TLR4 evasion, bacterial persistence and chronic inflammation

描述（由申请人提供）：慢性炎症导致显著的宿主病理学，并与许多疾病相关，包括自身免疫性疾病、动脉粥样硬化和感染性疾病。牙龈卟啉单胞菌是一种低丰度的口腔细菌，与炎性口腔骨丢失的发生和进展以及其他慢性炎性全身性疾病有关。该项目的总体目标是确定牙龈卟啉单胞菌逃避TLR 4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作为弱TLR 4激动剂和强TLR 4拮抗剂起作用的异质LPS脂质A种类来逃避TLR 4宿主免疫检测的机制。与逃避TLR 4信号传导相反，牙龈卟啉单胞菌是TLR 2的强激活剂，并利用TLR 2介导的机制细胞内进入巨噬细胞，其保护生物体免于通过细胞内降解溶酶体途径的免疫清除。许多逃避溶酶体破坏的病原体渗入自噬途径。自噬也用于分泌活性形式的IL-1 β，一种杀死细菌的媒介。我们假设牙龈卟啉单胞菌逃避TLR 4信号传导和操纵自噬的能力抑制IL-1？产生并促进巨噬细胞的存活，导致慢性炎症。利用相关基因敲除小鼠和基因修饰的牙龈卟啉单胞菌菌株，我们提出了以下目的来验证我们的假设：目的1。确定牙龈卟啉单胞菌介导的单核细胞TLR 4信号逃避在IL-1？生产和杀菌。目标二。确定牙龈卟啉单胞菌介导的单核细胞自噬在IL-1？生产和杀菌。目标3。确定牙龈卟啉单胞菌介导的单核细胞TLR 4逃逸在小鼠模型慢性炎症中的作用。目标4。确定牙龈卟啉单胞菌介导的单核细胞自噬操纵在小鼠模型慢性炎症中的作用。

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.