Single Nucleotide Polymorphisms in Pathogen Recognition Receptor Genes Are Associated with Susceptibility to Meningococcal Meningitis in a Pediatric Cohort

Abstract

Bacterial meningitis (BM) is a serious infection of the central nervous system, frequently occurring in childhood and often resulting in hearing loss, learning disabilities, and encephalopathy. Previous studies showed that genetic variation in innate immune response genes affects susceptibility, severity, and outcome of BM. The aim of this study is to describe whether single nucleotide polymorphisms (SNPs) in pathogen recognition gene products are associated with susceptibility to develop BM in single genes analysis as well as SNP combinations. Genotype frequencies of seven SNPs, in five immune response genes encoding for Toll-like receptors (TLRs), nucleotide oligomerization domain (NOD) proteins and caspase-1 (CASP1), in 391 children with meningococcal meningitis (MM) and 82 children with pneumococcal meningitis were compared with a large cohort of 1141 ethnically matched healthy controls. Carriage of TLR4 +896 GG mutant predisposed to susceptibility to develop MM (p = 1.2*10−5, OR = 9.4, 95% CI = 3.0–29.2). The NOD2 SNP8 mutant was significantly more frequent in MM patients compared to controls (p = 0.0004, OR = 12.2, 95% CI = 2.6–57.8). Combined carriage of TLR2 +2477 and TLR4 +896 mutants was strongly associated with MM (p = 4.2*10−5, OR = 8.6, 95% CI = 2.7–27.3). A carrier trait of TLR4 +896 and NOD2 SNP8 mutants was also strongly associated with susceptibility to develop MM (p = 4.2*10−5, OR = 10.6, 95% CI = 2.9–38.6). This study associates SNPs in TLR4 and NOD2 with susceptibility to develop MM.

Is Toxoplasma gondii a Trigger of Bipolar Disorder?

“…Finally, another recent gene-environment interaction study investigated the possible effect of interactions between serologically documented exposure to T. gondii , CMV, HSV-1 or HSV-2 and polymorphisms of TLR2 , TLR4 and NOD2 genes, which encode for pivotal pattern-recognition receptors, in a sample of 138 BD patients [130]. The genetic associations between TLR2 , TLR4 and NOD2 polymorphisms with susceptibility to infections, on the one hand, and BD, on the other, have been previously reported in the literature [131,132,133,134,135,136]. Oliveira et al [130], besides confirming the association between BD and T. gondii , first described a trend for an interaction between a TLR2 polymorphism and T. gondii seropositivity in conferring BD risk, suggesting that exposure to infection may modulate the immunogenetic background on BD.…”

Group B streptococcal meningitis in a previously healthy man

“…Abnormalities in complement pathways have been implicated in susceptibility to bacterial meningitis,7 and genetic polymorphisms in toll-like receptors involved in pathogen recognition have been identified in patients who have suffered from bacterial infections and viral encephalitis 8 9. Greater awareness of the genetic factors that influence an individual's susceptibility to meningitis may facilitate early recognition and treatment of the disease as well as extending vaccination programmes to at-risk groups.…”

Genes and their single nucleotide polymorphism involved in innate immune response in central nervous system in bacterial meningitis: review of literature data

“…[28] TLR2 rs5743708 TLR4 rs4986790 TLR4 rs4986791 CD14 -159CC FcγRIIA-R /R131 TLR4 rs4986790 ProPM p < 0.005 CD14- 159CC SuIPD p  <  0.05 FcγRIIA-R / R131 SuIPD p  <  0.001 remaining SNPs —no association 85 IPD409 BDIPDChildrenAustralia Yuan and al [29] TLR2 TLR4 total nucleotide variation TLR2 rs57437708 more common in patients p = 0.05197 IMD238 HCIMDChildren UK Smirnova et al [32] TLR2 rs5743708 TLR4 rs4986790 NOD1 rs6958571 NOD2 rs57 43293 NOD2 rs2066847 NOD2 rs2066844 CASP1 rs2282659 TLR4 rs4986790 SuMM NOD2 rs2066847 SuMM remaining SNPs —no association391 MM 82 PM1141 HCMMPMChildren Netherlands Van Wel et al [36] TLR4 rs4986790 TLR4 rs4986791no association252 MM251 HCMMChildrenGambiaAllen et al [35] TLR2 rs3804099 TLR3 rs3775291 TLR3 rs3775290 TLR9 rs352139 TLR9 rs352140no association218 MB330 HCBMChildrenChinaZhang et al [38]Bold values indicate significant results BD blood donors, BM bacterial meningitis, HC healthy controls, IPD invasive pneumococcal disease, IMD invasive meningococcal disease, MM meningococcal meningitis, PM pneumoccoccal meningitis, PB pneumoccoccal bacteraemia, SuPM susceptibility to pneumococcal meningitis, SuIPD susceptibility to invasive pneumococcal disease, SuIMD susceptibility to invasive meningococcal disease, SuMM susceptibility to meningococcal meningitis, ProIMD protection against invasive meningococcal disease, ProPM protection against pneumococcal meningitis …”