Kynurenine Pathway Activation in Human African Trypanosomiasis

Jeremy M. Sternberg, Caroline M. Forrest, R. Neil Dalton, Charles Turner, Jean Rodgers, Trevor W. Stone, Peter G. E. Kennedy

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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.
Original languageEnglish
Pages (from-to)806-812
Number of pages7
JournalThe journal of infectious diseases
Volume215
Issue number5
Early online date24 Dec 2016
DOIs
Publication statusPublished - 1 Mar 2017

Keywords

  • African trypanosomiasis
  • meningoencephalitic
  • neuroinflammation
  • kynurenine
  • tryptophan

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    Sternberg, J. M., Forrest, C. M., Dalton, R. N., Turner, C., Rodgers, J., Stone, T. W., & Kennedy, P. G. E. (2017). Kynurenine Pathway Activation in Human African Trypanosomiasis. The journal of infectious diseases, 215(5), 806-812. https://doi.org/10.1093/infdis/jiw623