Asthma is a complex disorder characterized by episodic airway obstruction and hyper-responsiveness, sometimes accompanied by airway remodeling. Although the underlying causes of asthma remain poorly understood, one contributing factor is exposure to respiratory pathogens. For example, asthmatics positive for Mycoplasma pneumoniae (M. pneumoniae) infection have demonstrated an improvement in pulmonary function after antibiotic treatment whereas patients that test negative do not, suggesting a causal relationship between M. pneumoniae infection and asthma symptom severity. Although there is a strong clinical correlation between M. pneumoniae infection and a sub-set of asthma cases, until recently, the identification of a virulence factor that might play a role in disease pathogenesis had remained elusive. This situation changed, however, when we discovered a 591 amino acid protein with ADP-ribosyltransferase (ART) activity in M. pneumoniae designated Community Acquired Respiratory Distress Syndrome ToXin (CARDS TX). The experiments outlined in this proposal are designed to uncover the structure and action of CARDS TX using a range of biophysical techniques. Using the well-established tools of single crystal X-ray diffraction, we will determine: 1) the three-dimensional structure of CARDS TX;2) CARDS TX in complex with its NAD"""""""""""""""" co-factor;3) CARDS TX in complex with neutralizing monoclonal antibody Fab fragments;and 4) CARDS TX in complex with recombinant extracellular domains of its cell surface receptor surfactant protein-A (SP-A). A longer term goal is to use these 3-D structures in conjunction with the information coming from Projects 1 and 2 as platforms for the design of CARDS TX inhibitors, which may represent novel therapeutic agents for the treatment of asthma and pulmonary inflammation.

Public Health Relevance

CARDS TX is a virulence protein used by Mycoplasma pneumoniae, the causative agent of asthma, pneumonia, and other inflammatory lung disorders in humans. The experiments outlined in this proposal will reveal the molecular structure of CARDS TX and will illuminate its mode of action. This information will in turn permit the design of novel diagnostic and therapeutic avenues for the treatment of asthma and other pulmonary diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI070412-09
Application #
8705992
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
9
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Texas Health Science Center
Department
Type
DUNS #
City
San Antonio
State
TX
Country
United States
Zip Code
78229
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