Discovery of Toll-like Receptor 4 as the Lipopolysaccharide Receptor

The identification of Toll-like receptor 4 as the receptor for bacterial lipopolysaccharide was the result of a positional cloning effort that Bruce Beutler and colleagues, including Alexander Poltorak, began in 1993 and carried on for five years. A single receptor for lipopolysaccharide, a component of the outer membrane of Gram-negative bacteria, had been presumed since the 1960s because mutations at one locus on mouse chromosome 4 abolished the response, yet it had eluded researchers. By analysing more than 2,000 meioses the team narrowed the locus to roughly 5.8 million base pairs, sequenced the interval and found damaging mutations in the Tlr4 gene in two lipopolysaccharide-resistant mouse strains. This showed that a mammalian Toll-like receptor forms the membrane-spanning part of the lipopolysaccharide receptor complex. The finding, reported in 1998, led to the wider recognition that Toll-like receptors sense microbes, and it was honoured in the 2011 Nobel Prize in Physiology or Medicine, shared by Beutler and Jules Hoffmann with Ralph Steinman.