The role of CARDS toxin in genesis and exacerbation of allergic inflammation

哮喘是一种慢性疾病，影响着2300多万美国人。导致哮喘的因素有 不同的但几个常见的和公认的危险因素包括遗传，环境，过敏原 暴露和感染非典型细菌病原体。摘要肺炎支原体是一种常见的非典型肺炎。 与儿童喘息和#年哮喘急性加重密切相关的细菌病原体 成年人。任何非典型细菌产物和哮喘之间缺乏因果联系，直到我们发现了一种M。 肺炎ADP核糖化/空泡毒素称为社区获得性呼吸窘迫综合征 毒素(卡片TX)存在于我们许多严重的难治性哮喘患者的呼吸道分泌物中， 有哮喘急性加重的患者，但在健康对照组中很少发现。这些数据强烈地 提示CARDS TX代表与一大亚群的致病机制紧密相连的单个分子 哮喘病例。我们建立了一个小鼠模型，使我们能够研究免疫机制。 在幼稚肺和特应性肺中负责CARDS TX介导的肺部炎症。vbl.使用 在我们的模型中，我们证明了接受一次rCARDS TX暴露的幼小鼠表现出 嗜酸性/淋巴细胞性炎症导致哮喘样表型。此外，致敏的小鼠 卵白蛋白或屋尘螨，并随后暴露在卡片TX中会加剧 嗜酸性/淋巴细胞炎症和高反应性。这个项目的目的是1)调查 卡介苗TX诱导细胞炎症反应的免疫学基础 CHARDS TX介导的哮喘样反应的分子和细胞成分 天真的老鼠。2)探讨卡介苗TX介导的变态反应加重的免疫学基础 发炎。我们将确定TX介导的CARD的细胞和分子机制 过敏性炎症加重。3)探讨卡介苗TX的免疫学基础 利用人体细胞的体外细胞培养模型促进炎症。我们将确定细胞 以及TX介导的T细胞功能改变的分子机制。

Asthma is a chronic disease impacting more than 23 million Americans. The factors leading to asthma are varied but several common and well-established risk factors include genetics, environment, allergen exposure, and infection with atypical bacterial pathogens. Mycoplasma pneumoniae is a common atypical bacterial pathogen strongly associated with wheezing in children and acute exacerbations of asthma in adults. A causal link between any atypical bacterial product and asthma was lacking, until, we identified a M. pneumoniae ADP-ribosylating/vacuolating toxin called Community Acquired Respiratory Distress Syndrome ToXin (CARDS TX) that is present in respiratory secretions of many of our severe refractory asthmatics and patients with acute exacerbations of asthma yet rarely detected in healthy controls. These data strongly suggest that CARDS TX represents a single molecule tightly linked to the pathogenesis of a large subset of asthma cases. We established a mouse model that allows us to investigate the immunological mechanisms responsible for CARDS TX-mediated pulmonary inflammation in both the naive and the atopic lung. Using our model, we demonstrated that naive mice receiving a single exposure to rCARDS TX exhibit an eosinophilic/lymphocytic inflammation leading to an asthma-like phenotype. Further, mice sensitized with OVA albumin or house dust mites and subsequently exposed to CARDS TX develop exacerbated eosinophilic/lymphocytic inflammation and hyperresponsiveness. The Aims for this project are 1) Investigate the immunological basis for the cellular inflammatory response induced by CARDS TX through elucidation of the molecular and cellular components responsible for the CARDS TX-mediated asthma-like responses in naive mice. 2) Investigate the immunological basis for CARDS TX-mediated exacerbation of allergic inflammation. We will determine the cellular and molecular mechanisms responsible for the CARDS TX-mediated exacerbation of allergic inflammation. 3) Investigate the immunological basis for CARDS TX promotion of inflammation using in vitro cell culture models with human cells. We will determine the cellular and molecular mechanisms responsible for the CARDS TX-mediated alteration of T-cell function.