Invasive Bacteria Accelerate Atherosclerosis through TLRs

入侵细菌通过 TLR 加速动脉粥样硬化

• 批准号: 7049670
• 负责人: Caroline A Genco
• 金额: $ 40.25万
• 依托单位: BOSTON MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-01 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7049670
• 关键词: Bacteroides gingivalis; aorta; apolipoprotein E; atherosclerosis; atherosclerotic plaque; bacteria infection mechanism; binding proteins; biological signal transduction; dietary lipid; genetically modified animals; host organism interaction; immunocytochemistry; inflammation; laboratory mouse; microorganism immunology; oral bacteria; receptor expression; toll like receptor

DESCRIPTION (provided by applicant): Accumulating evidence has implicated specific infectious agents, including Chlamydia pneumoniae and Porphyromonas gingivalis in the progression of atherosclerosis. However, the mechanisms by which infections contribute to the progression of atherosclerosis and the links among lipids, microbial antigens, and innate immune and inflammatory responses are not well understood. Toll-like receptors (TLR) are pattern recognition receptors that have key roles in detecting microbes and initiating inflammatory responses. Recently, expression of TLRs has been demonstrated, to be markedly augmented in human atherosclerotic lesions. Our studies indicate that TLR2 and TLR4 expression is enhanced in mouse atherosclerotic lesions following oral challenge with P. gingivalis in an apoE model of atherosclerosis. These are the first studies with any bacterial pathogen that have demonstrated a link between innate immune markers and infection-accelerated atherosclerosis in an animal model. In addition, we have demonstrated that TLR2, TLR4, and MyD88 (cytoplasmic adapter molecule) are required for host cell signaling in response to P. gingivalis and that TLR2 and MvD88 are required for local inflammation associated with P. gingivalis infection in a murine model. TLR2 and TLR4 expression is also enhanced in endothelial cells and macrophages in response to P. gingivalis infection and following infection, these cells become primed to respond to TLR4-ligands. Recent studies using TLR4 and MyD88 / ApoE mice have shown a substantial reduction in atherosclerosis lesion development compared to wildtype mice fed a high fat diet supporting the direct involvement of the TLR4 and MyD88-dependent signaling pathway in the development of lipid induced atherosclerosis in mice. Furthermore, our initial analysis of newly generated TLR2 / ApoE mice demonstrate that these mice develop less atherosclerotic plaque as compared to ApoE mice. Together these results raise the possibility that enhanced TLR expression and signaling may play a role in infection accelerated inflammation and atherosclerosis. The aims of this study are: 1. To define the role of bacterial induced systemic and aortic inflammation in the acceleration of atherosclerotic plaque accumulation in ApoE -/- mice orally challenged with P.-gingivalis at the acute phase. 2. To assess the role of TLR-MyD88-dependent signaling in atheromatous plaque development following P. gingivalis oral challenge. 3. To assess the role of the TLR-2 and TLR-4-dependent signaling pathway in atheromatous plaque development following P. gingivalis oral challenge. Improved understanding of the molecular mechanisms driving TLR over expression and signaling and the role of the resulting chronic inflammation during atherosclerosis may provide new targets for therapy.

描述（由申请人提供）：越来越多的证据表明特定的传染源，包括肺炎衣原体和牙龈卟啉单胞菌，与动脉粥样硬化的进展有关。然而，感染导致动脉粥样硬化进展的机制以及脂质、微生物抗原以及先天免疫和炎症反应之间的联系尚不清楚。 Toll 样受体 (TLR) 是一种模式识别受体，在检测微生物和启动炎症反应方面发挥着关键作用。最近，已证明 TLR 的表达在人类动脉粥样硬化病变中显着增强。我们的研究表明，在动脉粥样硬化的 apoE 模型中，经口牙龈卟啉单胞菌攻击后，小鼠动脉粥样硬化病变中的 TLR2 和 TLR4 表达增强。这些是首次针对任何细菌病原体进行的研究，在动物模型中证明了先天免疫标记物与感染加速的动脉粥样硬化之间的联系。此外，我们还证明，TLR2、TLR4 和 MyD88（细胞质接头分子）是响应牙龈卟啉单胞菌的宿主细胞信号转导所必需的，并且在小鼠模型中，TLR2 和 MvD88 是与牙龈卟啉单胞菌感染相关的局部炎症所必需的。内皮细胞和巨噬细胞中的 TLR2 和 TLR4 表达也因牙龈卟啉单胞菌感染而增强，并且感染后，这些细胞开始对 TLR4 配体做出反应。最近使用 TLR4 和 MyD88 / ApoE 小鼠的研究表明，与喂食高脂肪饮食的野生型小鼠相比，动脉粥样硬化病变的发展显着减少，这支持 TLR4 和 MyD88 依赖性信号通路直接参与小鼠脂质诱导的动脉粥样硬化的发展。此外，我们对新产生的 TLR2/ApoE 小鼠的初步分析表明，与 ApoE 小鼠相比，这些小鼠产生的动脉粥样硬化斑块较少。总之，这些结果提出了增强的 TLR 表达和信号传导可能在感染加速炎症和动脉粥样硬化中发挥作用的可能性。本研究的目的是： 1. 确定在急性期口服牙龈卟啉单胞菌的 ApoE -/- 小鼠中，细菌诱导的全身炎症和主动脉炎症在加速动脉粥样硬化斑块积累中的作用。 2. 评估 TLR-MyD88 依赖性信号传导在牙龈卟啉单胞菌口腔攻击后动脉粥样硬化斑块发展中的作用。 3. 评估 TLR-2 和 TLR-4 依赖性信号通路在牙龈卟啉单胞菌口腔攻击后动脉粥样硬化斑块发展中的作用。更好地了解驱动 TLR 过度表达和信号传导的分子机制以及动脉粥样硬化期间由此产生的慢性炎症的作用可能会为治疗提供新的靶点。