Asthma is a complex disease that afflicts over 15 million Americans. Despite the apparent increase inprevalence of disease within our population, asthma is still a poorly understood disease. This is in part dueto the complex mixture of genetic factors, environmental stimuli, and immune system status that impactsdisease development and progression. One under appreciated and controversial factor in the etiology ofasthma is the role that atypical bacterial infections, such as those caused by Mycoplasma pneumoniae, playin initiating, exacerbating and prolonging airway-related symptoms and pathologies. A major part of theconfusion is the lack of reliable and relevant diagnostic methodologies and bona fide virulence determinantsthat directly link M. pneumoniae to asthma pathogenesis. Recently a unique M. pneumoniae toxin (CARDSTX: Community Acquired Respiratory Distress Syndrome Toxin) was discovered (see Preliminary resultssection and Project 4) that replicates the cytokine responses, pathology, and changes in airway hyperresponsivenessobserved with M. pneumoniae respiratory infections and M. pneumoniae-assocatedasthma. We consider this finding a potential major breakthrough and hypothesize that CARDS TX may beresponsible for acute, chronic, and exacerbation of asthma. To test this hypothesis, we will take advantageof the BALB/c-ovalbumin model of allergic asthma to test the following Specific aims: 1) Determine thecontribution 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 CARDSTX in the pathogenesis of asthma associated with M. pneumoniae infection. Mice will be infected with wildtype M. pneumoniae or M. pneumoniae with a null mutation in the CARDS TX gene. Pathogenesis will beevaluated in the BALB/c mouse model with and without ovalbumin-induced airway hyper-responsiveness, toelucidate the role of CARDS TX in the context of the infectious model, and 3) Investigate the activity ofCARDS TX in vivo. We will refine our analysis of the impact of CARDS TX on M. pneumon/ae-mediatedrespiratory 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 airwayhyper-responsiveness. The studies outlined in this project provide an asthma experimental model tocorrelate with clinical findings from Project 3; experiments using chronic models of infection described inProject 1; mutants, reagents and biochemical and molecular observations developed in Project 4; andPathology Core B expertise.
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