INTERACTION OF ORAL SPIROCHETES WITH GINGIVAL EPITHELIUM

口腔螺旋体与牙龈上皮的相互作用

• 批准号: 6776056
• 负责人: Sheila A. Lukehart
• 金额: $ 24.09万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-01 至 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6776056
• 关键词: Treponema; bacteria infection mechanism; bacterial proteins; bactericidal immunity; cell migration; cytokine; defensins; endopeptidases; epithelium; gene expression; gingiva; human tissue; immune response; immunogenetics; oral bacteria; oral mucosa; protein binding; tissue /cell culture

DESCRIPTION (provided by applicant): Oral spirochetes, including Treponema denticola, comprise about 40 percent of the bacteria in periodontal pockets and are linked to the progression and severity of periodontal disease. Despite their obvious relevance to periodontal disease, they are vastly understudied. Oral spirochetes are usually found in close association with the gingival epithelium, but our understanding of how T. denticola and other oral spirochetes establish themselves at this interface is limited. T. denticola and other oral spirochetes likely have evolved strategies to avoid host immune defenses, specifically the defenses initiated by the epithelial cell. The proposed studies will focus on the interactions of spirochetes with gingival epithelial cells and the modulation of molecules produced by these cells in response to bacterial challenge. Our studies to date demonstrate that T. denticola is resistant to a-defensins, and the susceptibility of other oral treponemes to beta-defensins will be examined (Aim 1). To define the mechanisms used by T. denticola to resist beta-defensins killing, we will explore strategies used by other bacteria to resist antimicrobial peptides, including bacterial proteases, binding of defensin to cell surfaces, and efflux pumps (Aim 2). The ability of T. denticola and other oral treponemes to induce production of beta-defensins will be examined in Aim 3. Our preliminary data suggest that T. denticola inhibits the induction of inflammatory cytokines by other bacterial products, similar to the "chemokine paralysis" that has been described for Porphyromonas gingivalis LPS. We will examine the modulation of cytokines and adhesion molecules from epithelial cells stimulated by T. denticola (Aim 4), with the goal of identifying the signaling pathways that are affected by the spirochetes. Lastly, we will determine the components of T. denticola (Aim 5) that induce production of a-defensins and antagonize the induction of inflammatory cytokines. This study will further our understanding of the pathogenesis of periodontal disease by providing a more complete understanding of how T. denticola and other oral spirochetes evade the innate immune response.

描述（由申请人提供）：口腔螺旋体，包括齿垢密螺旋体，约占牙周袋细菌的 40%，与牙周病的进展和严重程度有关。尽管它们与牙周病有明显的相关性，但人们对它们的研究还远远不够。口腔螺旋体通常与牙龈上皮密切相关，但我们对牙菌和其他口腔螺旋体如何在该界面上建立的了解有限。 T. denticola 和其他口腔螺旋体可能已经进化出避免宿主免疫防御的策略，特别是由上皮细胞发起的防御。拟议的研究将重点关注螺旋体与牙龈上皮细胞的相互作用以及这些细胞响应细菌挑战产生的分子的调节。我们迄今为止的研究表明，齿垢密螺旋体对α-防御素具有抗性，并且将检查其他口腔密螺旋体对β-防御素的敏感性（目标1）。为了确定 T. denticola 抵抗 β-防御素杀伤的机制，我们将探索其他细菌抵抗抗菌肽的策略，包括细菌蛋白酶、防御素与细胞表面的结合和外排泵（目标 2）。目标 3 将检查 T. denticola 和其他口腔密螺旋体诱导产生 β-防御素的能力。我们的初步数据表明 T. denticola 抑制其他细菌产物诱导炎症细胞因子，类似于“趋化因子麻痹”牙龈卟啉单胞菌 LPS 已对此进行了描述。我们将检查 T. denticola 刺激的上皮细胞对细胞因子和粘附分子的调节（目标 4），目的是确定受螺旋体影响的信号传导途径。最后，我们将确定 T. denticola 中诱导α-防御素产生并拮抗炎症细胞因子诱导的成分（目标 5）。这项研究将通过更全面地了解牙周炎和其他口腔螺旋体如何逃避先天免疫反应，进一步加深我们对牙周病发病机制的理解。