Single Nucleotide Polymorphisms in Tlr9 Genes Are Highly Associated with Susceptibility to Bacterial Meningitis in Children

Background: Bacterial meningitis (BM) is a severe infection mainly caused by Streptococcus pneumoniae and Neisseria meningitidis (NM). However, genetically determined susceptibility to develop severe infections by these microorganisms is variable between individuals. Toll-like receptor 9 (TLR9) recognizes bacterial DNA leading to intracellular inflammatory signaling. Single nucleotide polymorphisms (SNPs) within the TLR9 gene are associated with susceptibility to several diseases, but no association with meningitis has been described up to now. Methods: We studied the role of TLR9 SNPs in host defense against BM. Two TLR9 SNPs and four TLR9 haplotypes were determined in 472 survivors of BM and compared to 392 healthy controls. Results: Carriage of the TLR9+2848-A mutant was significantly decreased in meningococcal meningitis (MM) patients compared to controls (p: 0.0098, OR: 0.6, 95% CI: 0.4 – 0.9). TLR9 haplotype I was associated with an increased susceptibility to MM (p: 0.0237, OR 1.3, 95% CI: 1.0 – 1.5). In silico analysis shows a very strong immunoinhibitory potential for DNA of NM upon recognition by TLR9 (CpG index of -106.8). Conclusions: This is the first reported association of TLR9 SNPs with susceptibility to BM, specifically MM, indicating a protective effect for the TLR9+2848-A allele. We hypothesize that the TLR9+2848-A mutant results in an upregulation of TLR9 induced immune response compensating the strong inhibitory potential of NM CpG DNA. TLR9 POLYMORPHISMS AND SUSCEPTIBILITY TO BM