Thuong, N. T. et al. A polymorphism in human TLR2 is associated with increased susceptibility to tuberculous meningitis. Genes Immun. 8, 422-428

University of Oxford, Oxford, England, United Kingdom
Genes and Immunity (Impact Factor: 2.91). 08/2007; 8(5):422-8. DOI: 10.1038/sj.gene.6364405
Source: PubMed


Tuberculous meningitis (TBM) results from the haematogenous dissemination of Mycobacterium tuberculosis from the lung to the brain. Dissemination is believed to occur early during infection, before the development of adaptive immunity. Toll-like receptor 2 (TLR2) mediates recognition of M. tuberculosis and initiates the innate immune response to infection. We hypothesized that polymorphisms in the TLR2 gene influence bacterial dissemination and the development of TBM. A case-control study was designed to test the hypothesis. Cases of bacteriologically confirmed pulmonary tuberculosis (TB) (n=183) and TBM (n=175), and cord blood controls (n=389) were enrolled in Vietnam. TLR2 genotype 597CC was associated with susceptibility to TB (odds ratio (OR)=2.22, 95% confidence interval (CI): 1.23-3.99). The association was found with meningeal rather than pulmonary TB (TBM vs control, OR=3.26, 95% CI: 1.72-6.18), and was strongest when miliary TB was found on chest radiography (controls vs TBM with miliary TB, OR=5.28, 95% CI: 2.20-12.65). Furthermore, the association increased with the severity of neurologic symptoms (grade I TBM, OR=1.93, 95% CI: 0.54-6.92; grade II, OR=3.32, 95% CI: 0.84-13.2; and grade III, OR=5.70, 95% CI: 1.81-18.0). These results demonstrate a strong association of TLR2 SNP T597C with the development of TBM and miliary TB and indicate that TLR2 influences the dissemination of M. tuberculosis.

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Available from: Nguyen Trong Hieu, May 28, 2014
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    • "Single nucleotide polymorphisms (SNPs) in immune response genes may be associated with susceptibility to diseases [7] [8]. SNPs in immune response genes may also influence susceptibility to infection or result in variation of individual response to pathogenic agents [9]. "
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    • "For example, individuals with TLR2 Arg753Gln single nucleotide polymorphisms (SNPs) are found to be more susceptible to TB compared to healthy controls of a Turkish cohort [53]. Several other SNPs such as TLR2 Arg677Trp, TLR2 597CC, and TLR2 T597C also show an association with susceptibility to TB in different cohorts [54–56] indicating that the TLR2 polymorphisms influence the susceptibility to Mtb infection. "
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    ABSTRACT: Tuberculosis, an infectious disease caused by Mycobacterium tuberculosis (Mtb), remains a major cause of human death worldwide. Innate immunity provides host defense against Mtb. Phagocytosis, characterized by recognition of Mtb by macrophages and dendritic cells (DCs), is the first step of the innate immune defense mechanism. The recognition of Mtb is mediated by pattern recognition receptors (PRRs), expressed on innate immune cells, including toll-like receptors (TLRs), complement receptors, nucleotide oligomerization domain like receptors, dendritic cell-specific intercellular adhesion molecule grabbing nonintegrin (DC-SIGN), mannose receptors, CD14 receptors, scavenger receptors, and FCγ receptors. Interaction of mycobacterial ligands with PRRs leads macrophages and DCs to secrete selected cytokines, which in turn induce interferon-γ- (IFNγ-) dominated immunity. IFNγ and other cytokines like tumor necrosis factor-α (TNFα) regulate mycobacterial growth, granuloma formation, and initiation of the adaptive immune response to Mtb and finally provide protection to the host. However, Mtb can evade destruction by antimicrobial defense mechanisms of the innate immune system as some components of the system may promote survival of the bacteria in these cells and facilitate pathogenesis. Thus, although innate immunity components generally play a protective role against Mtb, they may also facilitate Mtb survival. The involvement of selected PRRs and cytokines on these seemingly contradictory roles is discussed.
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    • "Several studies have explored the association between PTB susceptibility and SNPs of TLR2 gene, among which G2258A and T597C were the two most widely discussed SNPs. Lorenz et al. [15] found that the mutation of G2258A could decrease the response of macrophages to bacterial peptides, while Thuong et al. [16] reported that T597C might result in an attenuated early innate immune response to infection with M. tuberculosis. "
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    ABSTRACT: Publications regarding the associations of toll-like receptor 2 (TLR2) G2258A and T597C polymorphisms with pulmonary tuberculosis (PTB) susceptibility are inconsistent. A meta-analysis was conducted to investigate the relationship between TLR2 G2258A and T597C polymorphisms with PTB susceptibility. A systematic search was performed for published studies on the relationship between TLR2 polymorphisms and PTB susceptibility. Information was gathered from each eligible study, and statistically analyzed. 6 eligible studies, totaling 1301 cases and 1217 controls on G2258A genotypes, and 8 studies, totaling 2175 cases and 2069 controls on T597C genotypes, were included in the analysis. TLR2 2258G allele and 2258GG genotype were found to be associated with decreased PTB susceptibility (A vs. G: OR = 3.02, 95% CI: 2.22-4.12, P<0.001, GA+AA vs. GG: OR = 2.69, 95% CI = 1.49-4.87, P = 0.001). In the subgroup analyses, the 2258G allele and 2258GG genotype also exhibited a protective effect of PTB risk in Asians (A vs. G: OR = 2.95, 95% CI: 1.91-4.55, P<0.001; GA+AA vs. GG: OR = 3.59, 95% CI: 2.23-5.78, P<0.001), while no associations were observed in Caucasians. No significant associations between T597C polymorphism and PTB were found in the allele model (C vs. T: OR = 0.95, 95% CI: 0.86-1.04, P = 0.28), co-dominant model (CC vs. TT: OR = 0.88, 95% CI = 0.92-1.40, P = 0.25; CT vs. TT: OR = 0.92, 95% CI = 0.80-1.06, P = 0.28), recessive model (CC vs. TT+TC: OR = 0.96, 95% CI: 0.80-1.16, P = 0.69), or dominant model (TC+CC vs. TT: OR = 0.93, 95% CI = 0.76-1.15, P = 0.51). The associations of T597C polymorphism with PTB susceptibility, in the ethnic-specific analyses, were still not significant. TLR2 2258G allele may provide protective effects against PTB susceptibility, particularly among Asians, whereas TLR2 T597C polymorphism might not be associated with PTB susceptibility.
    Preview · Article · Oct 2013 · PLoS ONE
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