Role of Innate Immunity in Pathogenesis of Chlamydia Pneumonia Infection

描述（由申请人提供）：肺炎衣原体是社区获得性肺炎的重要病因，也是过敏性气道疾病和哮喘加重的重要诱因。新出现的证据表明toll样受体（TLRs）可能在宿主防御肺炎球菌感染中发挥作用。我们的研究表明，与野生型小鼠相比，MyD88-/-小鼠无法产生早期炎症反应，无法清除肺部的细菌，并发展为延迟和持续的肺部炎症，导致死亡率增加，但野生型（MyD88+/+）同窝对照小鼠迅速从感染中恢复。这些结果表明，TLR信号通过MyD88是宿主防御肺炎原体的重要组成部分。虽然体外骨髓源性巨噬细胞和树突状细胞中肺炎球菌诱导的细胞因子释放依赖于TLR2，但在TLR2-/-和TLR4-/-小鼠中，我们没有观察到细菌清除或肺部炎症消退的显著缺陷。这些观察结果表明，MyD88对宿主防御肺炎链球菌至关重要，但也表明MyD88-和/或tlr独立通路导致MyD88-/-小鼠的延迟和慢性肺部炎症。包括NOD1和NOD2在内的TLR/ myd88独立通路也可能参与先天宿主对这种专性细胞内生物的防御。我们还观察到，紫外线杀死或活的肺炎梭菌感染使小鼠对过敏原敏感，并加剧过敏原介导的嗜酸性气道炎症，并在肺部产生Th2型反应。这些研究提出了一些假设，我们将在这里提出的研究中对这些假设进行严格的测试，这些假设围绕一个中心假设进行组织：宿主对肺炎梭菌肺部感染和炎症的反应是通过TLR2/MyD88途径介导的，这些途径触发先天和适应性免疫防御，这反过来在肺炎梭菌感染的发病机制和宿主清除肺部细菌的反应中发挥重要作用。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IFN-y，但也增强过敏原介导的致敏和嗜酸性气道炎症和过敏性哮喘，由过敏原挑战通过促进肺中Th2偏倚引发。具体目的：1-研究TLR2/TLR4和myd88依赖性和非依赖性信号通路在小鼠抗肺炎梭菌诱导的肺部感染和炎症的先天和适应性宿主反应中的作用；2-确定并比较造血细胞和肺上皮细胞在肺炎梭菌诱导的免疫反应和肺部炎症中的作用3-确定肺炎梭菌感染对过敏原介导的肺嗜酸性气道炎症发展的影响。意义：我们提出的研究将有助于进一步了解先天和适应性免疫反应在宿主防御肺炎原感染中的作用，包括TLR/MyD88通路和NOD1/NOD2受体的作用，以及肺炎原感染加剧过敏原介导的嗜酸性气道炎症的分子机制，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.