Kynurenine Pathway Activation in Human African Trypanosomiasis

Abstract

Background.The kynurenine pathway of tryptophan oxidation is associated with central nervous system (CNS) inflammatory pathways. Inhibition of this pathway ameliorates CNS inflammation in rodent models of the late (meningoencephalitic) stage of human African trypanosomiasis (HAT). In this study, we evaluate whether the kynurenine pathway is activated in clinical HAT and associated with CNS inflammatory responses.Methods.We measured cerebrospinal fluid (CSF) tryptophan and kynurenine metabolite concentrations in patients infected with Trypanosoma brucei rhodesiense, using liquid chromatography–mass spectrometry.Results.Kynurenine concentration in CSF was increased in both the early and late stages of disease, with a progressive increase in tryptophan oxidation associated with stage progression. Kynurenine pathway activation was associated with increases in neuroinflammatory markers, but there was no clear relationship to neurological symptoms.Conclusions.CNS kynurenine pathway activation occurs during HAT, including cases prior to the current diagnostic cutoff for late-stage infection, providing evidence for early CNS involvement in HAT. Metabolite data demonstrate that the kynurenine-3-monooxygenase and kynurenine aminotransferase branches of the kynurenine pathway are active. The association between tryptophan oxidation and CNS inflammatory responses as measured by CSF interleukin 6 (IL-6) concentration supports a role of kynurenine metabolites in the inflammatory pathogenesis of late-stage HAT.

Metabolic Profiling of Central Nervous System Disease in Trypanosoma brucei rhodesiense Infection

“…The lack of clear discrimination of disease stage by CSF metabolites is consistent with our recent observations of kynurenine pathway activation in the CNS [ 30 ] and with a recent untargeted liquid chromatography mass spectrometry study of CSF from patients infected with T. b. gambiense , where metabolic signatures were only discriminatory between early and an advanced late stage of disease defined by CSF white blood cell concentrations of >20 cells/µL [ 12 ]. Thus, metabolic alterations and neuroinflammatory activation appear to be predictive of neurological sequelae in HAT but not of diagnostic stage.…”

The oral administration of silver nanoparticles activates the kynurenine pathway in rat brain independently of oxidative stress

“…Briefly, oxidation of L-tryptophan to kynurenine is catalyzed by the indoleamine 2,3-dioxygenase (IDO), while the non-enzymatic cyclization of kynurenine forms the quinolinate, which in turn can be converted to niacin. On the other hand, L-tryptophan can be transformed to form serotonin (neurotransmitter), which can be metabolized further to produce melatonin (neuro-hormone) [12]. Investigations have revealed that oxidative stress resulting from ROS production can affect the immune activity and neurotransmitter levels by influencing neurotransmitter synthesis [13].…”

Generation of neuroinflammation in human African trypanosomiasis

“…54 Activation of this pathway has been found through liquid chromatography-mass spectrometry analysis of CSF samples from patients with both early and late-stage HAT. 53 In these patients, significant increases in kynurenine levels, accompanied by decreased tryptophan concentrations, were observed in infected individuals compared to uninfected controls. 53 An association was also found between tryptophan catabolism and increased CSF IL-6 concentrations, providing further evidence to support a role for this pathway in the neuropathogenesis of HAT.…”

“…53 In these patients, significant increases in kynurenine levels, accompanied by decreased tryptophan concentrations, were observed in infected individuals compared to uninfected controls. 53 An association was also found between tryptophan catabolism and increased CSF IL-6 concentrations, providing further evidence to support a role for this pathway in the neuropathogenesis of HAT. Changes in the concentration of kynurenine pathway metabolites in the CSF were also identified in a metabolomics study, designed to detect potential biomarkers for late-stage HAT, although these changes were small.…”

“…Another pathway recently implicated in the generation of the neuroinflammatory reaction to trypanosome infection is the kynurenine pathway. 53,54 This pathway is fundamental in the oxidation of tryptophan, produces several neurotoxic and neuroprotective catabolites, and is important in influencing both the innate and adaptive immune response. 55 In a murine model of HAT, inhibition of kynurenine 3-monooxygenase, a key enzyme in this pathway, resulted in a significant reduction in the severity of the neuroinflammatory reaction exhibited during the late CNS stage of the infection.…”