Positional cloning of Lps, and the general role of toll-like receptors in the innate immune response

In mice (and by inference, in all mammals), a single pathway exists to serv e lipopolysaccharide (LPS) signal transduction, and as such, allelic mutati ons at a single locus entirely abolish responses to LPS in C3H/HeJ and C57B L/10ScCr mice, Positional cloning of this locus, known as Lps, revealed tha t mutations of the Toll-like receptor 4 gene (Tlr4) are responsible for end otoxin resistance, A quick succession of studies have shown Tlr4 to be the critical transmembrane component of the LPS signal transduction complex. As LPS sensing by Tlr4 depends on physical contact between the two molecules, Tlr4 is a direct interface with the microbial world. Eight other molecules with strong similarily to Tlr4 are presently known in mammals, and taking Tlr4 as a model, all may be guessed to participate in the early detection o f invasive pathogens. Acting together, the Toll-like receptors may be assum ed to present macrophages with a comprehensive "picture" of the micobial wo rld, and thus comprise the principal sensing molecules utilized by cells of the innate immune system.