title: Kynurenine Pathway Activation in Human African Trypanosomiasis.
abstract: 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.
  
  
  
  We measured cerebrospinal fluid (CSF) tryptophan and kynurenine metabolite concentrations in patients infected with Trypanosoma brucei rhodesiense, using liquid chromatography-mass spectrometry.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Institute of Biological and Environmental Sciences, University of Aberdeen, UK.
authors.forename: Jeremy M
authors.initials: JM
authors.lastname: Sternberg
authors.affiliation: Institute of Neuroscience and Psychology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
authors.forename: Caroline M
authors.initials: CM
authors.lastname: Forrest
authors.affiliation: WellChild Laboratory, Evelina London Children's Hospital, King's College London, United Kingdom.
authors.forename: R Neil
authors.initials: RN
authors.lastname: Dalton
authors.affiliation: WellChild Laboratory, Evelina London Children's Hospital, King's College London, United Kingdom.
authors.forename: Charles
authors.initials: C
authors.lastname: Turner
authors.affiliation: Institute of Biodiversity, Animal Health, and Comparative Medicine, College of Medical, Veterinary & Life Sciences, University of Glasgow, Glasgow, UK.
authors.forename: Jean
authors.initials: J
authors.lastname: Rodgers
authors.affiliation: Institute of Neuroscience and Psychology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
authors.forename: Trevor W
authors.initials: TW
authors.lastname: Stone
authors.affiliation: Department of Neurology, College of Medical, Veterinary, and Life Sciences, University of Glasgow, UK.
authors.forename: Peter G E
authors.initials: PGE
authors.lastname: Kennedy
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000134:cerebrospinal fluid; D002490:Central Nervous System / Q000469:parasitology / Q000473:pathology; D005260:Female; D006801:Humans; D007249:Inflammation / Q000134:cerebrospinal fluid / Q000469:parasitology; D007371:Interferon-gamma / Q000134:cerebrospinal fluid; D016753:Interleukin-10 / Q000134:cerebrospinal fluid; D015850:Interleukin-6 / Q000134:cerebrospinal fluid; D007737:Kynurenine / Q000134:cerebrospinal fluid*; D050601:Kynurenine 3-Monooxygenase / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D000637:Transaminases / Q000378:metabolism; D016833:Trypanosoma brucei rhodesiense / Q000302:isolation & purification; D014353:Trypanosomiasis, African / Q000134:cerebrospinal fluid*; D014364:Tryptophan / Q000134:cerebrospinal fluid*; D055815:Young Adult
chemical_list: D015415:Biomarkers; C573415:IFNG protein, human; C508609:IL10 protein, human; C508600:IL6 protein, human; D015850:Interleukin-6; D016753:Interleukin-10; D007737:Kynurenine; D007371:Interferon-gamma; D014364:Tryptophan; D050601:Kynurenine 3-Monooxygenase; D000637:Transaminases; C021481:kynurenine-oxoglutarate transaminase
keywords: African trypanosomiasis; kynurenine; meningoencephalitic; neuroinflammation; tryptophan