Abstract
BackgroundBacterial meningitis (BM) is characterized by an intense host inflammatory reaction, which contributes to the development of brain damage and neuronal sequelae. Activation of the kynurenine (KYN) pathway (KP) has been reported in various neurological diseases as a consequence of inflammation. Previously, the KP was shown to be activated in animal models of BM, and the association of the SNP AADAT + 401C/T (kynurenine aminotransferase II - KAT II) with the host immune response to BM has been described. The aim of this study was to investigate the involvement of the KP during BM in humans by assessing the concentrations of KYN metabolites in the cerebrospinal fluid (CSF) of BM patients and their relationship with the inflammatory response compared to aseptic meningitis (AM) and non-meningitis (NM) groups.MethodsThe concentrations of tryptophan (TRP), KYN, kynurenic acid (KYNA) and anthranilic acid (AA) were assessed by HPLC from CSF samples of patients hospitalized in the Giselda Trigueiro Hospital in Natal (Rio Grande do Norte, Brazil). The KYN/TRP ratio was used as an index of indoleamine 2,3-dioxygenase (IDO) activity, and cytokines were measured using a multiplex cytokine assay. The KYNA level was also analyzed in relation to AADAT + 401C/T genotypes.ResultsIn CSF from patients with BM, elevated levels of KYN, KYNA, AA, IDO activity and cytokines were observed. The cytokines INF-γ and IL-1Ra showed a positive correlation with IDO activity, and TNF-α and IL-10 were positively correlated with KYN and KYNA, respectively. Furthermore, the highest levels of KYNA were associated with the AADAT + 401 C/T variant allele.ConclusionThis study suggests a downward modulatory effect of the KP on CSF inflammation during BM.
Highlights
Despite the advances in antimicrobial and intensive care therapies against bacterial meningitis (BM), high mortality and morbidity rates have been observed [1]
We identified the association of the SNP AADAT + 401C/T with the host immune response to Bacterial meningitis (BM), and our results suggested that this SNP may affect the host’s ability to recruit leukocytes to the infection site [20]
BM was diagnosed in 13 patients, and the causative pathogens were Streptococcus pneumoniae (n = 7), Neisseria meningitidis (n = 1) and Proteus mirabilis (n = 1); for 4 patients, the bacterial species could not be identified
Summary
Despite the advances in antimicrobial and intensive care therapies against bacterial meningitis (BM), high mortality and morbidity rates have been observed [1]. Neurological sequelae, such as motor abnormalities, seizures, learning and memory impairment and mental retardation, are frequently reported after the disease. Bacterial invasion and proliferation within the cerebrospinal fluid (CSF) induce an intense inflammatory response that leads to the activation of several metabolic pathways. One such pathway is the kynurenine (KYN) pathway (KP), which has been shown to be activated in experimental pneumococcal meningitis [5,6]. The aim of this study was to investigate the involvement of the KP during BM in humans by assessing the concentrations of KYN metabolites in the cerebrospinal fluid (CSF) of BM patients and their relationship with the inflammatory response compared to aseptic meningitis (AM) and non-meningitis (NM) groups
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