| The innate immune system responds to a wide variety of pathogen associated molecules. Toll-like Receptors (TLRs) have been demonstrated to mediate many of these responses. Of the 10 TLRs encoded in the human genome, the specificities of only 4 have been described; the identification of the specificities of the remaining TLRs is an essential step for the understanding of TLRs in innate immunity. The experiments described in this dissertation demonstrate that TLR5 mediates the cellular response to bacterial flagellin, an essential subunit of the bacterial flagella. This is the first demonstration of TL5's ability to recognize a pathogen component. TLR5 is able to mediate the recognition of bacterial flagellin through interactions with the N- and C-terminal regions of flagellin; recognition results in activation of the Rel-family transcription factor NF-κB, leading to the expression of TNF and IL-6. Flagellin has been shown to be a potent stimulator of inflammatory responses, and the expression of flagellin is modulated by pathogens during the course of an infection, presumably to avoid the development of an effective immune response. These results indicate that TLR5 is an important pathogen recognition receptor in mammalian immunity against flagellated bacteria. |
