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Mycoplasma pneumoniae CARDS toxin mediated ADP-ribosylation of NLRP3 inflammasome

肺炎支原体卡毒素介导的 NLRP3 炎性体 ADP 核糖基化

基本信息

批准号：
9001254
负责人：
Santanu Bose
金额：
$ 18.97万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-02-01 至 2018-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9001254
关键词：
ADP Ribose Transferases ADP ribosylation Acute Adult Adult Respiratory Distress Syndrome Affect Alveolar Alveolar Macrophages Animals Binding Bronchoalveolar Lavage CASP1 gene Characteristics Child Chronic Cleaved cell Community Acquired Respiratory Distress Syndrome Toxin Complex Cytotoxin Data Diagnosis Disease Enzymes Epithelial Cells Event Extravasation Functional disorder Goals Health Histopathology Human Immune response Individual Inflammation Inflammatory Interleukin-1 Interleukin-1 beta Interleukins Knowledge Lead Link Lower respiratory tract structure Lung Lung Inflammation Lung diseases Lysosomes Mediating Mediator of activation protein Modality Modification Molecular Mus Mycoplasma pneumonia infection Mycoplasma pneumoniae Nuclear Organ Culture Techniques Pathogenesis Pathology Phenotype Play Population Post-Translational Protein Processing Potassium Primates Process Production Proteins Respiratory System Respiratory tract structure Rodent Role Severities Signal Transduction Site Specimen Stimulus Structure of respiratory epithelium Testing Therapeutic Intervention Tissues Toxin Trauma patient asthmatic base cell injury chemokine cytokine improved in vivo inflammatory lung disease innovation insight macrophage novel overexpression pathogen prevent respiratory ventilator-associated pneumonia

项目摘要

DESCRIPTION (provided by applicant): The proposed project asks fundamental and applied questions concerning the role that Mycoplasma pneumoniae (Mp) and its newly discovered ADP-ribosylating, vacuolating toxin, designated Community Acquired Respiratory Distress Syndrome (CARDS) toxin, play in the pathogenesis of airway disorders. CARDS toxin remarkably recapitulates the pro-inflammatory cytokine/chemokine profiles and histopathology that accompany Mp infection. In addition, inactivation of CARDS toxin significantly reduced the release of mature form interleukin-1ß (IL-1ß) during Mp infection. IL-1ß is a critical pro-inflammatory cytokine that dictates severity of inflammation associated with a wide spectrum of inflammatory diseases. Release of active mature IL-1ß is accomplished by inflammasome complex-mediated activation of caspase-1, the enzyme responsible for cleaving immature pro-IL-1ß into its mature form. NLRP3 is a key component of the inflammasome complex, and multiple signals and stimuli trigger formation of the NLRP3 inflammasome complex. In the airway, Mp and CARDS toxin are primarily detected in the alveolar macrophages, and our preliminary studies show NLRP3 inflammasome activation by CARDS toxin in primary macrophages leading to IL-1ß production. CARDS toxin co-localized with NLRP3 inflammasome in primary macrophages and interacted with NLRP3 as deduced by co-immunopreciptation analysis. Surprisingly, our preliminary studies demonstrated CARDS toxin-mediated ADP-ribosylation of NLRP3 and a requirement of ADP- ribosyltransferase (ART) activity of CARDS toxin for NLRP3 activation. Based on our preliminary results, we hypothesize that Mp and specifically CARDS toxin are key mediators of airway dysfunction and inflammation via CARDS toxin ART-related mechanisms involving NLRP3 inflammasome activation and resulting release of active mature IL-1ß in the airway. We plan to test this hypothesis by - a) studying the role of CARDS toxin ADP ribosylation and binding activities in NLRP3 inflammasome assembly and IL-1ß secretion, b) examining in vivo involvement of NLRP3 in CARDS toxin mediated IL-1ß production, c) investigating the role of IL- in triggering CARDS toxin-mediated lung inflammatory disease pathology, and d) elucidating the role of ART activity of CARDS toxin during in vivo IL-1ß production and inflammasome activation. Our long-term goal is to develop effective strategies to diagnose, treat and prevent Mp-related airway diseases in a substantial population of both children and adults. Understanding the mechanisms by which the inflammasome is activated via CARDS toxin should lead to therapeutic interventions and improved health in many individuals who suffer from acute and chronic airway and extrapulmonary pathologies linked to Mp infections. The proposed studies will also provide new insights about inflammasome activation mechanisms since post- translational ADP-ribosyltransferase-mediated modification of the inflammasome is a novel mechanism for inflammasome activation with subsequent release of IL-1ß and associated pathologies.