Elucidation of the immune mechanisms associated with tuberculosis (TB) development may help to control <i>M. tuberculosis</i> spread<i>.</i>OBJECTIVE: To investigate the role of TLR2, TLR4 and TLR9 in hindered in vitro microbicidal activity and increase T<sub>reg</sub> number during LTBI.
Our findings in three independent population samples indicate that variations in TLR2 and TLR9 might play important roles in determining susceptibility to TB.
Multilocus analyses between polymorphisms in SLC11A1 and 11 TB candidate genes detected interactions between SLC11A1 and inducible nitric oxide synthase (NOS2A) in Caucasians (rs3731863 [SLC11A1] x rs8073782 [NOS2A], P = 0.009; rs3731863 [SLC11A1] x rs17722851 [NOS2A], P = 0.007) and toll-like receptor 2 (TLR2) in African-Americans (rs3731865 [SLC11A1] x rs1816702, P = 0.005).
Our findings indicate that TLR2 engagement on CD4(+) T cells increases MTB Ag-specific responses and may contribute to protection against MTB infection.
We also found that individuals with the C allele of TLR-2T597C allele were more likely to have tuberculosis caused by the East-Asian/Beijing genotype (OR = 1.57 [95% C.I.1.15-2.15]) than other individuals.
The R753QTLR2 polymorphism has been associated with increased incidence of tuberculosis and infections with non-tuberculous mycobacteria in human populations, but the mechanisms by which this polymorphism affects TLR2 signaling are unclear.
We have previously found that gene polymorphisms that either inactivate the TLR2 gene product or have a dominant-negative role are associated with tuberculosis (TB) in Croatian population.
There was a significant difference between TLR2 gene Arg753Gln polymorphism and the risk of TB (additive model: P<0.01, OR=2.89, 95% CI: 2.13-3.91; GA vs. GG: P<0.01, OR=2.92, 95% CI: 2.09-4.08).
Using a trend test, we found that expression of Toll-like receptor 2 was greater from absence of infection to latent infection and from latent infection to active tuberculosis.
Protein O-mannosylation deficiency increases LprG-associated lipoarabinomannan release by Mycobacterium tuberculosis and enhances the TLR2-associated inflammatory response.
206 TB patients and 239 healthy controls from Hyderabad, India were analyzed for SNPs in the TLR1 and TLR2 genes, which were subsequently correlated to TB susceptibility.
Examples include variants of TLR4 in sepsis, malaria, inflammatory bowel disease and atherosclerosis; variants in TLR2 in tuberculosis and asthma; a variant in Mal (a key signal for TLR2 and TLR4) in malaria, tuberculosis and systemic lupus erythematosus; and variants in the kinase IRAK4 in pyogenic infections.
Furthermore, the levels of TLR2, TLR4 and IFN-γ mRNA expression were marked increased in the tuberculous PE when compared with the correspondent serum.
TLR2rs5743708 subgroup analysis identified the A allele to increase susceptibility to TB in the Asian ethnic group, while conferring protection in the Hispanic group.
Coinheritance of these polymorphisms with previously identified risk alleles in Toll-like receptor 2 and TIRAP was associated with an additive risk of tuberculosis susceptibility.
Animal studies have shown that TLR2-knockout mice are more susceptible to septicemia due to Staphylococcus aureus and Listeria monocytogenes, meningitis due to Streptococcus pneumoniae, and infection with Mycobacterium tuberculosis, suggesting that functional TLR2 polymorphisms may impair host response to a certain spectrum of microbial pathogens.
Our data suggest that the S/M genotype of the microsatellite (GT)n polymorphisms in intron 2 of the TLR2 gene may increase susceptibility to TB in Chinese, and the S/L genotype may act as a negative risk factor.
Material from M. tuberculosis and P. acne has been repeatedly detected in the sarcoidosis lesions, implying the involvement of the Toll-like receptor2 (TLR2) gene that responds to these intracellular pathogens.
Information on expression of TLR-2, myeloid differentiation factor (MyD88), IL-1R- associated kinase-4 (IRAK4) and nuclear factor kappa B (NF-kB) in HIV+LTBI+ and HIV+ patients with active TB disease is limited.