Mycoplasma pneumoniae is a common atypical bacterial pathogen strongly associated with acute and chronic airway diseases, including new-onset asthma and exacerbations, as well as persistent infections in children and adults. Knowledge on how M. pneumoniae causes infection with accompanying inflammatory pathways, pathologies and sequelae has been deficient. However, our identification of the Community Acquired Respiratory Distress Syndrome ToXin (CARDS TX), a bona fide ADP ribosylating and vacuolating toxin, has provided a direct causal link between M. pneumoniae and ainway inflammation and injury. This connection between M. pneumoniae, CARDS TX and lung hyper-responsiveness and inflammation is reinforced by SA-AADCRC research efforts demonstrating M. pneumoniae and CARDS TX direct clinical relevance and further supported by animal modeling and innovative diagnostic, pathological, biological, chemical and immunological assessments. Considering these findings and the structural and functional similarities and potential pathogenic significance of CARDS TX relative to pertussis and diphtheria toxins, we hypothesize that CARDS TX is a critical pathogenic contributor to M. pneumoniae-mediated asthma and related ainway diseases. To test this hypothesis, we will: 1. Characterize CARDS TX-mediated ADP-ribosyl transferase (ART) activity by detecting the CARDS TX minimal domain essential for ART function and by identifying the mammalian target proteins that are ADP-ribosylated by CARDS TX. 2. Characterize the CARDS TX binding region by identifying the minimal region(s) and essential amino acids that mediate binding to surfactant protein-A and mammalian cell receptor(s). 3. Generate monoclonal and polyclonal antibodies reactive against CARDS TX and determine epitopes of CARDS TX capable of inducing blocking/neutralizing antibodies. In the latter case, the availability of antibody reagents that neutralize and block CARDS TX activities, along with the collaborative studies outlined throughout this SA-AADCRC application should assist in the innovative design of therapeutic agents and improved diagnostics.
Our long-term goal is to develop effective strategies to diagnose, treat and prevent asthma and related airway diseases in a substantial population of both children and adults. We believe that this project is innovative and should lead to effective strategies to understand the role of M. pneumoniae infection and CARDS TX in asthma development and progression, thereby improving societal well-being.
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