Host Immune Responses to Chlamydia Pneumonaie Infection

宿主对肺炎衣原体感染的免疫反应

• 批准号: 8904888
• 负责人: Moshe Arditi
• 金额: $ 42.5万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-15 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8904888
• 关键词: Asthma; Atherosclerosis; Autoimmune Process; Bacteria; Bacterial Infections; Binding; Bronchus-Associated Lymphoid Tissue; CD4 Positive T Lymphocytes; Cells; Chlamydia; Chlamydophila pneumoniae; Chronic; Chronic Obstructive Airway Disease; Chronic lung disease; Communities; Cytokine Signaling; Data; Disease; Extrinsic asthma; Fibrosis; Generations; Genetic Polymorphism; Genetic Transcription; Goals; Health; Helper-Inducer T-Lymphocyte; Host Defense; Human; Immune; Immune System Diseases; Immune response; Immunity; Infection; Inflammation; Inflammatory; Interleukin-17; Knockout Mice; Laboratories; Lead; Link; Lung; Lung Inflammation; Malignant neoplasm of lung; Mediating; Molecular; Mus; Mycoses; Natural Immunity; Neutrophil Infiltration; Pathogenesis; Pathway interactions; Play; Pneumonia; Prevention therapy; Preventive; Production; RIPK2 gene; Regulation; Reporting; Respiratory Tract Infections; Risk Factors; Role; Signal Transduction; Smoker; T-Lymphocyte; Testing; adapter protein; base; improved; interleukin-22; microbial; novel; novel strategies; novel therapeutic intervention; novel therapeutics; pathogen; prevent; promoter; protective effect; receptor; respiratory; response; skin disorder; transcription factor

DESCRIPTION (provided by applicant): Chlamydia pneumoniae (CP), an intracellular pathogen, is a frequent cause of respiratory infections and contributes to chronic conditions such as allergic asthma exacerbations, chronic lung diseases, including exacerbating chronic obstructive pulmonary disease, and has been associated with the progression of other chronic inflammatory disease such as atherosclerosis and lung cancer in smokers. While the protective effects of IL-17/TH17 against certain microbial agents have been demonstrated, little is known about the role of IL- 17/TH17 in host defenses against CP infection and its role in CP-induced chronic lung inflammation. Better understanding of the role of IL-17 in pathogenesis of chronic lung infections and COPD associated with CP infection may lead to novel strategies for prevention and therapy. We previously investigated the contribution of NOD1, NOD2, and the RIP2 adapter protein on innate immune responses to CP lung infection in mice and discovered that Rip2 was critically required for host defenses and bacterial clearance, as Rip2-/- mice that survived initial infection developed a chronic lung inflammation and developed large numbers of inducible bronchus associated lymphoid tissues (iBALTs). Importantly, we discovered that the NODs/RIP2 pathway also regulates T cells and that TH17 responses in Rip2-/- mice are significantly upregulated. Preliminary data indicates that increased ROR� may be responsible for the enhanced TH17 skewing in Rip2-/- T-cells. A major goal of this project is to define the mechanism of chronic lung inflammation during CP infection, which appears to be driven by IL-17, and enhanced in the absence of Rip2 signaling. The main focus will be to investigate the novel mechanism that we discovered by which Rip2 deficiency results in enhanced Th17 skewing and the molecular mechanism of this regulation. The central hypothesis is that TH17 cells promote chronic inflammation following CP infection, and that lack of NODs/RIP2 signaling leads to increased IL-17 production, which in turn can induce severe chronic lung inflammation. We hypothesize that it is the upregulated RORα in Rip2-/- T-cells that results in enhanced Th17 skewing. To define the mechanisms by which CP induced IL- 17/TH17 responses lead to chronic lung inflammation, and to investigate the novel cross-talk between Rip2 and Th17 regulation and the role of RORα, we propose the following three Specific Aims: Aim1 is to determine the role of IL-17 in host defenses in CP lung infection and chronic lung inflammation. Aim 2 is to determine the mechanism of CP-induced increased chronic lung inflammation in Rip2-null mice and the role of Rip2/IL-17 cross-talk. Aim 3 is to investigate the mechanism of Rip2-induced regulation of Th17 skewing.

描述(申请人提供)：肺炎衣原体(CP)是一种细胞内病原体，是呼吸道感染的常见原因，可导致过敏性哮喘加重、慢性肺部疾病(包括加重慢性阻塞性肺疾病)等慢性疾病，并与其他慢性炎症性疾病(如动脉粥样硬化和吸烟者肺癌)的进展有关。虽然IL-17/TH17对某些微生物的保护作用已经被证明，但关于IL-17/TH17在宿主抵抗CP感染中的作用以及它在CP诱导的慢性肺部炎症中的作用还知之甚少。更好地了解IL-17在慢性肺部感染和慢性阻塞性肺疾病与CP感染相关的发病机制中的作用，可能会为预防和治疗提供新的策略。我们先前研究了NOD1、NOD2和RIP2接头蛋白在肺炎衣原体肺部感染小鼠先天免疫反应中的作用，发现RIP2对于宿主防御和细菌清除是至关重要的，因为最初感染存活的RIP2-/-小鼠发生了慢性肺部炎症并形成了大量可诱导的支气管相关淋巴组织(IBALT)。重要的是，我们发现NODS/RIP2通路也调节T细胞，并且RIP2-/-小鼠的TH17反应显著上调。初步数据显示，RoR�的增加可能是导致RIP2-/-T细胞TH17偏斜增强的原因。这个项目的一个主要目标是确定CP感染过程中慢性肺部炎症的机制，这种炎症似乎是由IL-17驱动的，并在没有RIP2信号的情况下增强。主要的焦点将是研究我们发现的RIP2缺乏导致Th17偏斜增强的新机制以及这种调节的分子机制。核心假设是TH17细胞促进了CP感染后的慢性炎症，而NODS/RIP2信号的缺失导致IL-17产生增加，进而导致严重的慢性肺部炎症。我们推测，是RIP2-/-T细胞中上调的RoRα导致了Th17偏斜的增强。为了明确CP诱导的IL-17/Th17反应导致慢性肺部炎症的机制，并研究RIP2和Th17调节之间的新的串扰以及RoRα的作用，我们提出了以下三个特异性目标：AIM1旨在确定IL-17在CP肺部感染和慢性肺部炎症中的宿主防御中的作用。目的2探讨环磷酰胺(CP)致RIP2基因缺失小鼠慢性肺部炎症增加的机制及RIP2/IL-17的相互作用。目的3研究RIP2对Th17偏斜的调节机制。