Trypanosoma bruceimetabolite 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 stagedependent 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.immunometabolism | innate immunity | immune evasion |

The Uptake and Metabolism of Amino Acids, and Their Unique Role in the Biology of Pathogenic Trypanosomatids

“…Additionally, several studies reported that products of aromatic amino-acid metabolism were increased in urine and blood of animals infected with T. b. gambiense and T. b. evansi [ 233 , 234 , 235 ]. Furthermore, it has been demonstrated that indolepyruvate can modulate the immune response in infected mice [ 236 ], which points to a role for aromatic amino acids in the successful establishment of an infection by T. brucei .…”

Metabolomic profiling of macrophages determines the discrete metabolomic signature and metabolomic interactome triggered by polarising immune stimuli

“…For example, they increase uptake of triglycerides via the CD36 receptor for use in fatty acid oxidation [ 7 ]. Recently it has been found that pathogen generated substrates such as butyrate or indolepyruvate promote an anti-inflammatory phenotype [ 8 , 9 ]. In the context of immune-tumour interactions, tumour associated macrophages reduce glucose availability and promote the formation of an organized tumor vasculature [ 10 ].…”

Indole-3-Pyruvic Acid, an Aryl Hydrocarbon Receptor Activator, Suppresses Experimental Colitis in Mice

“…IPA is synthesized by the action of aromatic amino acid transaminases. In addition, some microorganisms produce IPA by the deamination of tryptophan (19,20). IPA reduced damage in the striatum after transient forebrain ischemia in the rat (21).…”