Human Toll-like Receptor 1 Polymorphisms: Implications for Innate Immune Defense and Vertebrate TLR Evolution

摘要

Toll-like receptors (TLRs) constitute an essential family of pattern recognition molecules that, through direct recognition of conserved microbial components, initiate inflammatory responses after infection. Phylogenetic evidence suggests that vertebrate TLRs are under strong purifying selection for maintenance of function. Our laboratory is focused on a related group of vertebrate TLRs that comprise the TLR2 subfamily. The most closely related members, TLRs 1 and 6, appear to have arisen from a recent gene duplication event and have acquired differential microbial recognition specificity. We have characterized two single nucleotide polymorphisms (SNPs), P315L and I602S, in human TLR1 that effect receptor function through different mechanisms. The 315L variant is associated with deficient recognition of microbial products while the 602S variant is associated with aberrant trafficking of the receptor to the cell surface. Surprisingly, the 602S allele is associated with a decreased incidence of leprosy suggesting that Mycobacterium leprae subverts the TLR system as a mechanism of immune evasion. TLR1 I602S exhibits strikingly different allele frequencies among different races suggesting that if strong purifying selection took place, it was restricted by either additional genetic or environmental factors that were geographically constrained.