Abstract
BackgroundThe kynurenine (KYN) pathway has been shown to be altered in several diseases which compromise the central nervous system (CNS) including infectious diseases such as bacterial meningitis (BM). The aim of this study was to assess single nucleotide polymorphisms (SNPs) in four genes of KYN pathway in patients with meningitis and their correlation with markers of immune response in BM.MethodsOne hundred and one individuals were enrolled in this study to investigate SNPs in the following genes: indoleamine-2,3-dioxygenase (IDO1 gene), kynureninase (KYNU gene), kynurenine aminotransferase I (CCBL1 gene), and kynurenine aminotransferase II (AADAT gene). SNP analyses were performed by primer-introduced restriction analysis-PCR (PIRA-PCR) followed by RFLP. Cytokines were measured using multiplex bead assay while immunoglobulins (IG) by immunodiffusion plates and NF-kappaB and c-Jun by dot blot assay.ResultsThe variant allele of SNP AADAT+401C/T showed prevalent frequency in patients with BM. A significant decrease (p < 0.05) in TNF-α, IL-1β, IL-6, MIP-1αCCL3 and MIP-1β/CCL4 levels was observed in BM patients homozygous (TT) to the SNP AADAT+401C/T. Furthermore, a significant (p < 0.05) decrease in cell count was observed in cerebrospinal fluid (CSF) from patients with TT genotype. In addition, an increase in the IgG level in adults (p < 0.05) was observed. The variant allele for KYNU+715G/A was found with low frequency in the groups, and the SNPs in IDO1+434T/G, KYNU+693G/A, CCBL1+164T/C, and AADAT+650C/T had no frequency in this population.ConclusionsThis study is the first report of an association of SNP AADAT+401C/T with the host immune response to BM, suggesting that this SNP may affect the host ability in recruitment of leukocytes to the infection site. This finding may contribute to identifying potential targets for pharmacological intervention as adjuvant therapy for BM.
Highlights
The kynurenine (KYN) pathway has been shown to be altered in several diseases which compromise the central nervous system (CNS) including infectious diseases such as bacterial meningitis (BM)
KYN is converted to 3hydroxykynurenine (3-HK) by kynurenine-3-hydroxylase (KMO). Both KYN and 3-HK can be oxidized by kynureninase (KYNU) to anthranilic acid (AA) or 3-hydroxyantrhanilic acid (3-HAA), respectively; or they can be transaminated by kynurenine aminotransferase (KAT) to kynurenic acid (KYNA) or xanthurenic acid (XA), respectively
The results obtained for the single nucleotide polymorphisms (SNPs) AADAT+401C/T showed that among the 101 analyzed individuals the allelic frequencies were 0.59 and 0.40 for the alleles C and T respectively
Summary
The kynurenine (KYN) pathway has been shown to be altered in several diseases which compromise the central nervous system (CNS) including infectious diseases such as bacterial meningitis (BM). Bacterial meningitis (BM) is a severe infectious disease of the central nervous system (CNS) associated with acute inflammation that contributes to the development of subsequent brain damage. Bacterial infections and lipopolysaccharide (LPS) application are strong inducers of indoleamine-2,3-dioxygenase (IDO), the enzyme responsible for converting tryptophan to kynurenine (KYN) in the brain [3,4]. KYN is converted to 3hydroxykynurenine (3-HK) by kynurenine-3-hydroxylase (KMO). Both KYN and 3-HK can be oxidized by kynureninase (KYNU) to anthranilic acid (AA) or 3-hydroxyantrhanilic acid (3-HAA), respectively; or they can be transaminated by kynurenine aminotransferase (KAT) to kynurenic acid (KYNA) or xanthurenic acid (XA), respectively. 3-HAA can be oxidized to quinolinic acid (QUINA) by 3-hydroxyanthranilic acid oxidase (3-HAO) [3,4]
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