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Proc Natl Acad Sci U S A. 2016 Nov 29;113(48):E7778-E7787. Epub 2016 Nov 15.

Trypanosoma brucei metabolite indolepyruvate decreases HIF-1α and glycolysis in macrophages as a mechanism of innate immune evasion.

Author information

1
School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland; mcgettra@tcd.ie denolan@tcd.ie.
2
School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
3
Faculty of Medicine and Health Sciences, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
4
Department of Microbiology, Trinity College Dublin, Dublin 2, Ireland.
5
School of Medicine and Medical Science, The Conway Institute, University College Dublin, Dublin 4, Ireland.

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.

KEYWORDS:

Trypanosoma brucei; immune evasion; immunometabolism; innate immunity

PMID:
27856732
PMCID:
PMC5137691
DOI:
10.1073/pnas.1608221113
[Indexed for MEDLINE]
Free PMC Article

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