Host Immune Responses to Chlamydia Pneumonaie Infection

描述（由申请人提供）：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，有助于慢性疾病，如过敏性哮喘加重，慢性肺部疾病，包括慢性阻塞性肺疾病的加重，并且与其他慢性炎症性疾病的进展相关，如动脉粥样硬化和吸烟者的肺癌。虽然IL-17/TH17对某些微生物制剂的保护作用已被证明，但IL-17/TH17在宿主防御CP感染及其在CP诱导的慢性肺部炎症中的作用知之甚少。更好地了解IL-17在慢性肺部感染和慢性阻塞性肺病相关CP感染发病机制中的作用，可能会导致新的预防和治疗策略。我们之前研究了NOD1、NOD2和RIP2适配蛋白在小鼠对CP肺部感染的先天免疫反应中的作用，发现RIP2在宿主防御和细菌清除中是至关重要的，因为RIP2 -/-小鼠在初始感染中存活后会出现慢性肺部炎症，并产生大量诱导性支气管相关淋巴组织（iBALTs）。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。初步数据表明，ROR的增加可能是Rip2-/- t细胞中TH17偏斜增强的原因。本项目的一个主要目标是确定慢性肺部炎症在CP感染期间的机制，这似乎是由IL-17驱动的，并在缺乏Rip2信号的情况下增强。主要的重点将是研究我们发现的Rip2缺陷导致Th17偏斜增强的新机制和这种调节的分子机制。核心假设是TH17细胞促进CP感染后的慢性炎症，并且NODs/RIP2信号的缺乏导致IL-17产生增加，从而诱导严重的慢性肺部炎症。我们假设Rip2-/- t细胞中RORα的上调导致Th17偏斜增强。为了明确CP诱导IL-17 /TH17反应导致慢性肺部炎症的机制，并研究Rip2与TH17调控之间的新型串导以及RORα的作用，我们提出了以下三个具体目的：目的1是确定IL-17在慢性肺部感染和慢性肺部炎症中宿主防御中的作用。目的2是确定cp诱导Rip2缺失小鼠慢性肺部炎症增加的机制以及Rip2/IL-17串扰的作用。目的3：探讨rip2诱导Th17偏斜的调控机制。

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.