"Why couldn't I be made of stone......"
A diverse range of microbes, including viruses, bacteria, fungi, and protists, would like to colonize the human body and set up home in the nutrient-rich environment it provides. Fortunately, the immune response functions as a door bouncer, checking the credentials of the hopeful tenants, and turning away the riff-raff and hooligan microbes. But what alerts the body to potential danger? How are foreign organisms detected? The discovery of microbial-sensing proteins called Toll-like receptors is helping to answer these questions and transform our understanding of the response to infection.
What Do Toll-Like Receptors Do?
A small number of Toll-like receptors can detect a broad range of human pathogens, as well as a variety of other molecules that indicate tissue damage, by a process called pattern recognition. These receptors initiate two arms of the immune response — the innate and adaptive responses — that work together to fight infection in mammals. The innate response provides immediate protection. However, it is relatively nonspecific in its mode of attack on pathogens, which results in damage to healthy tissue if the innate immune response lasts too long. The adaptive response, on the other hand, generates antibody-secreting B cells and cytotoxic T cells that are specific and efficient at targeting pathogen. Unfortunately, this process takes longer to develop than the innate response.
Because Toll-like receptors function as first responders to danger signals, they are centrally significant in research efforts to combat infectious and inflammatory disease. New strategies for manipulating immune responses depend on understanding the cell biology of Toll-like receptors, including their structure, cell localization, signal transduction pathways, and expression patterns.
Once Upon a Time: The Possible Story of Viruses - Paige Brown
Pattern Recognition and Toll
Human cells have only about 25,000 protein-encoding genes, so it is impossible to have a different gene (and a different receptor) for each species of virus, bacteria, protist, and fungus. How, then, can the body identify all species of pathogens that pose a danger, even those it has never encountered before? In 1989, Charles Janeway proposed that cells use pattern recognition to detect pathogens (Janeway 1989). In other words, receptors bind to structural shapes or patterns called PAMPs (pathogen-associated molecular patterns) that are present in whole groups of pathogens, but not the host. According to Janeway's theory, receptors cannot identify a particular microbe with precision, but they can recognize it as a foreign organism.
The first human pattern-recognition receptors were identified ten years after Janeway's proposal. The breakthrough was made possible by an earlier discovery in the fruit fly Drosophila. For decades, researchers had used Drosophilato identify developmental mutations, but Drosophilawas not considered a good choice to model human immunity due to the lack of an adaptive response in insects (Beck & Habicht 1996). German scientists originally identified the Toll gene as the site of mutations that generated bizarre-looking flies. (They exclaimed that their results were "Toll!" which transIates to "Great!" in English.) Cloning the gene demonstrated that it encoded a membrane receptor (Hashimoto, Hudson & Anderson 1988).
A 1996 study reported that loss-of-function Toll mutations made Drosophila highly susceptible to fungal infections and that gain-of-function mutations led to increased production of certain antifungal proteins (Lemaitre et al. 1996). Comparisons of Toll mutations to mutations in other genes led to the conclusion that the Toll receptor plays a dominant role in detecting fungal infections and initiating the innate immune response. This exciting discovery provided researchers with the clue they needed to find human pathogen receptors. Using the amino acid sequence of Toll, they searched for related sequences in the Human Genome Project database and identified Toll-like receptors (Medzhitov, Preston-Hurlburt & Janeway 1997; Rock et al. 1998
Extract from Toll-Like Receptors: Sensors that Detect Infection
Citation: Christmas, P. (2010) Toll-Like Receptors: Sensors that Detect Infection. Nature Education 3(9):85
The Hunchback of Notre Dame (1930) - dvdbeaver
The first human pattern-recognition receptors were identified ten years after Janeway's proposal. The breakthrough was made possible by an earlier discovery in the fruit fly Drosophila. For decades, researchers had used Drosophilato identify developmental mutations, but Drosophilawas not considered a good choice to model human immunity due to the lack of an adaptive response in insects (Beck & Habicht 1996). German scientists originally identified the Toll gene as the site of mutations that generated bizarre-looking flies. (They exclaimed that their results were "Toll!" which transIates to "Great!" in English.) Cloning the gene demonstrated that it encoded a membrane receptor (Hashimoto, Hudson & Anderson 1988).
A 1996 study reported that loss-of-function Toll mutations made Drosophila highly susceptible to fungal infections and that gain-of-function mutations led to increased production of certain antifungal proteins (Lemaitre et al. 1996). Comparisons of Toll mutations to mutations in other genes led to the conclusion that the Toll receptor plays a dominant role in detecting fungal infections and initiating the innate immune response. This exciting discovery provided researchers with the clue they needed to find human pathogen receptors. Using the amino acid sequence of Toll, they searched for related sequences in the Human Genome Project database and identified Toll-like receptors (Medzhitov, Preston-Hurlburt & Janeway 1997; Rock et al. 1998
Extract from Toll-Like Receptors: Sensors that Detect Infection
Citation: Christmas, P. (2010) Toll-Like Receptors: Sensors that Detect Infection. Nature Education 3(9):85
The Hunchback of Notre Dame (1930) - dvdbeaver
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