TLR4 evasion, bacterial persistence and chronic inflammation

描述(申请人提供)：慢性炎症导致严重的宿主病理，并与许多疾病有关，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，与炎症性口腔骨质丢失和其他慢性炎症性全身疾病的发生和发展有关。这个项目的总体目标是确定牙龈假单胞菌逃避TLR4信号并操纵自噬以促进慢性炎症的机制。牙龈假单胞菌已经进化出逃避TLR4宿主免疫检测的机制，这种机制是通过表达一种不同种类的脂蛋白A来实现的，这种脂蛋白A具有弱的TLR4激动剂和强的TLR4拮抗剂的功能。与逃避TLR4信号不同，牙龈假单胞菌是TLR2的强激活剂，并利用TLR2介导的细胞内进入巨噬细胞的机制，通过细胞内降解的溶酶体途径保护机体免受免疫清除。许多逃避溶酶体破坏的病原体渗透到自噬途径中。自噬也被用来分泌IL-1的活性形式，它是细菌杀灭的媒介。我们假设牙龈假单胞菌逃避TLR4信号和操纵自噬的能力抑制IL-1？产生并促进巨噬细胞存活，导致慢性炎症。利用相关的基因敲除小鼠和转基因牙龈假单胞菌菌株，我们提出了以下目的来验证我们的假设：目的1.明确牙龈假单胞菌介导的单核细胞TLR4信号在IL-1中的逃逸作用。生产和杀菌。目的：明确牙龈假单胞菌介导的单核细胞自噬在IL-1中的作用。生产和杀菌。目的3.明确牙龈假单胞菌介导的单核细胞TLR4逃避在小鼠慢性炎症模型中的作用。目的4.明确牙龈假单胞菌介导的单核细胞自噬在小鼠慢性炎症模型中的作用。

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.