Toll-Like Receptor-1 (TLR1), TLR2 and TLR6 Gene Polymorphisms are Associated with Increased Susceptibility to Complicated Skin and Skin Structure Infections

Abstract

Background. Complicated skin and skin structure infections (cSSSIs) are characterized by infections with either Gram-positive and Gram-negative aerobic or anaerobic bacteria, as well as a polymicrobial etiology. These invading microorganisms are recognized by pattern recognition receptors (PRRs) of the innate immune system. This study assessed whether genetic variation in genes encoding PRRs influences the susceptibility to cSSSIs.Methods. 318 cSSSI patients and 328 healthy controls were genotyped for 9 non-synonymous single nucleotide polymorphisms (SNPs) in PRR genes coding for Toll-like receptors (TLR)1/2/4/6, NOD-like receptor 2 and signaling adaptor TIRAP. PBMCs obtained from 74 SNP-genotyped healthy individuals were stimulated with Staphylococcus aureus. IL-6 cytokine concentrations were determined in supernatants by ELISA.Results. Polymorphisms in TLR1 (S248N and R80T), TLR2 (P631H) and TLR6 (P249S) increased susceptibility to cSSSIs. Furthermore, PBMCs from individuals bearing the TLR1 248N or 80T allele showed lower IL-6 secretion upon stimulation with S. aureus. No association with susceptibility to cSSSIs was observed for polymorphisms TLR2 (R753Q), TLR4 (D299G and T399I), NOD2 (P268S) and TIRAP (S180 L).Conclusions. Polymorphisms in TLR1, TLR2 and TLR6 are associated with increased susceptibility to cSSSIs. For TLR1, impaired proinflammatory cytokine production due to the polymorphism is most likely the mechanism mediating this effect.