RESUMO
BACKGROUND: Single nucleotide variants in toll-like receptor genes play a crucial role in leprosy susceptibility or resistance. METHODS: With an epidemiology case-control study, associations between SNVs rs5743618 in TLR1, rs5743708 in TLR2, and rs5743810 in TLR6 and overall susceptibility for leprosy were estimated in 114 cases and 456 controls. Following that, stratified analysis was performed. DNA was extracted from peripheral blood. Genotyping was performed using predesigned TaqMan probes. RESULTS: The A/G genotype of rs5743810 behaved as a protective factor for the development of leprosy in the codominant (OR= 0.37; 95% CI = 016-0.86, p = 0.049) and over-dominant (OR = 0.38; 95% CI = 0.16-0.88, p = 0.019) inheritance models. The A/G and A/A genotypes behaved as a protective factor (OR = 0.39; 95% CI = 0.17-0.87, p = 0.016) in the dominant model. The SNVs rs5743618 and rs5743708 showed no association with any of the models. The CGG haplotype (rs5743618-rs5743708-rs5743810) behaved as a susceptibility factor for developing leprosy (OR = 1.86; 95% CI = 1.11-3.10, p = 0.019). The latter haplotype behaved as a susceptibility factor for leprosy development in women (OR = 2.39; 95% CI = 1.21-4.82, p = 0.013). CONCLUSIONS: The identified variants in the genes encoding TLRs, specifically rs5743810 in TLR6 and CGG (rs5743618-rs5743708-rs5743810) haplotypes, may somehow explain leprosy susceptibility in the studied population in a leprosy endemic region in Colombia.
RESUMO
Mycobacterium avium has been reported to signal through both Toll-like receptor (TLR2) and TLR9. To investigate the role of TLR6 in innate immune responses to M. avium, TLR6, MyD88, TLR2, and TLR2/6 KO mice were infected with this pathogen. Bacterial burdens were higher in the lungs and livers of infected TLR6, TLR2, TLR2/6, and MyD88 KO mice compared with those in C57BL/6 mice, which indicates that TLR6 is required for the efficient control of M. avium infection. However, TLR6 KO spleen cells presented with normal M. avium induced IFN-γ responses as measured by ELISA and flow cytometry. In contrast, the production of IFN-γ in lung tissue was diminished in all studied KO mice. Furthermore, only MyD88 deficiency reduced granuloma areas in mouse livers. Moreover, we determined that TLR6 plays an important role in controlling bacterial growth within macrophages and in the production of TNF-α, IL-12, and IL-6 by M. avium infected DCs. Finally, the lack of TLR6 reduced activation of MAPKs and NF-κB in DCs. In summary, TLR6 is required for full resistance to M. avium and for the activation of DCs to produce proinflammatory cytokines.