TLR4 evasion, bacterial persistence and chronic inflammation

TLR4 逃避、细菌持续存在和慢性炎症

• 批准号: 9117800
• 负责人: Caroline A Genco
• 金额: $ 13.43万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-24 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9117800
• 关键词: TLR4; evasion; bacterial; persistence; chronic

DESCRIPTION (provided by applicant): Chronic inflammation results in significant host pathology and is associated with a number of diseases including autoimmune diseases, atherosclerosis, and infectious diseases. Porphyromonas gingivalis is a low- abundance oral bacterium linked to the initiation and progression of inflammatory oral bone loss and to other chronic inflammatory systemic diseases. The overall goal of this Project is to define the mechanisms by which P. gingivalis evades TLR4 signaling and manipulates autophagy to promote chronic inflammation. P. gingivalis has evolved mechanisms to evade TLR4 host immune detection through expression of a heterogeneous LPS lipid A species that functions as weak TLR4 agonist and strong TLR4 antagonist. In contrast to evasion of TLR4 signaling, P. gingivalis is a strong activator of TLR2 and utilizes a TLR2 mediated mechanism for intracellular entry into macrophages, which protects the organism from immune clearance via the intracellular degradative lysosomal pathway. A number of pathogens that evade lysosomal destruction infiltrate the autophagic pathway. Autophagy is also utilized for the secretion of the active form of IL-1??, a mediator of bacterial killing. We hypothesize that the ability of P. gingivalis to evade TLR4 signaling and to manipulate autophagy dampens IL-1? production and promotes survival in macrophages, resulting in chronic inflammation. Using relevant knockout mice and genetically modified P. gingivalis strains, we propose the following aims to test our hypothesis: Aim 1. To define the role of P. gingivalis mediated evasion of TLR4 signaling in monocytic cells in IL-1?? production and bacterial killing. Aim 2. To define the role of P. gingivais mediated manipulation of autophagy in monocytic cells in IL-1?? production and bacterial killing. Aim 3. To define the role of P. gingivalis mediated TLR4 evasion in monocytic cells on chronic inflammation in a murine model. Aim 4. To define the role of P. gingivalis mediated manipulation of autophagy in monocytic cells on chronic inflammation in a murine model.

描述（由申请人提供）：慢性炎症会导致显着的宿主病理学变化，并与多种疾病相关，包括自身免疫性疾病、动脉粥样硬化和传染病。牙龈卟啉单胞菌是一种低丰度的口腔细菌，与炎症性口腔骨质流失和其他慢性炎症性全身性疾病的发生和进展有关。该项目的总体目标是确定牙龈卟啉单胞菌逃避 TLR4 信号传导并操纵自噬以促进慢性炎症的机制。牙龈卟啉单胞菌已经进化出通过表达异质 LPS 脂质 A 物种来逃避 TLR4 宿主免疫检测的机制，该物种充当弱 TLR4 激动剂和强 TLR4 拮抗剂。与逃避 TLR4 信号传导相反，牙龈卟啉单胞菌是 TLR2 的强激活剂，并利用 TLR2 介导的机制进入细胞内进入巨噬细胞，从而通过细胞内降解溶酶体途径保护生物体免受免疫清除。许多逃避溶酶体破坏的病原体渗透到自噬途径。自噬还用于分泌活性形式的 IL-1??，一种杀灭细菌的介质。我们假设牙龈卟啉单胞菌逃避 TLR4 信号传导和操纵自噬的能力会抑制 IL-1？产生并促进巨噬细胞的存活，导致慢性炎症。使用相关的基因敲除小鼠和转基因牙龈卟啉单胞菌菌株，我们提出以下目标来检验我们的假设： 目的 1. 确定牙龈卟啉单胞菌介导的单核细胞 IL-1 中 TLR4 信号逃避的作用？生产和杀灭细菌。目标 2. 明确牙龈卟啉单胞菌介导的单核细胞自噬操纵在 IL-1?? 中的作用生产和杀灭细菌。目标 3. 确定牙龈卟啉单胞菌介导的单核细胞 TLR4 逃避对小鼠模型慢性炎症的作用。目标 4. 确定牙龈卟啉单胞菌介导的单核细胞自噬操纵对小鼠模型慢性炎症的作用。