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）：口服螺旋体，包括treponema denticola，占牙周口袋中约40％的细菌，与牙周疾病的进展和严重程度有关。尽管它们与牙周疾病明显相关，但它们仍被大量研究。通常与牙龈上皮密切相关的口腔螺旋体，但是我们对牙霉菌和其他口腔螺旋体如何在该界面上建立自己的理解是有限的。 T.牙本质和其他口腔螺旋体可能具有避免宿主免疫防御的策略，特别是上皮细胞发起的防御能力。提出的研究将重点关注螺旋体与牙龈上皮细胞的相互作用，以及这些细胞对细菌挑战产生的分子的调节。迄今为止，我们的研究表明，将检查牙霉菌对A-防御素具有抗性，并且将检查其他口服treponemes对β-防御素的敏感性（AIM 1）。为了定义牙霉菌用来抵抗β-防御素杀戮的机制，我们将探索其他细菌用来抵抗抗菌肽的策略，包括细菌蛋白酶，结合防御素与细胞表面与细胞表面的结合和外排泵（AIM 2）。将在AIM 3中检查牙霉菌和其他口腔treponemes诱导β-防御素的产生的能力。我们的初步数据表明，T. denticola抑制了其他细菌产物诱导炎症细胞因子的诱导，类似于“趋化因子瘫痪”，与“趋化因子分析”相似。我们将检查由牙霉菌刺激的上皮细胞的细胞因子和粘附分子的调节（AIM 4），目的是识别受螺旋体影响的信号传导途径。最后，我们将确定诱导A-防御素的产生并拮抗炎症细胞因子的牙霉菌（AIM 5）的成分（AIM 5）。这项研究将通过对牙齿牙菌性和其他口腔螺旋体如何逃避先天免疫反应，从而进一步了解牙周疾病的发病机理。