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

Research output: Contribution to journalArticle

3 Citations (Scopus)
3 Downloads (Pure)

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

Fingerprint

African Trypanosomiasis
Kynurenine
Central Nervous System
Tryptophan
Cerebrospinal Fluid
kynurenine-oxoglutarate transaminase
Kynurenine 3-Monooxygenase
Trypanosoma brucei rhodesiense
Rodentia
Interleukin-6
Spectrum Analysis
Inflammation

Keywords

  • African trypanosomiasis
  • meningoencephalitic
  • neuroinflammation
  • kynurenine
  • tryptophan

Cite this

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

Kynurenine Pathway Activation in Human African Trypanosomiasis. / Sternberg, Jeremy M.; Forrest, Caroline M.; Dalton, R. Neil ; Turner, Charles ; Rodgers, Jean ; Stone, Trevor W.; Kennedy, Peter G. E. .

In: The journal of infectious diseases, Vol. 215, No. 5, 01.03.2017, p. 806-812.

Research output: Contribution to journalArticle

Sternberg, JM, Forrest, CM, Dalton, RN, Turner, C, Rodgers, J, Stone, TW & Kennedy, PGE 2017, 'Kynurenine Pathway Activation in Human African Trypanosomiasis' The journal of infectious diseases, vol. 215, no. 5, pp. 806-812. https://doi.org/10.1093/infdis/jiw623
Sternberg, Jeremy M. ; Forrest, Caroline M. ; Dalton, R. Neil ; Turner, Charles ; Rodgers, Jean ; Stone, Trevor W. ; Kennedy, Peter G. E. . / Kynurenine Pathway Activation in Human African Trypanosomiasis. In: The journal of infectious diseases. 2017 ; Vol. 215, No. 5. pp. 806-812.
@article{39fb0d8e66414f1a80b10a0c7269e51d,
title = "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.",
keywords = "African trypanosomiasis , meningoencephalitic , neuroinflammation, kynurenine , tryptophan",
author = "Sternberg, {Jeremy M.} and Forrest, {Caroline M.} and Dalton, {R. Neil} and Charles Turner and Jean Rodgers and Stone, {Trevor W.} and Kennedy, {Peter G. E.}",
note = "Financial support This work was supported by the Wellcome Trust (grants 082786 [to J. M. S.] and 094691 [to P. G. E. K.]). Potential conflicts of interest. All authors: No reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.",
year = "2017",
month = "3",
day = "1",
doi = "10.1093/infdis/jiw623",
language = "English",
volume = "215",
pages = "806--812",
journal = "The journal of infectious diseases",
issn = "0022-1899",
publisher = "Oxford University Press",
number = "5",

}

TY - JOUR

T1 - Kynurenine Pathway Activation in Human African Trypanosomiasis

AU - Sternberg, Jeremy M.

AU - Forrest, Caroline M.

AU - Dalton, R. Neil

AU - Turner, Charles

AU - Rodgers, Jean

AU - Stone, Trevor W.

AU - Kennedy, Peter G. E.

N1 - Financial support This work was supported by the Wellcome Trust (grants 082786 [to J. M. S.] and 094691 [to P. G. E. K.]). Potential conflicts of interest. All authors: No reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

PY - 2017/3/1

Y1 - 2017/3/1

N2 - 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.

AB - 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.

KW - African trypanosomiasis

KW - meningoencephalitic

KW - neuroinflammation

KW - kynurenine

KW - tryptophan

U2 - 10.1093/infdis/jiw623

DO - 10.1093/infdis/jiw623

M3 - Article

VL - 215

SP - 806

EP - 812

JO - The journal of infectious diseases

JF - The journal of infectious diseases

SN - 0022-1899

IS - 5

ER -