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

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 #
5U19AI070412-08
Application #
8513882
Study Section
Special Emphasis Panel (ZAI1-PA-I)
Project Start
Project End
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
8
Fiscal Year
2013
Total Cost
$142,546
Indirect Cost
$35,386
Name
University of Texas Health Science Center San Antonio
Department
Type
DUNS #
800772162
City
San Antonio
State
TX
Country
United States
Zip Code
78229
Ji, Hong; Zhang, Xue; Oh, Sunghee et al. (2015) Dynamic transcriptional and epigenomic reprogramming from pediatric nasal epithelial cells to induced pluripotent stem cells. J Allergy Clin Immunol 135:236-44
Medina, Jorge L; Coalson, Jacqueline J; Brooks, Edward G et al. (2014) Mycoplasma pneumoniae CARDS toxin exacerbates ovalbumin-induced asthma-like inflammation in BALB/c mice. PLoS One 9:e102613
Kannan, Thirumalai R; Krishnan, Manickam; Ramasamy, Kumaraguruparan et al. (2014) Functional mapping of community-acquired respiratory distress syndrome (CARDS) toxin of Mycoplasma pneumoniae defines regions with ADP-ribosyltransferase, vacuolating and receptor-binding activities. Mol Microbiol 93:568-81
Somarajan, Sudha R; Al-Asadi, Fadi; Ramasamy, Kumaraguruparan et al. (2014) Annexin A2 mediates Mycoplasma pneumoniae community-acquired respiratory distress syndrome toxin binding to eukaryotic cells. MBio 5:
Burks, Margaret L; Brooks, Edward G; Hill, Vanessa L et al. (2013) Assessing proxy reports: agreement between children with asthma and their caregivers on quality of life. Ann Allergy Asthma Immunol 111:14-9
Krishnan, Manickam; Kannan, T R; Baseman, Joel B (2013) Mycoplasma pneumoniae CARDS toxin is internalized via clathrin-mediated endocytosis. PLoS One 8:e62706
Kannan, T R; Hardy, R D; Coalson, J J et al. (2012) Fatal outcomes in family transmission of Mycoplasma pneumoniae. Clin Infect Dis 54:225-31
Medina, Jorge L; Coalson, Jacqueline J; Brooks, Edward G et al. (2012) Mycoplasma pneumoniae CARDS toxin induces pulmonary eosinophilic and lymphocytic inflammation. Am J Respir Cell Mol Biol 46:815-22
Johnson, Coreen; Kannan, T R; Baseman, Joel B (2011) Cellular vacuoles induced by Mycoplasma pneumoniae CARDS toxin originate from Rab9-associated compartments. PLoS One 6:e22877
Muir, Mark T; Cohn, Stephen M; Louden, Christopher et al. (2011) Novel toxin assays implicate Mycoplasma pneumoniae in prolonged ventilator course and hypoxemia. Chest 139:305-10

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