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

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、协作和创新的多学科努力，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，被称为社区获得性呼吸窘迫综合征毒素（CARDS TX），显著地复制了伴随肺炎支原体感染的促炎细胞因子/趋化因子谱和组织病理学。该项目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联合开展，包括4个项目，重点关注基础、临床和动物建模策略，以及2个支持核心（行政和病理），旨在为定义肺炎支原体与哮喘发病机制之间的关系带来一种全新的方法。积累了超过35年的大量文献，将肺炎支原体与哮喘的发病、加重和慢性联系起来，但没有单一的支原体毒力决定因素或支原体分子被证明是症状和相关病理的中介。缺乏可定义的肺炎支原体致病因子极大地阻碍了对肺炎支原体如何影响气道疾病的发生和进展的理解。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的一个主要重点是将adp核糖基化、空泡化肺炎支原体TX（项目4）的生化、分子和免疫学特性与哮喘患者的诊断和治疗（项目3和4）直接联系起来。通过这样做，我们希望证明CARDS TX是人类（项目3）和实验感染或中毒小鼠（项目1和2）哮喘相关病理生物学的关键介质。因此，我们打算(a)通过使用患者的鼻腔灌洗液、痰液和血清样本，通过新颖有效的CARDS TX靶向诊断评估（ELISA、免疫组织化学、抗原捕获和PCR方法），将CARDS TX与哮喘发病机制直接联系起来；(b)使用肺炎支原体感染和卡牌TX中毒的小鼠模型来检查急性和慢性哮喘阶段和治疗干预措施，以及卡牌TX对气道高反应性的影响；(c)进一步表征卡TX的adp核糖基化活性，并开发有效和快速的诊断方法，以协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、免疫发病机制和肺炎支原体生物学和毒力方面都有很强的跟踪记录和专业知识，并且有合作和共同发表的历史。

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.