LBP/CD14 interactions with bacterial components

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DESCRIPTION (Verbatim from Applicant's Abstract): Innate host inflammatory response mechanisms normally prevent microbial infection. In the clinically healthy periodontium, low level expression of select inflammatory mediators has been observed and is believed to provide inflammatory surveillance, protecting this tissue which is constantly exposed to bacteria. In periodontitis, the destruction of the tissue and bone surrounding the tooth root surface which is characteristic of this disease is believed to be due to high level expression of numerous innate host inflammatory mediators. Associated with the development of adult type periodontitis, the most common form of the disease, there is a characteristic shift in the dental plaque biofilm flora from mostly gram positive to mostly gram negative bacteria. The clinical correlation to disease associated with this shift is strong, however, it is not understood how these bacterial population changes influence the inflammatory response. The LBP / CD14 / Toll like receptor (TLR) system has been shown to facilitate innate host inflammatory responses to a wide variety of different bacteria. These key innate host defense proteins respond to both LTA from gram positive organisms and LPS from gram negative bacteria. Evidence suggests CD14 and TLR's may act together in regulating the intensity of inflammatory mediator production in response to different bacteria. CD14 interacts with a wide variety of different microbial ligands effectively concentrating them and "presenting" them to other innate host defense components such as TLRs. In contrast different TLRs are engaged with different microbial ligands resulting in activation of host cellular responses. However, the molecular mechanisms by which CD14 recognizes numerous different bacterial components and the contribution of specific structural features of LPS or LTA to CD14 or TLR interactions are not completely understood. Our overall hypothesis is: The innate host defense system recognizes bacteria in part by structural features present on lipopolysaccharide (LPS) and lipoteichoic acid (LTA) and modulates the inflammatory response accordingly. In this proposal, the structural features of LPS and LTA that influence CD14 and TLR binding and activation will be examined. We will determine the role of specific CD14 residues in LPS and LTA binding and transfer to TLR-2 and TLR-4, and determine the contribution of TLR-2 and TLR-4 to host cell activation with different structurally defined microbial ligands. These studies will provide further insight into how the innate host defense system recognizes and responds to different bacteria, a key component of both oral health and disease.