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...
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| Veröffentlicht in: | PLoS pathogens 2021-07, Vol.17 (7), p.e1009734-e1009734 |
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| creator | 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 |
| 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 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. |
| doi_str_mv | 10.1371/journal.ppat.1009734 |
| format | Article |
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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.</description><identifier>ISSN: 1553-7374</identifier><identifier>ISSN: 1553-7366</identifier><identifier>EISSN: 1553-7374</identifier><identifier>DOI: 10.1371/journal.ppat.1009734</identifier><identifier>PMID: 34310651</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Acetic acid ; African trypanosomiasis ; Animal diseases ; Animals ; Biology and Life Sciences ; Comparative analysis ; Dehydrogenases ; Divergence ; Drug development ; Drug resistance ; Electron transport ; Electron transport chain ; Energy metabolism ; Fatty acids ; Fatty-acid synthase ; Gene expression ; Genetic aspects ; Glucose ; Glycolysis ; Host-parasite relationships ; Host-pathogen interactions ; Hypotheses ; Inhibitors ; Insects ; Kinases ; Labeling ; Labelling ; Lipid Regulating Agents - pharmacology ; Livestock ; Malate ; Metabolism ; Metabolites ; Mice ; Microbial metabolism ; Mitochondria ; NMR ; Nuclear magnetic resonance ; Nucleotides ; Parasites ; Parasitological research ; Physical Sciences ; Physiological aspects ; Protozoa ; Pyruvate dehydrogenase (lipoamide) ; Pyruvic acid ; Research and Analysis Methods ; Sensitivity ; Trypanosoma ; Trypanosoma brucei brucei - drug effects ; Trypanosoma brucei brucei - metabolism ; Trypanosoma congolense ; Trypanosoma congolense - drug effects ; Trypanosoma congolense - metabolism ; Trypanosomiasis, African ; Vector-borne diseases</subject><ispartof>PLoS pathogens, 2021-07, Vol.17 (7), p.e1009734-e1009734</ispartof><rights>COPYRIGHT 2021 Public Library of Science</rights><rights>2021 Steketee et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 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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.</description><subject>Acetic acid</subject><subject>African trypanosomiasis</subject><subject>Animal diseases</subject><subject>Animals</subject><subject>Biology and Life Sciences</subject><subject>Comparative analysis</subject><subject>Dehydrogenases</subject><subject>Divergence</subject><subject>Drug development</subject><subject>Drug resistance</subject><subject>Electron transport</subject><subject>Electron transport chain</subject><subject>Energy metabolism</subject><subject>Fatty acids</subject><subject>Fatty-acid synthase</subject><subject>Gene expression</subject><subject>Genetic aspects</subject><subject>Glucose</subject><subject>Glycolysis</subject><subject>Host-parasite relationships</subject><subject>Host-pathogen interactions</subject><subject>Hypotheses</subject><subject>Inhibitors</subject><subject>Insects</subject><subject>Kinases</subject><subject>Labeling</subject><subject>Labelling</subject><subject>Lipid Regulating Agents - pharmacology</subject><subject>Livestock</subject><subject>Malate</subject><subject>Metabolism</subject><subject>Metabolites</subject><subject>Mice</subject><subject>Microbial metabolism</subject><subject>Mitochondria</subject><subject>NMR</subject><subject>Nuclear magnetic resonance</subject><subject>Nucleotides</subject><subject>Parasites</subject><subject>Parasitological research</subject><subject>Physical Sciences</subject><subject>Physiological aspects</subject><subject>Protozoa</subject><subject>Pyruvate dehydrogenase (lipoamide)</subject><subject>Pyruvic acid</subject><subject>Research and Analysis Methods</subject><subject>Sensitivity</subject><subject>Trypanosoma</subject><subject>Trypanosoma brucei brucei - drug effects</subject><subject>Trypanosoma brucei brucei - metabolism</subject><subject>Trypanosoma congolense</subject><subject>Trypanosoma congolense - drug effects</subject><subject>Trypanosoma congolense - metabolism</subject><subject>Trypanosomiasis, African</subject><subject>Vector-borne 