LBP/CD14 interactions with bacterial components

描述(逐字摘自申请者摘要)：先天性炎症性宿主 反应机制通常可以防止微生物感染。在临床上 健康的牙周组织，低水平表达选定的炎症介质 被观察到，并被认为提供了炎症监测，保护 这种不断暴露在细菌中的组织。对于牙周炎， 破坏牙根表面周围的组织和骨 这种疾病的特征被认为是由于高水平的表达 大量天然的宿主炎症介质。与开发相关的 成人型牙周炎是最常见的疾病形式，有 牙菌斑生物膜菌群从主要革兰氏菌群的特征转变 对大多数革兰氏阴性细菌呈阳性。临床与疾病的相关性 与这种转变相关的是强大的，然而，还不能理解这些 细菌种群的变化会影响炎症反应。LBP/ CD14/Toll样受体(TLR)系统被证明促进先天宿主 对各种不同细菌的炎症反应。这些关键字 天然宿主防御蛋白对革兰氏阳性菌的两种LTA都有反应 革兰氏阴性菌的内毒素。有证据表明CD14和TLR可能会采取行动 共同调节炎症介质产生的强度 对不同细菌的反应。CD14与多种不同的 微生物配体有效地将它们集中起来，并将它们“呈现”给其他生物 固有的主机防御组件，如TLR。相比之下，不同的TLR 与不同的微生物配基结合，从而激活宿主 细胞反应。然而，CD14识别的分子机制 众多不同的细菌成分和特定的贡献 脂多糖或LTA与CD14或TLR相互作用的结构特征不是 完全理解。我们的总体假设是：先天的宿主防御 系统通过细菌表面的结构特征部分识别细菌 和脂磷壁酸(LTA)，并调节 相应的炎症反应。在这项提案中， 影响CD14和TLR结合和激活的LP和LTA将是 检查过了。我们将确定特定的CD14残基在内毒素和LTA中的作用 结合和转移到TLR-2和TLR-4，并确定其贡献 TLR-2和TLR-4对宿主细胞的激活具有不同的结构定义 微生物配体。这些研究将提供进一步的洞察力，了解 固有的宿主防御系统识别并响应不同的细菌，这是一个关键 口腔健康和口腔疾病的组成部分。

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.