Role of CARDS Toxin in M. pneumoniae Associated Asthma in Mice

哮喘是一种复杂的疾病，折磨着超过1500万美国人。尽管……明显增加

Asthma is a complex disease that afflicts over 15 million Americans. Despite the apparent increase in prevalence of disease within our population, asthma is still a poorly understood disease. This is in part due to the complex mixture of genetic factors, environmental stimuli, and immune system status that impacts disease development and progression. One under appreciated and controversial factor in the etiology of asthma is the role that atypical bacterial infections, such as those caused by Mycoplasma pneumoniae, play in initiating, exacerbating and prolonging airway-related symptoms and pathologies. A major part of the confusion is the lack of reliable and relevant diagnostic methodologies and bona fide virulence determinants that directly link M. pneumoniae to asthma pathogenesis. Recently a unique M. pneumoniae toxin (CARDS TX: Community Acquired Respiratory Distress Syndrome Toxin) was discovered (see Preliminary results section and Project 4) that replicates the cytokine responses, pathology, and changes in airway hyperresponsiveness observed with M. pneumoniae respiratory infections and M. pneumoniae-assoc\ated asthma. We consider this finding a potential major breakthrough and hypothesize that CARDS TX may be responsible for acute, chronic, and exacerbation of asthma. To test this hypothesis, we will take advantage of the BALB/c-ovalbumin model of allergic asthma to test the following Specific aims: 1) Determine the contribution of our newly discovered ADP ribosylating, vacuolating CARDS TX to the pathogenesis of M. pneumoniae associated allergic asthma using established murine models, 2) Investigate the role of CARDS TX in the pathogenesis of asthma associated with M. pneumoniae infection. Mice will be infected with wild type M. pneumoniae or M. pneumoniae with a null mutation in the CARDS TX gene. Pathogenesis will be evaluated in the BALB/c mouse model with and without ovalbumin-induced airway hyper-responsiveness, to elucidate the role of CARDS TX in the context of the infectious model, and 3) Investigate the activity of CARDS TX in vivo. We will refine our analysis of the impact of CARDS TX on M. pneumon/ae-mediated respiratory disease through the analysis of CARDS TX-induced gene expression, localization/co-localization, and biochemical activity in vivo using the BALB/c mouse model with and without ovalbumin-induced airway hyper-responsiveness. The studies outlined in this project provide an asthma experimental model to correlate with clinical findings from Project 3; experiments using chronic models of infection described in Project 1; mutants, reagents and biochemical and molecular observations developed in Project 4; and Pathology Core B expertise.