title: Trypanosoma brucei metabolite indolepyruvate decreases HIF-1α and glycolysis in macrophages as a mechanism of innate immune evasion.
abstract: The parasite Trypanasoma brucei causes African trypanosomiasis, known as sleeping sickness in humans and nagana in domestic animals. These diseases are a major burden in the 36 sub-Saharan African countries where the tsetse fly vector is endemic. Untreated trypanosomiasis is fatal and the current treatments are stage-dependent and can be problematic during the meningoencephalitic stage, where no new therapies have been developed in recent years and the current drugs have a low therapeutic index. There is a need for more effective treatments and a better understanding of how these parasites evade the host immune response will help in this regard. The bloodstream form of T. brucei excretes significant amounts of aromatic ketoacids, including indolepyruvate, a transamination product of tryptophan. This study demonstrates that this process is essential in bloodstream forms, is mediated by a specialized isoform of cytoplasmic aminotransferase and, importantly, reveals an immunomodulatory role for indolepyruvate. Indolepyruvate prevents the LPS-induced glycolytic shift in macrophages. This effect is the result of an increase in the hydroxylation and degradation of the transcription factor hypoxia-inducible factor-1α (HIF-1α). The reduction in HIF-1α levels by indolepyruvate, following LPS or trypanosome activation, results in a decrease in production of the proinflammatory cytokine IL-1β. These data demonstrate an important role for indolepyruvate in immune evasion by T. brucei.
authors.affiliation: School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland; mcgettra@tcd.ie denolan@tcd.ie.
authors.forename: Anne F
authors.initials: AF
authors.lastname: McGettrick
authors.affiliation: School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Corcoran
authors.affiliation: School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
authors.forename: Paul J G
authors.initials: PJ
authors.lastname: Barry
authors.affiliation: School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
authors.forename: Jennifer
authors.initials: J
authors.lastname: McFarland
authors.affiliation: School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
authors.forename: Cécile
authors.initials: C
authors.lastname: Crès
authors.affiliation: Faculty of Medicine and Health Sciences, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Curtis
authors.affiliation: School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
authors.forename: Edward
authors.initials: E
authors.lastname: Franklin
authors.affiliation: Department of Microbiology, Trinity College Dublin, Dublin 2, Ireland.
authors.forename: Sinéad C
authors.initials: SC
authors.lastname: Corr
authors.affiliation: School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
authors.forename: K Hun
authors.initials: KH
authors.lastname: Mok
authors.affiliation: School of Medicine and Medical Science, The Conway Institute, University College Dublin, Dublin 4, Ireland.
authors.forename: Eoin P
authors.initials: EP
authors.lastname: Cummins
authors.affiliation: School of Medicine and Medical Science, The Conway Institute, University College Dublin, Dublin 4, Ireland.
authors.forename: Cormac T
authors.initials: CT
authors.lastname: Taylor
authors.affiliation: School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
authors.forename: Luke A J
authors.initials: LA
authors.lastname: O'Neill
authors.affiliation: School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland; mcgettra@tcd.ie denolan@tcd.ie.
authors.forename: Derek P
authors.initials: DP
authors.lastname: Nolan
mesh_terms: D000818:Animals; D002460:Cell Line; D006019:Glycolysis; D057809:HEK293 Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics* / Q000378:metabolism; D057131:Immune Evasion; D007113:Immunity, Innate; D007211:Indoles / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism / Q000469:parasitology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000378:metabolism* / Q000469:parasitology; D008810:Mice, Inbred C57BL; D011773:Pyruvates / Q000378:metabolism*; D014346:Trypanosoma brucei brucei / Q000276:immunology*; D014353:Trypanosomiasis, African / Q000276:immunology* / Q000469:parasitology
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007211:Indoles; D008070:Lipopolysaccharides; D011773:Pyruvates
keywords: Trypanosoma brucei; immune evasion; immunometabolism; innate immunity