Pattern Recognition of P. gingivalis Virulence Factors

牙龈卟啉单胞菌毒力因子的模式识别

• 批准号: 6817958
• 负责人: Georgios Hajishengallis
• 金额: $ 20.65万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6817958
• 关键词: Bacteroides gingivalis; CD antigens; CD14 molecule; SDS polyacrylamide gel electrophoresis; bacteria infection mechanism; bacterial proteins; biological signal transduction; cell adhesion molecules; clinical research; flow cytometry; host organism interaction; human subject; ion exchange chromatography; laboratory mouse; molecular shape; periodontitis; pilus; receptor binding; tissue /cell culture; toll like receptor; virulence

DESCRIPTION: Toll-like receptors (TLRs) and other pattern-recognition receptors (PRRs) form functional receptor complexes that recognize pathogen-associated molecular patterns (PAMPs). Activation of the TLR signaling pathway by PAMPs leads to induction of immune and inflammatory responses. Porphyromonas gingivalis is an important pathogen in human periodontitis. A major cell surface component of this oral pathogen is the fimbriae, which function as an adhesin. Strikingly, fimbriae activate transcription factor NF-KappaB and induce production of proinflammatory cytokines through interactions with several PRRs. Understanding the molecular basis of how the host recognizes and responds to P. gingivalis fimbriae is essential for developing molecular approaches to control periodontal inflammation. Therefore, the objective of this grant is to elucidate the proinflammatory interactions of fimbriae with PRRs. The application proposes that fimbriae function as a PAMP and interact in a regulated mode, and through discrete epitopes, with different binding PRRs resulting in the activation of proinflammatory TLR signaling. Fimbrial epitopes involved in cellular binding and/or activation will be identified using fimbrial peptides and mutant fimbriae. Importantly, epitopes involved in binding but not activation may find application as antagonists of fimbria-induced inflammation. Experiments in our laboratory have shown that TLR2 and TLR4 mediate fimbria-induced signaling, but initial recognition of fimbriae is mediated by a cooperation between CD14 and CD11 b/CD18, which thus appear to serve as TLR co-receptors. It is posited that fimbriae initially bind to CD14, and the fimbriae/CD14 complex induces TLR2-mediated "inside-out" signaling that leads to activation of the ligand-binding capacity of CD11b/CD18. PRR-fimbriae interactions will be examined in human monocytes and mouse macrophages derived from normal and PRR-deficient mice. Elucidation of the mechanisms whereby PRRs recognize and respond to fimbriae and identification of fimbrial antagonists may facilitate the design of novel approaches to therapeutic intervention in both periodontitis and atherosclerosis, where P. gingivalis has also been implicated.

描述：Toll样受体（TLR）和其他模式识别受体（PRR）形成功能受体复合物，识别与病原体相关的分子模式（PAMP）。通过PAMPS激活TLR信号通路会导致免疫和炎症反应的诱导。牙龈卟啉单胞菌是人类牙周炎的重要病原体。该口腔病原体的主要细胞表面成分是纤维化，其作用充当粘附蛋白。引人注目的是，Fimbriae激活转录因子NF-kappab，并通过与多个PRR的相互作用诱导促炎细胞因子的产生。了解宿主如何识别和响应牙龈假单胞菌的分子基础对于开发分子方法控制牙周炎症至关重要。因此，该赠款的目的是阐明fimbriae与PRR的促炎相互作用。该应用提出，Fimbriae充当弹药，并在调节模式下进行相互作用，并通过离散的表位，具有不同的结合PRR，导致促炎性TLR信号传导的激活。将使用纤维化肽和突变纤维膜来鉴定参与细胞结合和/或激活的纤维膜表位。重要的是，涉及结合但不活化的表位可能会发现作为膜肌诱导的炎症的拮抗剂的应用。我们实验室中的实验表明，TLR2和TLR4介导了纤维化诱导的信号传导，但是对fimbriae的初始识别是由CD14和CD11 B/CD18之间的合作介导的，因此似乎是TLR共受体。假设Fimbriae最初与CD14结合，而Fimbriae/CD14复合物诱导TLR2介导的“内部 - 外出”信号传导，从而导致CD11b/CD18的配体结合能力激活。将在人的单核细胞和源自正常和PRR缺陷型小鼠的小鼠巨噬细胞中检查PRR纤维膜相互作用。阐明了PRR认识并对膜片做出反应的机制，并鉴定纤维状拮抗剂可能会促进牙周炎和动脉粥样硬化的新方法进行新的治疗方法的设计，那里也涉及牙龈疟原虫。