Leishmania Encodes a Bacterium-like 2,4-Dienoyl-Coenzyme A Reductase That Is Required for Fatty Acid beta-Oxidation and Intracellular Parasite Survival

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Autor(es): dc.contributorRobert Koch Inst-
Autor(es): dc.contributorUniv Edinburgh-
Autor(es): dc.contributorUniv Glasgow-
Autor(es): dc.contributorUniv Melbourne-
Autor(es): dc.contributorUniversidade Estadual Paulista (Unesp)-
Autor(es): dc.contributorLeibniz Inst Mol Pharmacol-
Autor(es): dc.creatorSemini, Geo-
Autor(es): dc.creatorPaape, Daniel-
Autor(es): dc.creatorBlume, Martin-
Autor(es): dc.creatorSernee, M. Fleur-
Autor(es): dc.creatorPeres-Alonso, Diego [UNESP]-
Autor(es): dc.creatorCalvignac-Spencer, Sebastien-
Autor(es): dc.creatorDoellinger, Joerg-
Autor(es): dc.creatorJehle, Stefan-
Autor(es): dc.creatorSaunders, Eleanor-
Autor(es): dc.creatorMcConville, Malcolm J.-
Autor(es): dc.creatorAebischer, Toni-
Data de aceite: dc.date.accessioned2022-02-22T00:56:42Z-
Data de disponibilização: dc.date.available2022-02-22T00:56:42Z-
Data de envio: dc.date.issued2021-06-25-
Data de envio: dc.date.issued2021-06-25-
Data de envio: dc.date.issued2020-05-01-
Fonte completa do material: dc.identifierhttp://dx.doi.org/10.1128/mBio.01057-20-
Fonte completa do material: dc.identifierhttp://hdl.handle.net/11449/209482-
Fonte: dc.identifier.urihttp://educapes.capes.gov.br/handle/11449/209482-
Descrição: dc.descriptionLeishmania spp. are protozoan parasites that cause a spectrum of important diseases in humans. These parasites develop as extracellular promastigotes in the digestive tract of their insect vectors and as obligate intracellular amastigotes that infect macrophages and other phagocytic cells in their vertebrate hosts. Promastigote-to-amastigote differentiation is associated with marked changes in metabolism, including the upregulation of enzymes involved in fatty acid beta-oxidation, which may reflect adaptation to the intracellular niche. Here, we have investigated the function of one of these enzymes, a putative 2,4-dienoyl-coenzyme A (CoA) reductase (DECR), which is specifically required for the beta-oxidation of polyunsaturated fatty acids. The Leishmania DECR shows close homology to bacterial DECR proteins, suggesting that it was acquired by lateral gene transfer. It is present in other trypanosomatids that have obligate intracellular stages (i.e., Trypanosoma cruzi and Angomonas) but is absent from dixenous parasites with an exclusively extracellular lifestyle (i.e., Trypanosoma brucer). A DECR-green fluorescent protein (GFP) fusion protein was localized to the mitochondrion in both promastigote and amastigote stages, and the levels of expression increased in the latter stages. A Leishmania major Delta decr null mutant was unable to catabolize unsaturated fatty acids and accumulated the intermediate 2,4-decadienoyl-CoA, confirming DECR's role in beta-oxidation. Strikingly, the L. major Delta decr mutant was unable to survive in macrophages and was avirulent in BALB/c mice. These findings suggest that beta-oxidation of polyunsaturated fatty acids is essential for intracellular parasite survival and that the bacterial origin of key enzymes in this pathway could be exploited in developing new therapies. IMPORTANCE The Trypanosomatidae are protozoan parasites that infect insects, plants, and animals and have evolved complex monoxenous (single host) and dixenous (two hosts) lifestyles. A number of species of Trypanosomatidae, including Leishmania spp., have evolved the capacity to survive within intracellular niches in vertebrate hosts. The adaptations, metabolic and other, that are associated with development of intracellular lifestyles remain poorly defined. We show that genomes of Leishmania and Trypanosomatidae that can survive intracellularly encode a 2,4-dienoyl-CoA reductase that is involved in catabolism of a subclass of fatty acids. The trypanosomatid enzyme shows closest similarity to the corresponding bacterial enzymes and is located in the mitochondrion and essential for intracellular growth of Leishmania. The findings suggest that acquisition of this gene by lateral gene transfer from bacteria by ancestral monoxenous Trypanosomatidae likely contributed to the development of a dixenous lifestyle of these parasites.-
Descrição: dc.descriptionFederal Ministry of Education and Research (BMBF)-
Descrição: dc.descriptionDFG research fellowship-
Descrição: dc.descriptionEuropean Commission Marie Curie Excellence grant-
Descrição: dc.descriptionDeutsche Forschungsgemeinschaft-
Descrição: dc.descriptionRobert Koch Inst, Dept Infect Dis, Mycot & Parasit Agents & Mycobacteria FG16, Berlin, Germany-
Descrição: dc.descriptionUniv Edinburgh, Inst Immunol & Infect Res, Edinburgh, Midlothian, Scotland-
Descrição: dc.descriptionUniv Glasgow, Wellcome Ctr Integrat Parasitol, Glasgow, Lanark, Scotland-
Descrição: dc.descriptionRobert Koch Inst, Metab Microbial Pathogens NG2, Berlin, Germany-
Descrição: dc.descriptionUniv Melbourne, Bio21 Mol Sci & Biotechnol Inst, Dept Biochem & Mol Biol, Parkville, Vic, Australia-
Descrição: dc.descriptionUniv Estadual Paulista, Inst Biociencias, Dept Parasitol, Botucatu, SP, Brazil-
Descrição: dc.descriptionRobert Koch Inst, Epidemiol Highly Pathogen Microorganisms, Berlin, Germany-
Descrição: dc.descriptionRobert Koch Inst, Prote & Spect ZBS 6, Berlin, Germany-
Descrição: dc.descriptionLeibniz Inst Mol Pharmacol, Dept NMR Supported Struct Biol, Berlin, Germany-
Descrição: dc.descriptionUniv Estadual Paulista, Inst Biociencias, Dept Parasitol, Botucatu, SP, Brazil-
Descrição: dc.descriptionFederal Ministry of Education and Research (BMBF): 01KI1715-
Descrição: dc.descriptionEuropean Commission Marie Curie Excellence grant: Ext-25435-
Descrição: dc.descriptionDeutsche Forschungsgemeinschaft: AE16/5-1-
Descrição: dc.descriptionDeutsche Forschungsgemeinschaft: AE16/5-2-
Formato: dc.format19-
Idioma: dc.languageen-
Publicador: dc.publisherAmer Soc Microbiology-
Relação: dc.relationMbio-
???dc.source???: dc.sourceWeb of Science-
Palavras-chave: dc.subjectKinetoplastida-
Palavras-chave: dc.subjectlateral gene transfer-
Palavras-chave: dc.subjectmitochondrial metabolism-
Palavras-chave: dc.subjectvirulence factors-
Título: dc.titleLeishmania Encodes a Bacterium-like 2,4-Dienoyl-Coenzyme A Reductase That Is Required for Fatty Acid beta-Oxidation and Intracellular Parasite Survival-
Tipo de arquivo: dc.typelivro digital-
Aparece nas coleções:Repositório Institucional - Unesp

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