Biochemical, molecular and immunological characterization of Mycoplasma pneumoni

肺炎支原体的生化、分子和免疫学特征

• 批准号: 8328001
• 负责人: JOEL Barry BASEMAN
• 金额: $ 42.24万
• 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: 2011-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8328001
• 关键词: ADP ribosylation; Acute; Adult; Adult Respiratory Distress Syndrome; Allergic inflammation; Alveolar; Amino Acids; Animal Model; Antibodies; Asthma; Binding; Biochemical; Biological; Biological Assay; Cells; Chemicals; Chest; Child; Chronic; Clinical; Collection; Community Acquired Respiratory Distress Syndrome Toxin; Dendritic Cells; Development; Diagnosis; Diagnostic; Diphtheria Toxin; Disease; Epithelial; Epitopes; Essential Amino Acids; Fibroblasts; Functional disorder; Future; Goals; Human; Immune; Incidence; Individual; Infection; Inflammation; Inflammatory; Injury; Knowledge; Lead; Length; Link; Lung; Lymphocyte; Mammalian Cell; Mediating; Mediator of activation protein; Molecular; Monitor; Monoclonal Antibodies; Mus; Mycoplasma; Mycoplasma pneumoniae; Passive Immunization; Pathology; Pathway interactions; Patients; Personal Satisfaction; Pertussis Toxin; Phenotype; Pneumonia; Population; Predisposition; Progress Reports; Property; Proteins; Pulmonary Surfactant-Associated Protein A; Pyroglyphidae; Reagent; Relative (related person); Research; Resistance; Role; Sampling; Site; Specimen; Structure; Structure of respiratory epithelium; Testing; Therapeutic Agents; Tissues; Toxin; Transcriptional Regulation; Transferase; Translational Regulation; Trauma; Ventilator; Virulence; clinically relevant; design; improved; innovation; macrophage; microbial; neutralizing antibody; novel; pathogen; polyclonal antibody; prevent; receptor; small molecule; therapeutic vaccine; vaccine candidate

Mycoplasma pneumoniae is a common atypical bacterial pathogen strongly associated with acute and chronic airway diseases, including new-onset asthma and exacerbations, as well as persistent infections in children and adults. Knowledge on how M. pneumoniae causes infection with accompanying inflammatory pathways, pathologies and sequelae has been deficient. However, our identification of the Community Acquired Respiratory Distress Syndrome ToXin (CARDS TX), a bona fide ADP ribosylating and vacuolating toxin, has provided a direct causal link between M. pneumoniae and ainway inflammation and injury. This connection between M. pneumoniae, CARDS TX and lung hyper-responsiveness and inflammation is reinforced by SA-AADCRC research efforts demonstrating M. pneumoniae and CARDS TX direct clinical relevance and further supported by animal modeling and innovative diagnostic, pathological, biological, chemical and immunological assessments. Considering these findings and the structural and functional similarities and potential pathogenic significance of CARDS TX relative to pertussis and diphtheria toxins, we hypothesize that CARDS TX is a critical pathogenic contributor to M. pneumoniae-mediated asthma and related ainway diseases. To test this hypothesis, we will: 1. Characterize CARDS TX-mediated ADP-ribosyl transferase (ART) activity by detecting the CARDS TX minimal domain essential for ART function and by identifying the mammalian target proteins that are ADP-ribosylated by CARDS TX. 2. Characterize the CARDS TX binding region by identifying the minimal region(s) and essential amino acids that mediate binding to surfactant protein-A and mammalian cell receptor(s). 3. Generate monoclonal and polyclonal antibodies reactive against CARDS TX and determine epitopes of CARDS TX capable of inducing blocking/neutralizing antibodies. In the latter case, the availability of antibody reagents that neutralize and block CARDS TX activities, along with the collaborative studies outlined throughout this SA-AADCRC application should assist in the innovative design of therapeutic agents and improved diagnostics.

支原体肺炎是一种常见的非典型细菌病原体，与急性和 慢性气道疾病，包括新的哮喘和恶化，以及持续的感染 儿童和成人。有关肺炎开发菌如何引起感染和随附炎症的知识 途径，病理和后遗症一直缺乏。但是，我们对社区的认同 获得的呼吸窘迫综合征毒素（Cards TX），一种真正的ADP核糖基和空泡 毒素已经提供了肺炎支原体与Ainway炎症和损伤之间的直接因果关系。这 M.肺炎，卡片TX和肺部超反应性和炎症之间的联系是 SA-AADCRC的研究工作证明了肺炎和卡片的直接临床 相关性，并得到动物建模和创新诊断，病理，生物学， 化学和免疫学评估。考虑这些发现以及结构和功能 卡片Tx相对于百日咳和白喉毒素的相似性和潜在的致病意义，我们 假设Cards TX是肺炎支原体介导的哮喘和 相关的Ainway疾病。为了检验这一假设，我们将：1。表征卡TX介导的ADP-核糖基 通过检测卡片TX最小域，对艺术功能和通过 识别由卡片Tx对ADP-核糖基化的哺乳动物靶蛋白。 2。表征 卡片TX结合区域通过识别介导的最小区域和必需氨基酸 与表面活性剂蛋白A和哺乳动物细胞受体的结合（S）。 3。产生单克隆和多克隆 反应反对卡Tx的抗体，并确定能够诱导的卡片的表位 阻断/中和抗体。在后一种情况下，中和和 Block Cards TX活动以及整个SA-AADCRC的合作研究 应用应协助治疗剂的创新设计和改进的诊断。