Kynurenine pathway activation in Human African trypanosomiasis

Sternberg, J. M., Forrest, C. M., Dalton, R. N., Turner, C., Rodgers, J. , Stone, T. W. and Kennedy, P. G.E. (2017) Kynurenine pathway activation in Human African trypanosomiasis. Journal of Infectious Diseases, 215(5), pp. 806-812. (doi:10.1093/infdis/jiw623) (PMID:28013248) (PMCID:PMC5388295)

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Abstract

Background: The kynurenine pathway of tryptophan oxidation is associated with 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 if it is associated with CNS inflammatory responses. Methods: We measured cerebrospinal fluid (CSF) tryptophan and kynurenine metabolite concentrations in Trypanosoma brucei rhodesiense patients using liquid chromatography-mass spectrometry. Results: Kynurenine concentration was increased in both early and late stage disease CSF, 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 cut off 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 IL-6 concentration supports a role of kynurenine metabolites in the inflammatory pathogenesis of late stage HAT.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Forrest, Dr Caroline and Stone, Professor Trevor and Kennedy, Professor Peter and Rodgers, Dr Jean
Authors: Sternberg, J. M., Forrest, C. M., Dalton, R. N., Turner, C., Rodgers, J., Stone, T. W., and Kennedy, P. G.E.
College/School:College of Medical Veterinary and Life Sciences > Institute of Biodiversity Animal Health and Comparative Medicine
College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
College of Medical Veterinary and Life Sciences > Institute of Neuroscience and Psychology
Journal Name:Journal of Infectious Diseases
Publisher:Oxford University Press
ISSN:0022-1899
ISSN (Online):1537-6613
Published Online:24 December 2016
Copyright Holders:Copyright © 2016 The Authors
First Published:First published in Journal of Infectious Diseases 215(5):806-812
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
457901Defining the therapeutic role of IL-10 in African trypanosomiasis.Peter KennedyWellcome Trust (WELLCOME)082786/Z/07/ZIII - PARASITOLOGY
554901Defining the role of kynurenine pathway metabolites in the inflammatory response to trypanosome invasion of the CNSPeter KennedyWellcome Trust (WELLCOME)094691/Z/10/ZIII - PARASITOLOGY