text: When microbes were first recognized as the cause of infectious diseases, it was immediately clear that multicellular organisms must be capable of recognizing them when infected and, hence, capable of recognizing molecules unique to microbes. A large body of literature, spanning most of the last century, attests to the search for the key molecules and their receptors. More than 100 years ago, Richard Pfeiffer, a student of Robert Koch, coined the term "endotoxin" to describe a substance produced by Gram-negative bacteria that could provoke fever and shock in experimental animals. In the decades that followed, endotoxin was chemically characterized and identified as a lipopolysaccharide (LPS) produced by most Gram-negative bacteria. This lipopolysaccharide is an integral part of the gram-negative membrane and is released upon destruction of the bacterium. Other molecules (bacterial lipopeptides, flagellin, and unmethylated DNA) were shown in turn to provoke host responses that are normally protective. However, these responses can be detrimental if they are excessively prolonged or intense. It followed logically that there must be receptors for such molecules, capable of alerting the host to the presence of infection, but these remained elusive for many years. Toll-like receptors are now counted among the key molecules that alert the immune system to the presence of microbial infections.
  The prototypic member of the family, the toll receptor (; Tl) in the fruit fly Drosophila melanogaster, was discovered in 1985 by 1995 Nobel Laureates Christiane Nüsslein-Volhard and Eric Wieschaus and colleagues. It was known for its developmental function in embryogenesis by establishing the dorsal-ventral axis. It was named after Christiane Nüsslein-Volhards 1985 exclamation, "" ("Thats amazing!"), in reference to the underdeveloped ventral portion of a fruit fly larva. It was cloned by the laboratory of Kathryn Anderson in 1988. In 1996, toll was found by Jules A. Hoffmann and his colleagues to have an essential role in the fly's immunity to fungal infection, which it achieved by activating the synthesis of antimicrobial peptides.
  The first reported human toll-like receptor was described by Nomura and colleagues in 1994, mapped to a chromosome by Taguchi and colleagues in 1996. Because the immune function of toll in Drosophila was not then known, it was assumed that TIL (now known as TLR1) might participate in mammalian development. However, in 1991 (prior to the discovery of TIL) it was observed that a molecule with a clear role in immune function in mammals, the interleukin-1 (IL-1) receptor, also had homology to drosophila toll; the cytoplasmic portions of both molecules were similar.
  In 1997, Charles Janeway and Ruslan Medzhitov showed that a toll-like receptor now known as TLR4 could, when artificially ligated using antibodies, induce the activation of certain genes necessary for initiating an adaptive immune response. TLR 4 function as an LPS sensing receptor was discovered by Bruce A. Beutler and colleagues. These workers used positional cloning to prove that mice that could not respond to LPS had mutations that abolished the function of TLR4. This identified TLR4 as one of the key components of the receptor for LPS.
  In turn, the other TLR genes were ablated in mice by gene targeting, largely in the laboratory of Shizuo Akira and colleagues. Each TLR is now believed to detect a discrete collection of molecules – some of microbial origin, and some products of cell damage – and to signal the presence of infections.
  Plant homologs of toll were discovered by Pamela Ronald in 1995 (rice XA21) and Thomas Boller in 2000 (Arabidopsis FLS2).
  In 2011, Beutler and Hoffmann were awarded the Nobel Prize in Medicine or Physiology for their work. Hoffmann and Akira received the Canada Gairdner International Award in 2011.