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metabolism between Trypanosoma congolense and Trypanosoma brucei results in differential sensitivity to metabolic inhibition</title><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></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c661t-7f4bc7bc60590a4d9a5290c4d4e7fea7547bf0c6a34ddafe754ad0df0c034ebc3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Acetic acid</topic><topic>African trypanosomiasis</topic><topic>Animal diseases</topic><topic>Animals</topic><topic>Biology and Life Sciences</topic><topic>Comparative analysis</topic><topic>Dehydrogenases</topic><topic>Divergence</topic><topic>Drug 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(Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Biological Science Database</collection><collection>Access via ProQuest (Open Access)</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PLoS pathogens</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Steketee, Pieter C</au><au>Dickie, Emily A</au><au>Iremonger, James</au><au>Crouch, Kathryn</au><au>Paxton, Edith</au><au>Jayaraman, Siddharth</au><au>Alfituri, Omar A</au><au>Awuah-Mensah, Georgina</au><au>Ritchie, Ryan</au><au>Schnaufer, Achim</au><au>Rowan, Tim</au><au>de Koning, Harry P</au><au>Gadelha, Catarina</au><au>Wickstead, Bill</au><au>Barrett, Michael P</au><au>Morrison, Liam J</au><au>Clayton, Christine</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Divergent metabolism between Trypanosoma congolense and Trypanosoma brucei results in differential sensitivity to metabolic inhibition</atitle><jtitle>PLoS pathogens</jtitle><addtitle>PLoS Pathog</addtitle><date>2021-07-01</date><risdate>2021</risdate><volume>17</volume><issue>7</issue><spage>e1009734</spage><epage>e1009734</epage><pages>e1009734-e1009734</pages><issn>1553-7374</issn><issn>1553-7366</issn><eissn>1553-7374</eissn><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.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>34310651</pmid><doi>10.1371/journal.ppat.1009734</doi><orcidid>https://orcid.org/0000-0002-6367-5588</orcidid><orcidid>https://orcid.org/0000-0002-8476-8679</orcidid><orcidid>https://orcid.org/0000-0003-3677-5898</orcidid><orcidid>https://orcid.org/0000-0002-9963-1827</orcidid><orcidid>https://orcid.org/0000-0002-4620-9091</orcidid><orcidid>https://orcid.org/0000-0001-6572-0226</orcidid><orcidid>https://orcid.org/0000-0003-2132-5560</orcidid><orcidid>https://orcid.org/0000-0001-9310-4762</orcidid><orcidid>https://orcid.org/0000-0002-4509-5045</orcidid><orcidid>https://orcid.org/0000-0002-8304-9066</orcidid><orcidid>https://orcid.org/0000-0001-9323-6415</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1553-7374 |
| ispartof | PLoS pathogens, 2021-07, Vol.17 (7), p.e1009734-e1009734 |
| issn | 1553-7374 1553-7366 1553-7374 |
| language | eng |
| recordid | cdi_plos_journals_2561941044 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central Open Access; Public Library of Science (PLoS) Journals Open Access; PubMed Central |
| subjects | Acetic acid African trypanosomiasis Animal diseases Animals Biology and Life Sciences Comparative analysis Dehydrogenases Divergence Drug development Drug resistance Electron transport Electron transport chain Energy metabolism Fatty acids Fatty-acid synthase Gene expression Genetic aspects Glucose Glycolysis Host-parasite relationships Host-pathogen interactions Hypotheses Inhibitors Insects Kinases Labeling Labelling Lipid Regulating Agents - pharmacology Livestock Malate Metabolism Metabolites Mice Microbial metabolism Mitochondria NMR Nuclear magnetic resonance Nucleotides Parasites Parasitological research Physical Sciences Physiological aspects Protozoa Pyruvate dehydrogenase (lipoamide) Pyruvic acid Research and Analysis Methods Sensitivity Trypanosoma Trypanosoma brucei brucei - drug effects Trypanosoma brucei brucei - metabolism Trypanosoma congolense Trypanosoma congolense - drug effects Trypanosoma congolense - metabolism Trypanosomiasis, African Vector-borne diseases |
| title | Divergent metabolism between Trypanosoma congolense and Trypanosoma brucei results in differential sensitivity to metabolic inhibition |
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