Role of Innate Immunity in Pathogenesis of Chlamydia Pneumonia Infection

描述(申请人提供)：肺炎衣原体是社区获得性肺炎的重要原因，也是过敏性呼吸道疾病和哮喘加重的重要原因。新的证据表明，Toll样受体(TLRs)可能在宿主抵抗肺炎衣原体感染中发挥作用。我们的研究表明，MyD88-/-小鼠无法进行早期炎症反应，未能清除肺部的细菌，并出现延迟和持续的肺部炎症，导致与野生型小鼠相比死亡率增加，但野生型(MyD88+/+)产仔对照组小鼠迅速从感染中恢复。这些结果表明，通过MyD88的TLR信号是宿主抵御肺炎衣原体的重要组成部分。虽然肺炎衣原体在体外由骨髓来源的巨噬细胞和树突状细胞诱导的细胞因子释放是TLR2依赖的，但我们没有观察到TLR2-/-和TLR4-/-小鼠在细菌清除或肺部炎症消退方面存在显著缺陷。这些观察表明，MyD88对宿主抵抗肺炎衣原体至关重要，但也表明MyD88和/或TLR非依赖的途径导致了MyD88-/-小鼠的延迟和慢性肺部炎症。TLR/MyD88不依赖的途径，包括NOD1和NOD2，也可能参与宿主对这种专性胞内有机体的天然防御。我们还观察到紫外线灭活或活的肺炎衣原体感染使小鼠对变应原敏感，并通过肺内Th2型反应加剧变应原介导的嗜酸性呼吸道炎症。这些研究提出了假说，我们将在这里提出的研究中对这些假说进行严格的检验，这些假说是围绕一个中心假说组织的：宿主对肺炎衣原体肺部感染和炎症的反应是通过TLR2/MyD88途径介导的，该途径触发了先天和获得性免疫防御，进而在肺炎衣原体感染的发病机制和宿主对清除肺部细菌的反应中发挥了重要作用。由此产生的初始炎症与强烈的细胞因子反应有关，以清除急性感染，包括干扰素-γ，但也可通过促进肺内Th2偏向来增强变应原介导的致敏作用和嗜酸性气道炎，以及由变应原激发的过敏性哮喘。具体目的是：1-研究TLR2/TLR4和MyD88依赖和非依赖的信号通路在肺炎衣原体诱导的小鼠先天和适应性宿主抗肺部感染和炎症反应中的作用；2-确定和比较造血细胞和肺上皮细胞在肺炎衣原体诱导的免疫反应和肺部炎症中的作用；3-确定肺炎衣原体感染对变应原介导的嗜酸性气道炎症发展的影响。意义：我们的研究将有助于更好地理解先天性和获得性免疫反应在宿主抵御肺炎衣原体感染中的作用，包括TLR/MyD88途径和NOD1/NOD2受体的作用，以及肺炎衣原体感染加剧变应原介导的嗜酸性呼吸道炎症的分子机制，并可能为治疗和/或预防过敏性哮喘提供新的靶点。

DESCRIPTION (provided by applicant): Chlamydia pneumoniae is an important cause of community acquired pneumonia that also significantly contributes to allergic airway disease and exacerbation of asthma. Emerging evidence suggests that Toll-Like Receptors (TLRs) may play a role in host defenses against C. pneumoniae infection. Our studies show that MyD88-/- mice were unable to mount an early inflammatory response, failed to clear the bacteria from their lungs, and developed a delayed and sustained lung inflammation that led to increased mortality compared to wild type mice, but wild-type (MyD88+/+) littermate control mice rapidly recovered from infection. These results indicate that TLR signaling via MyD88 is an essential component of host defenses against C. pneumoniae. While C. pneumoniae -induced cytokine release in vitro from bone marrow derived macrophages and dendritic cells are TLR2-dependent, we did not observe a significant defect in bacterial clearance or resolution of lung inflammation in TLR2-/- and TLR4-/- mice. These observations suggest that MyD88 is critical to host defense against C. pneumoniae, but also indicate that MyD88- and/or TLR-independent pathways lead to the delayed and chronic lung inflammation in MyD88-/- mice. TLR/MyD88-independent pathways which include NOD1 and NOD2 may also be involved in innate host defenses against this obligate intracellular organism. We also observed that UV killed or live C. pneumoniae infection sensitizes the mice for allergens and exacerbates allergen-mediated eosinophilic airway inflammation with a Th2 type response in the lung. These studies have driven hypotheses that we will critically test in studies proposed here and that are organized around a central hypothesis: Host response to C. pneumoniae lung infection and inflammation is mediated through TLR2/MyD88 pathways that trigger innate and adaptive immune defenses which in turn play an important role in the pathogenesis of C. pneumoniae infection and host responses to clear the bacteria from the lungs. The resulting initial inflammation which is associated with intense cytokine responses to clear the acute infection, including IFN-y but also enhances allergen-mediated sensitization and eosinophilic airway inflammation and allergic asthma triggered by allergen challenge by promoting a Th2 bias in the lung. Specific Aims are: 1- To investigate the role of TLR2/TLR4 and MyD88-dependent and-independent signaling pathways in innate and adaptive host responses against C. pneumoniae- induced lung infection and inflammation in mice; 2- To determine and compare the roles of hematopoietic and lung epithelial cells in C. pneumoniae- induced immune responses and lung inflammation 3- To determine the impact of C, pneumoniae infection on the development of allergen-mediated eosinophilic airway inflammation of the lung. Significance: Our proposed studies will lead to improved understanding of the role of innate and adaptive immune responses in host defenses against C. pneumoniae infection, including the role of TLR/MyD88 pathway and NOD1/NOD2 receptors, as well as the molecular mechanisms by which C. pneumoniae infection exacerbates allergen- mediated eosinophilic airway inflammation, and may provide new targets for treatment and/or prevention of allergic asthma.