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 hyperreactivity 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. pnet/mon/ae-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, hyperreactivity, 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 hyperreactivity 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.
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