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.
This project is relevant to the NIH's mission to improve human health because it investigates the molecular mechanisms contributing to the development of asthma due to atypical bacterial infection. This study has the potential to provide insight into the how a bacterial toxin can cause and worsen asthma in humans. Our animal models and translational studies will provide the baseline knowledge and tools to for novel asthma interventions.
|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|
Showing the most recent 10 out of 20 publications