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.
|Ramasamy, Kumaraguruparan; Balasubramanian, Sowmya; Manickam, Krishnan et al. (2018) Mycoplasma pneumoniae Community-Acquired Respiratory Distress Syndrome Toxin Uses a Novel KELED Sequence for Retrograde Transport and Subsequent Cytotoxicity. MBio 9:|
|Maselli, Diego J; Medina, Jorge L; Brooks, Edward G et al. (2018) The Immunopathologic Effects of Mycoplasma pneumoniae and Community-acquired Respiratory Distress Syndrome Toxin. A Primate Model. Am J Respir Cell Mol Biol 58:253-260|
|Segovia, Jesus A; Chang, Te-Hung; Winter, Vicki T et al. (2018) NLRP3 Is a Critical Regulator of Inflammation and Innate Immune Cell Response during Mycoplasma pneumoniae Infection. Infect Immun 86:|
|Sundaram, Aparna; Chen, Chun; Khalifeh-Soltani, Amin et al. (2017) Targeting integrin ?5?1 ameliorates severe airway hyperresponsiveness in experimental asthma. J Clin Invest 127:365-374|
|Wood, Pamela R; Kampschmidt, Jordan C; Dube, Peter H et al. (2017) Mycoplasma pneumoniae and health outcomes in children with asthma. Ann Allergy Asthma Immunol 119:146-152.e2|
|Benedetto, Roberta; Ousingsawat, Jiraporn; Wanitchakool, Podchanart et al. (2017) Epithelial Chloride Transport by CFTR Requires TMEM16A. Sci Rep 7:12397|
|Steed, Ashley L; Christophi, George P; Kaiko, Gerard E et al. (2017) The microbial metabolite desaminotyrosine protects from influenza through type I interferon. Science 357:498-502|
|Shen, Haiqian; Gonzalez-Juarbe, Norberto; Blanchette, Krystle et al. (2016) CD8(+) T cells specific to a single Yersinia pseudotuberculosis epitope restrict bacterial replication in the liver but fail to provide sterilizing immunity. Infect Genet Evol 43:289-96|
|Buchheit, Kathleen M; Cahill, Katherine N; Katz, Howard R et al. (2016) Thymic stromal lymphopoietin controls prostaglandin D2 generation in patients with aspirin-exacerbated respiratory disease. J Allergy Clin Immunol 137:1566-1576.e5|
|Cahill, Katherine N; Raby, Benjamin A; Zhou, Xiaobo et al. (2016) Impaired E Prostanoid2 Expression and Resistance to Prostaglandin E2 in Nasal Polyp Fibroblasts from Subjects with Aspirin-Exacerbated Respiratory Disease. Am J Respir Cell Mol Biol 54:34-40|
Showing the most recent 10 out of 41 publications