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Single nucleotide polymorphisms in TLR9 are highly associated with susceptibility to bacterial meningitis in children

Marieke S Sanders1, Gijs Th J van Well, Sander Ouburg

  • 1Department of Pathology, Laboratory for Immunogenetics, VU University Medical Center, Amsterdam, The Netherlands.

Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America
|January 25, 2011
PubMed
Abstract

Insights

Genetic variations in Toll-like receptor 9 (TLR9) single nucleotide polymorphisms (SNPs) are linked to bacterial meningitis (BM) susceptibility. The TLR9+2848-A allele shows a protective effect against meningococcal meningitis (MM).

Area of Science:

  • Immunology
  • Genetics
  • Infectious Diseases

Background:

  • Bacterial meningitis (BM) is a severe infection with variable genetic susceptibility.
  • Toll-like receptor 9 (TLR9) recognizes bacterial DNA, initiating inflammatory signaling.
  • Single nucleotide polymorphisms (SNPs) in TLR9 are linked to various diseases, but not previously to meningitis.

Purpose of the Study:

  • To investigate the association between TLR9 SNPs and host defense against bacterial meningitis.
  • To determine the role of specific TLR9 SNPs and haplotypes in susceptibility to meningococcal meningitis (MM).

Main Methods:

  • Genotyping of two TLR9 SNPs and four TLR9 haplotypes in 472 BM survivors and 392 healthy controls.
  • Statistical analysis including odds ratio (OR) and confidence interval (CI) calculation.
  • In silico analysis of Neisseria meningitidis (NM) DNA's immunoinhibitory potential upon TLR9 recognition.

Main Results:

  • The TLR9+2848-A mutant allele was significantly less frequent in MM patients (OR: 0.6, CI: 0.4-0.9).
  • TLR9 haplotype I was associated with increased MM susceptibility (OR: 1.3, CI: 1.0-1.5).
  • In silico analysis revealed a strong immunoinhibitory effect of NM CpG DNA on TLR9 signaling (CpG index: -106.8).

Conclusions:

  • TLR9 SNPs are associated with susceptibility to bacterial meningitis, particularly MM.
  • The TLR9+2848-A allele demonstrates a protective effect against MM.
  • This protective effect may stem from an up-regulated TLR9 immune response to NM CpG DNA.

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