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

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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.