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INTERACTION OF ORAL SPIROCHETES WITH GINGIVAL EPITHELIUM

口腔螺旋体与牙龈上皮的相互作用

基本信息

批准号：
7151199
负责人：
Sheila A. Lukehart
金额：
$ 23.9万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-03-01 至 2008-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7151199
关键词：
Address Affect Bacteria Binding Biochemical Cell Adhesion Molecules Cell surface Cells Chemotactic Factors Complex Data Defensins Endopeptidases Epithelial Epithelial Cells Epithelium Genetic Transcription Gingiva Goals Human Immune Immune response Inflammatory Interleukin-8 Lesion Leukocyte Trafficking Leukocytes Link Membrane Methods Oral Order Spirochaetales Paralysed Pathogenesis Peptide Hydrolases Periodontal Diseases Periodontal Pocket Porphyromonas gingivalis Predisposition Production Resistance Severities Signal Pathway Stimulus Treponema denticola Treponema maltophilum Treponema medium Treponema vincentii antimicrobial peptide bactericide beta-Defensins chemokine cytokine efflux pump extracellular human TACSTD1 protein human TACSTD2 protein killings microorganism oral spirochetes periplasm protein expression resistance mechanism response

项目摘要

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，包括齿密螺旋体，约占牙周袋中细菌的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，但对它们的研究还很少。口腔螺旋体通常与牙龈上皮密切相关，但我们对齿状螺旋体和其他口腔螺旋体如何在这一界面上生存的了解是有限的。齿状毛滴虫和其他口腔螺旋体可能已经进化出了避开宿主免疫防御的策略，特别是由上皮细胞发起的防御。拟议的研究将集中在螺旋体与牙龈上皮细胞的相互作用以及这些细胞产生的分子对细菌攻击的反应的调节。到目前为止，我们的研究表明齿状毛滴虫对a-防御素具有耐药性，并将检测其他口服密螺旋体对β-防御素的敏感性(目标1)。为了确定齿芽孢杆菌用来抵抗β-防御素杀伤的机制，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、防御素与细胞表面的结合和外排泵(目标2)。齿状螺旋体和其他口服密螺旋体诱导产生β-防御素的能力将在目标3中进行检验。我们的初步数据表明，齿状螺旋体可以抑制其他细菌产物对炎性细胞因子的诱导，类似于牙龈卟啉单胞菌脂多糖所描述的“趋化因子麻痹”。我们将研究齿状毛滴虫(目标4)刺激的上皮细胞对细胞因子和黏附分子的调节，目的是确定受螺旋体影响的信号通路。最后，我们将确定齿纹夜蛾(Aim 5)诱导a-防御素产生和拮抗炎性细胞因子诱导的成分。这项研究将对齿状螺旋体和其他口腔螺旋体如何逃避天然免疫反应提供更完整的理解，从而进一步了解牙周病的发病机制。