Role of unique ADP-ribosylating vacuolating Mycoplasma pneumoniae toxin in asthma

独特的 ADP-核糖基化空泡肺炎支原体毒素在哮喘中的作用

• 批准号: 7274288
• 负责人: JOEL Barry BASEMAN
• 金额: $ 155.53万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-15 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7274288
• 关键词: Role; unique; ADP; ribosylating; vacuolating

DESCRIPTION (provided by applicant): The San Antonio/Dallas Asthma and Allergic Diseases Cooperative Research Center represents an integrative, collaborative and innovative multidisciplinary effort to investigate the role of a unique Mycoplasma pneumoniae toxin in asthma and related airway diseases. This toxin, designated Community Acquired Respiratory Distress Syndrome Toxin (CARDS TX) remarkably replicates the proinflammatory cytokine/chemokine profiles and histopathology that accompany M. pneumoniae infection. This consortium between The University of Texas Health Science Center at San Antonio and The University of Texas Southwestern Medical School in Dallas combines 4 projects, which focus on basic, clinical and animal modeling strategies, with 2 support cores (administrative and pathology) to bring a totally new approach to defining the relationship between M. pneumoniae and the pathogenesis of asthma. A substantial literature, which has accumulated over thirty-five years, connects M. pneumoniae to onset, exacerbation, and chronicity of asthma, yet no single mycoplasma virulence determinant, or mycoplasma molecule for that matter, has been shown to be a mediator of symptoms and associated pathologies. This lack of definable M. pneumoniae pathogenic factors has greatly hampered an understanding of how M. pneumoniae influences the development and progression of airway diseases. This is especially challenging in complex diseases like asthma, where genetic, immunologic, infectious and environmental variables appear to affect disease development and progression. A major focus of the AADCRC is to directly link the biochemical, molecular and immunological properties of the ADP-ribosylating, vacuolating M. pneumoniae CARDS TX (Project 4), to diagnosis and treatment of asthmatic patients (Projects 3 and 4). By so doing, we hope to demonstrate that CARDS TX is a key mediator of asthma-associated pathobiology in humans (Project 3) and in experimentally infected or intoxicated mice (Projects 1 and 2). Therefore, we intend to (a) directly connect CARDS TX to asthma pathogenesis through novel and effective CARDS TX-targeted diagnostic assessments (ELISA, immunohistochemistry, antigen capture and PCR methodologies) using patient's nasal lavage, sputum and serum samples; (b) use mouse models of M. pneumoniae infection and CARDS TX intoxication to examine both acute and chronic stages of asthma and therapeutic interventions as well as the impact of CARDS TX on airway hyper-reactivity; and (c) further characterize ADP-ribosylating activities of CARDS TX and develop effective and rapid diagnostics to assist in the treatment and control of asthma and related pathologies. The key investigators of each project and core have strong track records and expertise in asthma, airway-related pathologies, immunopathogenesis and M. pneumoniae biology and virulence as well as a history of collaboration and co-publication. PROJECT 1: Novel Mycoplasma pneumoniae CARDS Toxin as Mediator of Airway Dysfunction in Mice (Hardy, R.) DESCRIPTION (provided by applicant): There is growing evidence linking M. pneumoniae respiratory infection and the inception, exacerbation, and chronicity of asthma in a subset of asthmatics. However, the pathogenic microbiologic mechanisms involved in this link have not been well characterized. Of great significance, Drs. Baseman and Kannan have now identified a novel M. pneumoniae toxin, CARDS TX. Our consortium of researchers (Drs. Baseman, Coalson, Dube, Kannan, Peters, and Hardy) has preliminary evidence of CARDS TX playing a pathogenic role in the airway inflammation, airway obstruction, airway hyper-reactivity associated with respiratory M. pneumoniae infection. The hypothesis for the proposed research is that CARDS TX mediates the ability of M. pneumoniae to induce acute asthma exacerbations and is responsible for the deleterious long-term effects of mycoplasma respiratory tract infection. In addition, we hypothesize that therapeutic interventions directed against CARDS TX will ameliorate M. pneumoniae-associated reactive airway disease and asthma. Briefly, the Specific aims are to 1) understand the specific contribution of active CARDS TX to the airway obstruction, hyper-reactivity, and inflammation observed in M. pneumoniae respiratory infection, 2) determine if the host immune response to CARDS TX is protective against the respiratory manifestations of M. pneumoniae infection, and 3) determine the effect of bacterial protein synthesis inhibitor therapy on CARDS TX protein production in M. pneumoniae respiratory infection. The long-term goal of these investigations is to develop disease modifying strategies to treat children and adults with mycoplasma-associated reactive airway disease and asthma. This project focuses on investigating the novel M. pneumoniae toxin, CARDS TX, in our established acute and chronic murine model of M. pneumoniae respiratory infection in which airway inflammation, airway obstruction, and airway hyper-reactivity have been previously characterized by our laboratory. BALB/c mice will be exposed to M. pneumoniae (wild-type and CARDS TX null mutant) or recombinant CARDS TX to determine the contribution of CARDS TX to the airway manifestations of M. pneumoniae infection. In addition, therapeutic interventions directed against CARDS TX will be assessed in our murine model with the goal of translational applicability to the treatment of reactive airway disease and asthma associated with M. pneumoniae in children and adults.

