Please use this identifier to cite or link to this item:
https://www.arca.fiocruz.br/handle/icict/59168
Type
ArticleCopyright
Restricted access
Embargo date
2099-12-31
Collections
Metadata
Show full item record
THE NEUROTOXIC BRANCH OF THE KYNURENINE PATHWAY IS HIGHLY ACTIVATED IN THE CENTRAL NERVOUS SYSTEM OF PATIENTS WITH PNEUMOCOCCAL MENINGITIS
Author
Affilliation
Fundação Oswaldo Cruz. Instituto René Rachou. Imunologia de Doenças Virais. Belo Horizonte, MG, Brazil/Universidade Federal de Minas Gerais. Programa de Pós-Graduação em Bioquímica e Imunologia. Belo Horizonte, MG, Brazil
Universidade Federal dos Vales do Jequitinhonha e Mucuri. Faculdade de Medicina. Diamantina, MG, Brazil
Estado de Minas Gerais. Fundação Hospitalar de Minas Gerais. Hospital Infantil João Paulo II. Belo Horizonte, MG, Brazil
Fundação Oswaldo Cruz. Instituto René Rachou. Grupo Integrado de Pesquisas em Biomarcadores. Belo Horizonte, MG, Brazil
Fundação Oswaldo Cruz. Instituto René Rachou. Grupo Integrado de Pesquisas em Biomarcadores. Belo Horizonte, MG, Brazil
Universidade Federal de Minas Gerais. Departamento de Microbiologia. Laboratório de Virologia. Belo Horizonte, MG, Brazil
Fundação Oswaldo Cruz. Instituto René Rachou. Química de Produtos Naturais Bioativos. Belo Horizonte, MG, Brazil
Fundação Oswaldo Cruz. Instituto René Rachou. Imunologia de Doenças Virais. Belo Horizonte, MG, Brazil
Universidade Federal dos Vales do Jequitinhonha e Mucuri. Faculdade de Medicina. Diamantina, MG, Brazil
Estado de Minas Gerais. Fundação Hospitalar de Minas Gerais. Hospital Infantil João Paulo II. Belo Horizonte, MG, Brazil
Fundação Oswaldo Cruz. Instituto René Rachou. Grupo Integrado de Pesquisas em Biomarcadores. Belo Horizonte, MG, Brazil
Fundação Oswaldo Cruz. Instituto René Rachou. Grupo Integrado de Pesquisas em Biomarcadores. Belo Horizonte, MG, Brazil
Universidade Federal de Minas Gerais. Departamento de Microbiologia. Laboratório de Virologia. Belo Horizonte, MG, Brazil
Fundação Oswaldo Cruz. Instituto René Rachou. Química de Produtos Naturais Bioativos. Belo Horizonte, MG, Brazil
Fundação Oswaldo Cruz. Instituto René Rachou. Imunologia de Doenças Virais. Belo Horizonte, MG, Brazil
Abstract
Background: Acute bacterial meningitis (ABM) causes excessive activation of N-methyl-D-aspartate receptors (NMDAr), leading to cortical and hippocampal neuron death. As opposite, enteroviral meningitis is more frequently benign. The kynurenine (KYN) pathway is the major catabolic route of tryptophan (TRP) and some of its metabolites are agonists or antagonists of NMDAr. Methods: In order to investigate the pathogen-specific patterns of KYN pathway modulation in the central nervous system of children with acute meningococcal (MM), pneumococcal (PM) or enteroviral (VM) meningitis, the cerebrospinal fluid (CSF) concentrations of TRP, KYN, kynurenic acid (KYNA) and quinolinic acid (QUINA) were evaluated by ultra-high performance liquid chromatography (uHPLC) coupled to mass spectrometry. In addition, CSF levels of IL-6, IL-10 and TNF-α were quantified by multi-analyte flow assay. The data was mined and integrated using statistical and machine learning methods. Results: The three forms of meningitis investigated herein up-regulated the neurotoxic branch of the KYN pathway within the intrathecal space. However, this response, represented by the concentration of QUINA, was six and nine times higher in PM patients compared to MM or VM, respectively. CSF levels of IL-6, TNF-α, and IL10 were increased in MM and PM patients when compared to controls. In VM, CSF IL-6 and IL-10, but not TNF-α were increased compared to controls, although not reaching the high levels found in bacterial meningitis. No correlation was found between the concentrations or the ratios of any pair of KYN metabolites and any cytokine or standard cytochemical parameter tested. Conclusions: CNS infection with meningococci, pneumococci, and enteroviruses intrathecally activate the KYN pathway, favoring its neurotoxic branch. However, in PM, higher CSF levels of QUINA, compared to MM and VM, may contribute to its poorer neurologic outcome.
Share