The role of CARDS toxin in genesis and exacerbation of allergic inflammation

University Of Texas Hlth Science Center, San Antonio TX

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Abstract

Asthma is a chronic disease impacting more than 23 million Americans. The factors leading to asthma are varied but several common and well-established risk factors include genetics, environment, allergen exposure, and infection with atypical bacterial pathogens. Mycoplasma pneumoniae is a common atypical bacterial pathogen strongly associated with wheezing in children and acute exacerbations of asthma in adults. A causal link between any atypical bacterial product and asthma was lacking, until, we identified a M. pneumoniae ADP-ribosylating/vacuolating toxin called Community Acquired Respiratory Distress Syndrome ToXin (CARDS TX) that is present in respiratory secretions of many of our severe refractory asthmatics and patients with acute exacerbations of asthma yet rarely detected in healthy controls. These data strongly suggest that CARDS TX represents a single molecule tightly linked to the pathogenesis of a large subset of asthma cases. We established a mouse model that allows us to investigate the immunological mechanisms responsible for CARDS TX-mediated pulmonary inflammation in both the naive and the atopic lung. Using our model, we demonstrated that naive mice receiving a single exposure to rCARDS TX exhibit an eosinophilic/lymphocytic inflammation leading to an asthma-like phenotype. Further, mice sensitized with OVA albumin or house dust mites and subsequently exposed to CARDS TX develop exacerbated eosinophilic/lymphocytic inflammation and hyperresponsiveness. The Aims for this project are 1) Investigate the immunological basis for the cellular inflammatory response induced by CARDS TX through elucidation of the molecular and cellular components responsible for the CARDS TX-mediated asthma-like responses in naive mice. 2) Investigate the immunological basis for CARDS TX-mediated exacerbation of allergic inflammation. We will determine the cellular and molecular mechanisms responsible for the CARDS TX-mediated exacerbation of allergic inflammation. 3) Investigate the immunological basis for CARDS TX promotion of inflammation using in vitro cell culture models with human cells. We will determine the cellular and molecular mechanisms responsible for the CARDS TX-mediated alteration of T-cell function.