Role of Innate Immune System in Pathogen Induced Chronic Inflammation

描述（由申请人提供）：慢性炎症在破坏性事件中达到高潮，导致显著的宿主病理，并与许多人类疾病相关，包括自身免疫性疾病、传染病、肿瘤疾病和炎症性血管斑块积累。致病菌肺炎衣原菌和牙龈卟啉菌诱导慢性炎症反应，尽管这些病原体如何诱导和维持慢性炎症尚不清楚。本P01的中心假设是病原刺激通过先天免疫识别调节炎症介质对宿主免疫细胞功能的调节，从而导致慢性炎症性疾病。为了验证这一假设，我们提出以下目标：目标1。定义内皮细胞、巨噬细胞和血小板对牙龈假单胞菌和肺炎假单胞菌的反应诱导炎症介质的信号通路。目标2。确定转录因子在牙龈假单胞菌和肺炎假单胞菌炎症反应中的作用。目标3。确定牙龈假单胞菌和肺炎假单胞菌刺激炎症介质如何通过这些途径调节内皮细胞、血小板和巨噬细胞功能。目标4。确定这些信号通路在小鼠模型牙龈假单胞菌和肺炎假单胞菌诱导血栓形成和慢性炎症的发病机制中的作用。以下项目提出了详细的研究，以实现这些目标：项目1：先天免疫和病原体诱导的炎症在血小板功能中的作用；急性和慢性肺炎原体感染的先天免疫防御。项目3：先天免疫、脂质信号和慢性感染。项目4-先天免疫机制参与牙龈假单胞菌诱导的慢性炎症。以下核心将为这些项目服务：A.行政核心，B.体外核心和C.动物核心。这些协作和协同研究将确定特异性先天免疫信号分子在牙龈假单胞菌和肺炎假单胞菌诱导的与慢性炎症过程相关的细胞炎症反应中的作用。此外，使用已定义的炎症动物模型，我们将描述这些先天免疫途径在体内炎症过程中的作用。增强对参与促炎介质表达和功能性免疫反应的特异性先天免疫信号通路的作用的理解，将为慢性炎症疾病的新疗法提供有希望的途径。

DESCRIPTION (provided by applicant): Chronic inflammation culminates in devastating events, results in significant host pathology, and is associated with a number of human diseases including autoimmune diseases, infectious diseases, neoplastic diseases, and inflammatory vascular plaque accumulation. The pathogenic bacteria Chlamydophila pneumoniae and Porphyromanas gingivalis induce a chronic inflammatory response, although how these pathogens induce and maintain chronic inflammation is not well defined. The central hypothesis of this P01 is that pathogen stimulation via innate immune recognition modulates inflammatory mediator regulation of host immune cell function resulting in chronic inflammatory disorders. To test this hypothesis we propose the following Aims: Aim 1. To define the signaling pathways by which inflammatory mediators are induced in response to P. gingivalis and C. pneumoniae in endothelial cells, macrophages, and platelets. Aim 2. To define the contribution of transcription factors in inflammatory responses to P. gingivalis and C. pneumoniae. Aim 3. To define how P. gingivalis and C. pneumoniae stimulation of inflammatory mediators via these pathways modulates endothelial cell, platelet and macrophage function. Aim 4. To define the role of these signaling pathways in the pathogenesis of P. gingivalis and C. pneumoniae induced thrombosis and chronic inflammation in a mouse model. The following Projects propose detailed studies to address these Aims: Project 1-The Role of Innate Immunity and Pathogen-Induced Inflammation in Platelet Function; Project 2-Innate Immune Defenses Against Acute and Chronic Infection with C. pneumoniae. Project 3- Innate Immunity, Lipid Signaling, and Chronic Infection. & Project 4- Innate Immune Mechanisms Involved in P. gingivalis-Induced Chronic Inflammation. The following Cores will service these Projects: A. Administrative Core, B. In Vitro Core, and C. Animal Core. These collaborative and synergistic studies will define the role of specific innate immune signaling molecules in P. gingivalis and C. pneumoniae induced inflammatory responses in cells relevant to chronic inflammatory processes. Furthermore, using defined animal models of inflammation we will characterize the roles of these innate immune pathways in inflammatory processes in vivo. Enhanced understanding of the roles of specific innate immune signaling pathways, which participate in proinflammatory mediator expression and functional immune responses will provide a promising avenue for novel therapies for chronic inflammatory disorders. PROJECT 1: THE ROLE OF INNATE IMMUNITY AND PATHOGEN-INDUCED INFLAMMATION IN PLATELET FUNCTION (FREEDMAN, J) PROJECT 1 DESCRIPTION (provided by applicant): While there is evidence that chronic inflammation and infection promotes plaque formation, acute infections are associated with a transient five-fold increased risk of unstable coronary and vascular syndromes caused by platelet dependent thrombosis. While many strains of bacteria induce platelet aggregation, the mechanisms by which bacteria stimulate platelets has had minimal investigation. In preliminary data utilizing comprehensive microarray analyses, and a large community cohort of almost 2,000 subjects, we found distinct patterns of platelet gene expression in patients with cardiovascular disease. While several TLRs were detected in platelets, the expression of TLR2 and IL1R in particular were increased in patients with cardiovascular disease. Importantly, the functionality of TLR in platelets was established as incubation of platelets with TLR2 ligands dose-dependently induced platelet activation and aggregation. In addition, we found enhanced platelet function and platelet-monocyte/neutrophil binding with C. pneumoniae infection in vivo, and P. gingivalis incubation. The central hypothesis of the overall program project is that "Pathogen stimulation via innate immune recognition modulates inflammatory mediator regulation of host immune cell function resulting in chronic inflammatory disorders". The central hypothesis of Project 1 is that bacteria mediate pro-thrombotic and -inflammatory processes in platelets via innate immune pathways. To investigate this hypothesis, we propose the following Aims: Aim 1. To define the role of TLR2 and IL-1R in C. pneumoniae and P. gingivalis enhanced platelet function. Aim 2. To define C. pneumoniae and P. gingivalis mediated modulation of TLR2- and IL1R-dependent signaling pathways in platelets and NFkappaB-dependent transcription in megakaryocytes. Aim 3. To define the role of TLR2 and IL-1 R in platelet specific responses to C. pneumoniae and P. gingivalis dependent thrombosis in vivo.