描述（由申请人提供）： 圣安东尼奥/达拉斯哮喘和过敏性疾病合作研究中心代表了一种综合，协作和创新的多学科努力，旨在调查哮喘和相关气道疾病中独特的支原体肺炎毒素的独特作用。这种毒素，指定的社区获得了呼吸窘迫综合征毒素（Cards TX），可显着复制伴有肺炎支原体感染的促炎性细胞因子/趋化因子谱和组织病理学。得克萨斯大学圣安东尼奥大学健康科学中心与达拉斯西南医学院的德克萨斯大学健康科学中心之间的该财团结合了4个项目，该项目的重点是基本，临床和动物建模策略，并与2个支持核心（行政和病理学）结合了一个全新的方法，以确定肺炎M.和Asthma的病原体之间的关系。在三十五年内积累的大量文献将肺炎支原体连接到哮喘的发作，加剧和慢性病，但没有单一的支原体毒力确定性或支原体分子是症状和相关的病理学的伴侣。这种缺乏可定义的肺炎肺炎致病因素极大地阻碍了对肺炎支原体如何影响气道疾病的发展和进展的理解。这在哮喘等复杂疾病中尤其具有挑战性。 AADCRC的主要重点是将ADP-核糖基化的生化，分子和免疫学特性直接连接起来，吸水肺炎切片卡（项目4）（项目4），与哮喘患者的诊断和治疗（项目3和4）。通过这样做，我们希望证明卡片TX是人类哮喘相关病原体学的关键介体（项目3）和实验感染或陶醉的小鼠（项目1和2）。因此，我们打算（a）使用患者的鼻腔灌洗，痰液和血清样品，通过新颖且有效的卡片诊断评估（ELISA，免疫组织化学，抗原捕获和PCR方法）将卡片TX直接连接到哮喘发病机理； （b）使用肺炎支原体感染和卡片TX中毒的小鼠模型检查哮喘和治疗干预措施的急性和慢性阶段，以及卡片TX对气道高反应性的影响； （c）进一步表征卡片TX的ADP-核糖基化活性，并开发有效而快速的诊断，以帮助治疗和控制哮喘和相关病理。每个项目和核心的主要研究人员在哮喘，与气道相关的病理学，免疫病变和肺炎生物学生物学和毒力以及协作和共同出版的历史方面具有强大的记录和专业知识。 项目1：新颖的支原体肺炎卡毒素作为小鼠气道功能障碍的调解人（Hardy，R。） 描述（由申请人提供）： 越来越多的证据将肺炎支原体呼吸道感染以及在哮喘患者子集中哮喘的造成，加剧和慢性。然而，该联系涉及的致病微生物机制尚未得到很好的特征。重要的是，博士。 Baseman和Kannan现在已经确定了一部小说M.肺炎M. pneumoniae Toxin，Cards TX。我们的研究人员联盟（Baseman，Coalson，Dube，Kannan，Peters和Hardy博士都有纸牌TX的初步证据，在气道炎症，气道阻塞，气道障碍物，气道高反应性中起着致病作用。拟议的研究的假设是，卡片TX介导了肺炎支原体诱导急性哮喘的能力，并负责支原体呼吸道感染的有害长期影响。此外，我们假设针对Cards TX的治疗干预措施将改善与肺炎相关的反应性气道疾病和哮喘。简而言之，具体目的是1）了解主动卡Tx对气道阻塞，过度反应性和炎症的特定贡献，在肺炎支原体呼吸道呼吸道感染中观察到的炎症，2）确定宿主对卡片Tx的免疫反应对卡片Tx的免疫反应是否具有保护性，是否可以保护对肺炎M.的呼吸道表现，并确定核核蛋白质的效应蛋白质蛋白质的效果蛋白质蛋白质的效果蛋白质构成蛋白质的效果，并构成细菌的效应。肺炎呼吸道感染。这些调查的长期目标是制定修改疾病，以治疗与支原体相关的反应性气道疾病和哮喘治疗儿童和成人。该项目的重点是研究新型的肺炎毒素毒素。 BALB/C小鼠将暴露于肺炎支原体（野生型和卡片TX NULL突变体）或重组卡TX，以确定卡片TX对肺炎支原体感染的气道表现的贡献。此外，将在我们的Murine模型中评估针对Cards TX的治疗干预措施，其目的是将与儿童和成人中与肺炎支原体相关的反应性气道疾病和哮喘的治疗。