An immunomodulatory role for indole-3-pyruvate, an excreted metabolite of the parasite Trypanosoma Brucei
Citation:
CORCORAN, SARAH ELIZABETH, An immunomodulatory role for indole-3-pyruvate, an excreted metabolite of the parasite Trypanosoma Brucei, Trinity College Dublin.School of Biochemistry & Immunology.BIOCHEMISTRY, 2017Download Item:
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Abstract:
Human African trypanosomiasis, more commonly known as sleeping sickness, is one of the world's neglected diseases. Trypanosoma brucei, an extracellular parasitic protozoan of the genus Trypanosoma, is the causative agent. The bloodstream stage of infection has a key feature: the increased production of aromatic keto acids. The keto acids were previously thought to be excreted by-products of parasite metabolism. In this study, I have identified an immunomodulatory role for the parasite derived aromatic keto acid, indole-3-pyruvate (I3P) as well as for a structurally similar dietary indole compound, indole-3-carbinol (I3C).
I3P is a keto acid formed by the transamination of tryptophan by the parasite enzyme aspartate aminotransferase (cASAT). I3P potently inhibited the induction of the pro-inflammatory cytokine IL-1β by murine macrophages at both the mRNA and protein level while having no effect on the production of the cytokines IL-6 or TNFα. The inhibition of IL-1β was due to the impairment of the HIF1α signalling pathway by I3P. I3P promoted the hydroxylation of HIF1α, leading to its degradation. Furthermore, the induction of the prostaglandin synthesising enzyme COX2, which is also produced in response to LPS stimulation, was strongly potentiated by I3P. Interestingly a primary downstream product of LPS-induced COX2, PGE2, was robustly decreased by I3P treatment. Thus there exists an intriguing disconnect in the pathway, where the rate limiting enzyme in the production of PGE2; COX2, is increased, while the product, PGE2, is inhibited.
I3P is a known ligand of the xenobiotic detoxifying aryl-hydrocarbon receptor (AhR). This receptor has been shown to directly modulate immune responses in certain settings. Further to this, AhR signalling utilises some common pathway components to the HIF pathway, opening the possibility of pathway crosstalk. This study indicated that AhR activation is not required for the inhibition of LPS-induced IL-1β by I3P, but revealed a partial dependance on the AhR in the augmentation of COX2 by I3P. Similar to I3P, the AhR agonist 3-methylcholanthrene (3MC) also boosted COX2 production and inhibited the production of PGE2 by macrophages in response to LPS. I3P may therefore modulate the expression of endogenous inflammatory mediators in order to limit host defence against T. brucei, but also to possibly prevent detrimental inflammation and maintain host survival.
Another example of a naturally occurring indole compound with anti-inflammatory properties is I3C, an autolysis product of glucosinolate present in Brassica vegetables (broccoli, turnips, cabbage and Brussels sprouts). It has been shown to have anti-inflammatory and anti-tumour properties. I3C also decreased LPS-induced HIF-protein and inhibited production of the pro-inflammatory cytokine IL-1β.
I have therefore identified an immunomodulatory role for certain indole componds, both parasite derived and dietary. These discoveries have implications in the identification of new therapeutic approaches for African sleeping sickness and contribute to our understanding of anti-inflammatory effects of a common dietary component. Both compounds may have potential for development as inhibitors of inflammation.
 
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http://people.tcd.ie/scorcorDescription:
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Author: CORCORAN, SARAH ELIZABETH
Advisor:
O'Neill, LukePublisher:
Trinity College Dublin. School of Biochemistry & Immunology. Discipline of BiochemistryType of material:
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