSRC)BB/S001034/1III - Parasitology
170547The Wellcome Centre for Molecular Parasitology ( Core Support )Andrew WatersWellcome Trust (WELLCOTR)104111/Z/14/ZRIII - Parasitology