The kynurenine pathway is involved in bacterial meningitis
Background:
Bacterial 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.
Methods:
The 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.
Results:
In 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.
Conclusion:
This study suggests a downward modulatory effect of the KP on CSF inflammation during BM.
Insights
The kynurenine pathway (KP) is activated in bacterial meningitis (BM), with elevated metabolites and cytokines in cerebrospinal fluid (CSF). This suggests the KP may modulate inflammation in BM.
Area of Science:
- Neuroscience
- Immunology
- Biochemistry
Background:
- Bacterial meningitis (BM) involves intense inflammation contributing to brain damage.
- The kynurenine pathway (KP), implicated in neurological diseases, was previously studied in BM animal models.
- Genetic variations in kynurenine aminotransferase II (KAT II) have been linked to BM immune responses.
Purpose of the Study:
- To investigate the KP's role in human BM by analyzing cerebrospinal fluid (CSF) metabolite concentrations.
- To correlate KP metabolite levels with inflammatory markers in BM patients.
- To compare these findings with aseptic meningitis (AM) and non-meningitis (NM) groups.
Main Methods:
- HPLC analysis of tryptophan (TRP), kynurenine (KYN), kynurenic acid (KYNA), and anthranilic acid (AA) in CSF samples.
- Calculation of the KYN/TRP ratio as an index of indoleamine 2,3-dioxygenase (IDO) activity.
- Cytokine measurement using multiplex assays and analysis of KYNA levels in relation to AADAT+401C/T genotypes.
Main Results:
- Elevated KYN, KYNA, AA, IDO activity, and cytokine levels were observed in BM patients' CSF.
- Specific correlations were found between cytokines (INF-γ, IL-1Ra, TNF-α, IL-10) and KP metabolites/activity.
- Higher KYNA levels were associated with the AADAT+401 C/T variant allele.
Conclusions:
- The KP appears to be activated in human bacterial meningitis.
- KP metabolites and activity correlate with inflammatory markers in BM.
- The KP may exert a downward modulatory effect on CSF inflammation during BM.
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