Bruce Beutler
The Scripps Res. Inst., La Jolla, CA
In 1998, we ascribed the endotoxin-unresponsive state of C3H/HeJ and C57BL/10ScCr mice to mutations at the Toll-like receptor 4 locus (Tlr4). Previously an orphan receptor with homology to the Drosophila Toll protein, TLR4 emerged as the signaling component of the mammalian endotoxin receptor. Subsequent cloning work carried out in our laboratory and elsewhere has led to the recognition of a human TLR family with 10 members in all. The knockout of TLRs 2 and 9 revealed that they act to transduce signals from bacterial lipopeptides and bacterial DNA, respectively. It is currently believed that the TLRs stand at the interface between host and pathogen and act as direct sensors of microbial infection. They are members of an ancient family of proteins that fulfill a defensive function not only in animals of most genera, but in many plants as well. From this conceptual vantage point, the TLR field has moved in several directions. First, the specificity of several of the receptors remains unknown. Second, there has been strong interest in understanding molecular details of the signaling pathway utilized by each of the TLRs and by the TLR-homologous IL-1 and IL-18 receptors. And third, the effect of mutations on TLR function in human populations has been investigated in the hope of determining whether inter-individual differences in susceptibility to infection may be ascribed to structural variation at these loci. A strong correlation between TLR2 and TLR4 mutations and susceptibility to meningococcal infection has been established by sequencing the coding region of these loci in DNA samples obtained from hundreds of patients and ethnically matched controls. Insofar as a considerable fraction of susceptibility and resistance to meningococcal infection may be explained by mutations at only 2 TLR loci, the mutations at the full complement of TLR loci (and mutations affecting accessory signaling proteins) may account for much of the variation in human infectious disease susceptibility. Contact Author about this Abstract
