Kynurenine Is a Cerebrospinal Fluid Biomarker for Bacterial and Viral Central Nervous System Infections

Abstract Background The tryptophan–kynurenine–nicotinamide adenine dinucleotide (oxidized; NAD+) pathway is closely associated with regulation of immune cells toward less inflammatory phenotypes and may exert neuroprotective effects. Investigating its regulation in central nervous system (CNS) infec...

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Published in:The Journal of infectious diseases 2019-06, Vol.220 (1), p.127-138
Main Authors: Sühs, Kurt-Wolfram, Novoselova, Natalia, Kuhn, Maike, Seegers, Lena, Kaever, Volkhard, Müller-Vahl, Kirsten, Trebst, Corinna, Skripuletz, Thomas, Stangel, Martin, Pessler, Frank
Format: Article
Language:English
Subjects:
Adenine
Adolescent
Adult
Aged
Aged, 80 and over
Autoimmune Diseases - metabolism
Autoimmune Diseases - microbiology
Autoimmune Diseases - virology
Bacteria
Bells palsy
Biomarkers
Biomarkers - metabolism
Blood levels
Borreliosis
Central nervous system
Central Nervous System Infections - metabolism
Central Nervous System Infections - microbiology
Central Nervous System Infections - virology
Cerebrospinal fluid
Cerebrospinal Fluid - microbiology
Cerebrospinal Fluid - virology
Encephalitis
Female
Gilles de la Tourette syndrome
Glutamic acid receptors
Glutamic acid receptors (ionotropic)
Herpes simplex
Humans
Hydrocephalus
Infections
Inflammation
Inflammation - metabolism
Inflammation - microbiology
Inflammation - virology
Kynurenine - metabolism
Lactic acid
Lactic Acid - metabolism
Leukocyte Count - methods
Male
Medical diagnosis
Meningitis
Middle Aged
Multiple sclerosis
N-Methyl-D-aspartic acid receptors
NAD
Nervous system
Neuroprotection
Paralysis
Phenotypes
Tryptophan
Tryptophan - metabolism
Varicella
Young Adult
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Summary:Abstract Background The tryptophan–kynurenine–nicotinamide adenine dinucleotide (oxidized; NAD+) pathway is closely associated with regulation of immune cells toward less inflammatory phenotypes and may exert neuroprotective effects. Investigating its regulation in central nervous system (CNS) infections would improve our understanding of pathophysiology and end-organ damage, and, furthermore, open doors to its evaluation as a source of diagnostic and/or prognostic biomarkers. Methods We measured concentrations of kynurenine (Kyn) and tryptophan (Trp) in 221 cerebrospinal fluid samples from patients with bacterial and viral (due to herpes simplex, varicella zoster, and enteroviruses) meningitis/encephalitis, neuroborreliosis, autoimmune neuroinflammation (due to anti-N-methyl-D-aspartate receptor [NMDA] encephalitis and multiple sclerosis), and noninflamed controls (ie, individuals with Bell palsy, normal pressure hydrocephalus, or Tourette syndrome). Results Kyn concentrations correlated strongly with CSF markers of neuroinflammation (ie, leukocyte count, lactate concentration, and blood-CSF-barrier dysfunction), were highly increased in bacterial and viral CNS infections, but were low or undetectable in NMDA encephalitis, multiple sclerosis, and controls. Trp concentrations were decreased mostly in viral CNS infections and neuroborreliosis. Multiple logistic regression analysis revealed that combinations of Kyn concentration, Trp concentration, and Kyn/Trp concentration ratio with leukocyte count or lactate concentration were accurate classifiers for the clinically important differentiation between neuroborreliosis, viral CNS infections, and autoimmune neuroinflammation. Conclusions The Trp-Kyn-NAD+ pathway is activated in CNS infections and provides highly accurate CSF biomarkers, particularly when combined with standard CSF indices of neuroinflammation. This study of kynurenine and tryptophan concentrations in human cerebrospinal fluid revealed marked induction of the kynurenine-tryptophan pathway in bacterial and viral meningitis/encephalitis. It highlights these metabolites as accurate biomarkers, particularly for differentiating among neuroborreliosis, viral meningitis/encephalitis, and autoimmune neuroinflammation.
ISSN:0022-1899
1537-6613
DOI:10.1093/infdis/jiz048