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: 7134895
• 负责人: JOEL Barry BASEMAN
• 金额: $ 150.79万
• 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/7134895
• 关键词: Mycoplasma pneumoniae; asthma; clinical research; infection; pneumonia; role; toxin

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个综合的、协作的和创新的多学科努力，以研究一种独特的肺炎支原体毒素在哮喘和相关气道疾病中的作用。这种毒素，命名为社区获得性呼吸窘迫综合征毒素（CITTX），显著复制了伴随M.肺炎感染。这个由位于圣安东尼奥的德克萨斯大学健康科学中心和位于达拉斯的德克萨斯大学西南医学院组成的联盟结合了4个项目，重点是基础，临床和动物模型策略，2个支持核心（管理和病理学），为定义M.肺炎和哮喘的发病机制。大量的文献，这已经积累了35年，连接M。肺炎支原体与哮喘的发作、恶化和慢性化之间的关系，但没有单一的支原体毒力决定簇或支原体分子被证明是症状和相关病理的介导者。缺乏可定义的M。肺炎支原体致病因子的研究极大地阻碍了对肺炎支原体致病机理的理解。肺炎影响气道疾病的发生和发展。这在哮喘等复杂疾病中尤其具有挑战性，因为遗传、免疫、感染和环境变量似乎会影响疾病的发展和进展。AADCRC的一个主要焦点是将ADP-核糖基化、空泡化M的生物化学、分子和免疫学特性直接联系起来。pneumoniae pneumon通过这样做，我们希望证明，在人类（项目3）和实验感染或中毒的小鼠（项目1和2）中，BTX是哮喘相关病理生物学的关键介质。因此，我们打算（a）使用患者的鼻灌洗液、痰液和血清样品，通过新颖有效的靶向MTX的诊断评估（ELISA、免疫组织化学、抗原捕获和PCR方法学），将MTX与哮喘发病机制直接联系起来;（B）使用M.本发明的目的在于：（a）研究肺炎链球菌感染和肺炎克雷伯氏菌毒素中毒的特征，以检查哮喘的急性和慢性阶段和治疗干预以及肺炎克雷伯氏菌毒素对气道高反应性的影响;以及（c）进一步表征肺炎克雷伯氏菌毒素的ADP-核糖基化活性，并开发有效和快速的诊断方法，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者在哮喘、气道相关病理学、免疫发病机制和M。pneumoniae生物学和毒力以及合作和共同出版的历史。 项目1：新型肺炎支原体毒素作为小鼠气道功能障碍的介导剂（哈代，R.） 描述（由申请人提供）： 越来越多的证据表明M。肺炎呼吸道感染与哮喘的发病、加重和慢性化。然而，参与这一联系的致病微生物学机制尚未得到很好的表征。具有重要意义的是，贝斯曼和凯南博士现在已经确定了一种新的M。肺炎毒素（Pneumoniae toxin，Pneumoniae TX）。我们的研究人员联盟（Baseman、Coalson、Dube、Kannan、Peters和哈代博士）有初步证据表明，BTX在呼吸道炎症、气道阻塞、与呼吸道M相关的气道高反应性中起致病作用。肺炎感染。本研究的假设是，BTX介导了M.肺炎支原体感染导致急性哮喘恶化，并导致呼吸道支原体感染的有害长期效应。此外，我们假设，针对AMTX的治疗干预将改善M。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）了解活性MTX对M.肺炎支原体呼吸道感染，2）确定宿主对MPTX的免疫应答是否对MPTX的呼吸道表现具有保护性。pneumoniae感染，和3）确定细菌蛋白合成抑制剂治疗对M.肺炎呼吸道感染。这些研究的长期目标是开发疾病改善策略，以治疗支原体相关反应性气道疾病和哮喘的儿童和成人。本课题主要研究小说M. pneumoniae toxin，pneumoniae toxin，pneumoniae TX，在我们建立的急性和慢性小鼠M.肺炎呼吸道感染，其中气道炎症、气道阻塞和气道高反应性先前已被我们的实验室表征。BALB/c小鼠将暴露于M. pneumoniae肺炎支原体（野生型和pneumoniae TX无效突变体）或重组pneumoniae TX以确定pneumoniae TX对肺炎支原体的气道表现的贡献。肺炎感染。此外，将在我们的鼠模型中评估针对MSTX的治疗干预，目的是转化适用于治疗与M相关的反应性气道疾病和哮喘。肺炎在儿童和成人。