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

CARDS毒素在过敏性炎症发生和恶化中的作用

• 批准号: 8181913
• 负责人: PETER H DUBE
• 金额: $ 40.47万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8181913
• 关键词: Acute; Adult; African American; Albumins; Allergens; Allergic; Allergic inflammation; American; Animal Model; Animals; Asthma; Bacterial Infections; Bacterial Toxins; Biochemical; Cell Culture Techniques; Cell physiology; Cells; Child; Chronic; Chronic Disease; Clinical; Community Acquired Respiratory Distress Syndrome Toxin; Data; Development; Diagnostic; Disease; Environment; Exhibits; Exposure to; Genetic; Goals; Health; Human; Immune system; In Vitro; Infection; Inflammation; Inflammatory Response; Intervention; Knowledge; Link; Lung; Lymphocyte; Mediating; Mediator of activation protein; Mission; Modeling; Molecular; Mus; Mycoplasma pneumoniae; Nature; Pathogenesis; Pathology; Phenotype; Pneumonia; Process; Pyroglyphidae; Recombinants; Refractory; Risk Factors; Role; T-Lymphocyte; Testing; Tissues; Toxin; Wheezing; Woman; Work; asthmatic patient; base; improved; insight; mouse model; novel; pathogen; patient population; respiratory; response; single molecule; success; tool; translational study

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.

哮喘是一种慢性疾病，影响超过2300万美国人。导致哮喘的因素有 多种多样，但有几个常见和公认的风险因素，包括遗传，环境，过敏原 暴露和感染非典型细菌病原体。肺炎支原体是常见的非典型肺炎 细菌病原体与儿童喘息和哮喘急性加重密切相关， 成年人了任何非典型的细菌产物和哮喘之间的因果关系是缺乏的，直到，我们确定了一个M。 被称为社区获得性呼吸窘迫综合征的肺炎ADP-核糖基化/空泡化毒素 Toxin（Toxin TX）存在于许多严重难治性哮喘患者的呼吸道分泌物中， 哮喘急性加重患者，但在健康对照中很少检测到。这些数据强烈 提示，TXB 2代表一个与一个大的亚群的发病机制紧密相关的单分子， 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MTX介导的肺部炎症。使用 在我们的模型中，我们证明了接受单次暴露于rBTX的幼稚小鼠表现出 嗜酸性/淋巴细胞炎症导致哮喘样表型。此外，小鼠致敏与 OVA白蛋白或屋尘螨，随后暴露于MTX， 嗜酸性/淋巴细胞炎症和高反应性。该项目的目的是1）调查 通过阐明以下免疫学基础，为雷公藤多甙诱导的细胞炎症反应奠定基础： 负责MTX介导的哮喘样反应的分子和细胞成分， 幼稚的老鼠2)探讨MTX介导的过敏性疾病加重的免疫学基础 炎症我们将确定负责CTX介导的细胞和分子机制， 过敏性炎症加重。3)探讨梅毒螺旋体病的免疫学基础 使用人细胞的体外细胞培养模型促进炎症。我们将确定 以及负责MTX介导的T细胞功能改变的分子机制。