“The Toll-like receptors (TLRs) are the principal source of host awareness of infection.”

The Toll-like receptors (TLRs) are the principal source of host awareness of infection. They sense lipopolysaccharides (LPS), double-stranded RNA, unmethylated DNA, bacterial lipopeptides, glucans, and other molecules of microbial origin. Their discovery as such has been one of the key advances in immunology during the last decade. Our paper reviews the discovery itself, tells what has been learned of TLR signaling through forward and reverse genetic methods, and offers insight into the practical developments that may flow from our new understanding.

The TLRs are highly cross-disciplinary in their importance, and this likely explains the popularity of the review. Because they are fundamentally innate immune sensors, the TLRs fill a large gap in the picture of how innate immune cells recognize infection. The TLRs are ultimately responsible for most things that befall the host when an infection is present, including the sepsis syndrome, shock, and sometimes death. The innate immune system serves an adjuvant effect in activating the adaptive immune system, and the TLRs also, in part, explain adjuvanticity.

Yes. The prospect for blocking TLR signaling for the treatment of the symptoms of infection or inflammatory disease, and the possibility that autoimmune diseases may involve endogenous ligands for the TLR, are being actively considered as therapeutic approaches.

We have described how the host immune system "knows" that an infection is present, and the biochemical pathways that are activated by this awareness.

Both Bruce Beutler and Richard J. Ulevitch are longstanding endotoxin (lipopolysaccharide; LPS) researchers, and LPS has been taken as a model inducer of innate immune responses for more than a century. Richard J. Ulevitch discovered that CD14 was a biologically relevant LPS receptor on mammalian cells. Bruce Beutler discovered the function of TLR4 as the transmembrane component of the LPS receptor. This led directly to the discovery that the TLRs sense discrete molecules of microbial origin and initiate the innate immune response.