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学，并且与许多人类疾病相关，包括自身免疫性疾病、感染性疾病、肿瘤性疾病和炎性血管斑块积聚。病原菌嗜肺炎衣原体和牙龈卟啉单胞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还没有很好的定义。该P01的中心假设是通过先天免疫识别的病原体刺激调节宿主免疫细胞功能的炎症介质调节，导致慢性炎症性疾病。为了验证这一假设，我们提出了以下目标：目标1。明确牙龈卟啉单胞菌和念珠菌诱导炎症介质的信号通路。内皮细胞、巨噬细胞和血小板中的肺炎。目标2.明确转录因子在牙龈卟啉单胞菌和念珠菌炎症反应中的作用。肺炎。目标3.为了明确牙龈卟啉单胞菌和C.肺炎链球菌通过这些途径刺激炎症介质调节内皮细胞、血小板和巨噬细胞功能。目标4。明确这些信号通路在牙龈卟啉单胞菌和念珠菌致病中的作用。肺炎杆菌在小鼠模型中诱导血栓形成和慢性炎症。以下项目提出了详细的研究，以解决这些目标：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;项目2-先天免疫防御对急性和慢性感染的C。肺炎。项目3-先天免疫，脂质信号和慢性感染。&项目4-参与牙龈卟啉单胞菌诱导的慢性炎症的先天免疫机制。以下核心将为这些项目提供服务：管理核心，B。In Vitro Core和C.动物核心这些合作和协同研究将确定特定的先天免疫信号分子在牙龈卟啉单胞菌和念珠菌中的作用。肺炎克雷伯氏菌在与慢性炎症过程相关的细胞中诱导炎症反应。此外，使用定义的炎症动物模型，我们将表征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应答的特异性先天免疫信号通路的作用的理解将为慢性炎症性疾病的新疗法提供有希望的途径。 项目1：天然免疫和病原体诱导的炎症在血小板功能中的作用（Freedman，J） 项目1描述（由申请人提供）：虽然有证据表明慢性炎症和感染促进斑块形成，但急性感染与血小板依赖性血栓形成引起的不稳定冠状动脉和血管综合征的风险一过性增加5倍相关。虽然许多细菌菌株诱导血小板聚集，但细菌刺激血小板的机制几乎没有研究。在利用全面的微阵列分析和近2,000名受试者的大型社区队列的初步数据中，我们发现了心血管疾病患者血小板基因表达的不同模式。虽然在血小板中检测到几种TLR，但在心血管疾病患者中TLR 2和IL 1 R的表达尤其增加。重要的是，血小板中TLR的功能性被确定为血小板与TLR 2配体的孵育剂量依赖性地诱导血小板活化和聚集。此外，我们发现血小板功能和血小板-单核细胞/中性粒细胞与C.肺炎杆菌感染和牙龈卟啉单胞菌孵育。整个计划项目的中心假设是“通过先天免疫识别的病原体刺激调节宿主免疫细胞功能的炎症介质调节，导致慢性炎症性疾病”。项目1的中心假设是细菌通过先天免疫途径介导血小板中的促血栓形成和炎症过程。为了研究这一假设，我们提出以下目标： 目标1.探讨TLR 2和IL-1 R在C.肺炎链球菌和牙龈卟啉单胞菌增强血小板功能。 目标2.定义C.肺炎链球菌和牙龈卟啉单胞菌介导血小板中TLR 2和IL 1 R依赖性信号传导途径和巨核细胞中NF κ B依赖性转录的调节。 目标3。目的探讨TLR 2和IL-1 R在血小板对C.肺炎链球菌和牙龈卟啉单胞菌依赖的体内血栓形成。

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.