Abstract
BackgroundBacterial meningitis (BM) is an infectious disease that results in high mortality and morbidity. Despite efficacious antibiotic therapy, neurological sequelae are often observed in patients after disease. Currently, the main challenge in BM treatment is to develop adjuvant therapies that reduce the occurrence of sequelae. In recent papers published by our group, we described the associations between the single nucleotide polymorphisms (SNPs) AADAT +401C > T, APEX1 Asn148Glu, OGG1 Ser326Cys and PARP1 Val762Ala and BM. In this study, we analyzed the associations between the SNPs TNF -308G > A, TNF -857C > T, IL-8 -251A > T and BM and investigated gene-gene interactions, including the SNPs that we published previously.MethodsThe study was conducted with 54 BM patients and 110 healthy volunteers (as the control group). The genotypes were investigated via primer-introduced restriction analysis-polymerase chain reaction (PIRA-PCR) or polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP) analysis. Allelic and genotypic frequencies were also associated with cytokine and chemokine levels, as measured with the x-MAP method, and cell counts. We analyzed gene-gene interactions among SNPs using the generalized multifactor dimensionality reduction (GMDR) method.ResultsWe did not find significant association between the SNPs TNF -857C > T and IL-8 -251A > T and the disease. However, a higher frequency of the variant allele TNF -308A was observed in the control group, associated with changes in cytokine levels compared to individuals with wild type genotypes, suggesting a possible protective role. In addition, combined inter-gene interaction analysis indicated a significant association between certain genotypes and BM, mainly involving the alleles APEX1 148Glu, IL8 -251 T and AADAT +401 T. These genotypic combinations were shown to affect cyto/chemokine levels and cell counts in CSF samples from BM patients.ConclusionsIn conclusion, this study revealed a significant association between genetic variability and altered inflammatory responses, involving important pathways that are activated during BM. This knowledge may be useful for a better understanding of BM pathogenesis and the development of new therapeutic approaches.Electronic supplementary materialThe online version of this article (doi:10.1186/s12881-015-0218-6) contains supplementary material, which is available to authorized users.
Highlights
Bacterial meningitis (BM) is an infectious disease that results in high mortality and morbidity
We described the associations between BM and the single nucleotide polymorphisms (SNPs) Aminoadipate aminotransferase (AADAT) +401C > T [12], APEX1 Asn148Glu, 8-oxoguanine DNA glycosylase-1 (OGG1) Ser326Cys and PARP1 Val762Ala [13]
Of a total of 163 individuals genotyped for the SNP TNF -308G > A, 70 % were homozygous for the wild type allele, 26 % were heterozygous, and 4 % were homozygous for the variant allele
Summary
Bacterial meningitis (BM) is an infectious disease that results in high mortality and morbidity. Several bacterial species that are pathogenic to humans have the potential to cause meningitis, but a relatively small number of pathogens, as Haemophilus influenzae type b [Hib], Streptococcus pneumoniae and Neisseria meningitides, are responsible for the majority of acute BM cases [5, 6] These primary pathogens utilize distinct but overlapping sets of Toll-like receptors (TLRs) to trigger the inflammatory response, inducing NF-κB activation in a MyD88-dependent pathway [7,8,9]. Corroborating these data, in a recent study published by our group, we observed a similar profile of cytokine expression during pneumococcal and meningococcal meningitis [10]. Tumor necrosis factor (TNF-α), IL-1β and IL-6 are the major early response cytokines that trigger a cascade of inflammatory mediators, including other cytokines, chemotactic cytokines (chemokines) such as CXCL8/ IL-8, MIP-1α/CCL3, MIP-1β/CCL4, MCP-1/CCL2, prostaglandins, matrix metalloproteinases (MMPs), reactive oxygen species (ROS) and reactive nitrogen intermediates (RNI) [2, 9, 11]
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