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Divergent metabolism between Trypanosoma congolense and Trypanosoma brucei results in differential sensitivity to metabolic inhibition
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. congole...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8384185/ https://www.ncbi.nlm.nih.gov/pubmed/34310651 http://dx.doi.org/10.1371/journal.ppat.1009734 |
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author | 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. |
author_facet | 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. |
author_sort | Steketee, Pieter C. |
collection | PubMed |
description | 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 EC(50) 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. |
format | Online Article Text |
id | pubmed-8384185 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-83841852021-08-25 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. PLoS Pathog Research Article 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 EC(50) 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. Public Library of Science 2021-07-26 /pmc/articles/PMC8384185/ /pubmed/34310651 http://dx.doi.org/10.1371/journal.ppat.1009734 Text en © 2021 Steketee et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article 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 |
title | Divergent metabolism between Trypanosoma congolense and Trypanosoma brucei results in differential sensitivity to metabolic inhibition |
title_full | Divergent metabolism between Trypanosoma congolense and Trypanosoma brucei results in differential sensitivity to metabolic inhibition |
title_fullStr | Divergent metabolism between Trypanosoma congolense and Trypanosoma brucei results in differential sensitivity to metabolic inhibition |
title_full_unstemmed | Divergent metabolism between Trypanosoma congolense and Trypanosoma brucei results in differential sensitivity to metabolic inhibition |
title_short | Divergent metabolism between Trypanosoma congolense and Trypanosoma brucei results in differential sensitivity to metabolic inhibition |
title_sort | divergent metabolism between trypanosoma congolense and trypanosoma brucei results in differential sensitivity to metabolic inhibition |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8384185/ https://www.ncbi.nlm.nih.gov/pubmed/34310651 http://dx.doi.org/10.1371/journal.ppat.1009734 |
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