Role of CARDS Toxin in M. pneumoniae Associated Asthma in Mice

哮喘是一种复杂的疾病，困扰着超过1500万美国人。尽管明显增加了 尽管哮喘在我们人群中的流行情况仍然是一种知之甚少的疾病。这部分是由于 遗传因素、环境刺激和影响免疫系统状态的复杂混合物 疾病的发展和进展。在病因学上被低估和有争议的因素 哮喘是非典型细菌感染，例如由肺炎支原体引起的感染所起的作用 在引发、加重和延长与呼吸道相关的症状和病理方面。世界上最重要的一部分 混乱是缺乏可靠和相关的诊断方法和真正的毒力决定因素 将肺炎支原体与哮喘发病机制直接联系起来。最近一种独特的肺炎支原体毒素(卡片 TX：发现社区获得性呼吸窘迫综合征毒素)(见初步结果 部分和项目4)复制了呼吸道高反应性中的细胞因子反应、病理和变化 肺炎支原体呼吸道感染和肺炎支原体感染的观察 哮喘。我们认为这一发现是一个潜在的重大突破，并假设卡片TX可能是 对哮喘的急性、慢性和恶化负责。为了检验这一假设，我们将利用 对BALB/c-卵清蛋白过敏性哮喘模型的检测有以下具体目的：1)测定 我们新发现的ADP核糖化、空泡化卡片Tx在M。 利用已建立的小鼠过敏性哮喘模型研究肺炎相关过敏性哮喘，2)研究CARD的作用 TX在肺炎支原体感染相关性哮喘发病机制中的作用小白鼠将感染野生动物 卡氏Tx基因零突变的肺炎支原体或肺炎支原体。发病机制将是 在BALB/c小鼠模型中评估卵蛋白诱导的气道高反应性， 阐明CARDS TX在感染模型中的作用，以及3)研究CARS TX的活性 活体内的卡片TX。我们将改进我们对卡介苗TX对肺炎分枝杆菌/AE介导的影响的分析。 通过分析CARDS TX诱导的基因表达，定位/共定位， BALB/c小鼠模型在有或无卵白蛋白诱导的呼吸道中的体内生化活性 反应过度。该项目中概述的研究为哮喘提供了一个实验模型 与项目3的临床结果相关；使用慢性感染模型的实验描述 项目1；项目4中开发的突变体、试剂以及生化和分子观测；以及 病理学核心B专业知识。

Asthma is a complex disease that afflicts over 15 million Americans. Despite the apparent increase in prevalence of disease within our population, asthma is still a poorly understood disease. This is in part due to the complex mixture of genetic factors, environmental stimuli, and immune system status that impacts disease development and progression. One under appreciated and controversial factor in the etiology of asthma is the role that atypical bacterial infections, such as those caused by Mycoplasma pneumoniae, play in initiating, exacerbating and prolonging airway-related symptoms and pathologies. A major part of the confusion is the lack of reliable and relevant diagnostic methodologies and bona fide virulence determinants that directly link M. pneumoniae to asthma pathogenesis. Recently a unique M. pneumoniae toxin (CARDS TX: Community Acquired Respiratory Distress Syndrome Toxin) was discovered (see Preliminary results section and Project 4) that replicates the cytokine responses, pathology, and changes in airway hyperresponsiveness observed with M. pneumoniae respiratory infections and M. pneumoniae-assoc\ated asthma. We consider this finding a potential major breakthrough and hypothesize that CARDS TX may be responsible for acute, chronic, and exacerbation of asthma. To test this hypothesis, we will take advantage of the BALB/c-ovalbumin model of allergic asthma to test the following Specific aims: 1) Determine the contribution of our newly discovered ADP ribosylating, vacuolating CARDS TX to the pathogenesis of M. pneumoniae associated allergic asthma using established murine models, 2) Investigate the role of CARDS TX in the pathogenesis of asthma associated with M. pneumoniae infection. Mice will be infected with wild type M. pneumoniae or M. pneumoniae with a null mutation in the CARDS TX gene. Pathogenesis will be evaluated in the BALB/c mouse model with and without ovalbumin-induced airway hyper-responsiveness, to elucidate the role of CARDS TX in the context of the infectious model, and 3) Investigate the activity of CARDS TX in vivo. We will refine our analysis of the impact of CARDS TX on M. pneumon/ae-mediated respiratory disease through the analysis of CARDS TX-induced gene expression, localization/co-localization, and biochemical activity in vivo using the BALB/c mouse model with and without ovalbumin-induced airway hyper-responsiveness. The studies outlined in this project provide an asthma experimental model to correlate with clinical findings from Project 3; experiments using chronic models of infection described in Project 1; mutants, reagents and biochemical and molecular observations developed in Project 4; and Pathology Core B expertise.