Tuesday, April 16, 2024
4/16/2024
Project Summary Asthma exacerbations among U.S children result in 640,000 emergency department visits and 14 million missed school days annually. Viral infections trigger the majority of exacerbations in children, of which human rhinoviruses (HRV) are the most common. The airway epithelium plays central roles in regulating inflammation, airway remodeling responses, and innate immune responses to infection. The most striking response of airway epithelial cells (AECs) to viral infection is expression of type I and III interferons (IFN I/III) and IFN stimulated genes (ISG). Some have reported deficient IFN I/III responses to viral infection by asthmatic AECs and postulated that deficient epithelial IFN responses to viruses predispose to exacerbations, whereas others have not observed differences in AEC IFN responses to viruses between asthmatic and healthy AECs. In our unique cohort of well characterized asthmatic and healthy children, from whom we obtain bronchial and nasal AECs and conduct mechanistic experiments using air-liquid-interface organotypic culture models, we have observed significant heterogeneity in IFN I/III responses to HRV and RSV infection. For example, among our asthmatic AEC donors we have noted associations between high type I/III IFN responses and lower donor lung function, as well as distinct subgroups of exacerbation prone asthmatics with deficient IFN I/III responses to HRV. Heterogeneity in AEC IFN I/III responses to viral infections may be explained by polymorphisms in genes coding for viral sensors and/or key steps in signal transduction pathways upstream of IFN I and III. The overall goal my research program is to understand how airway epithelial responses influence viral-triggered exacerbations and airway remodeling mechanisms in asthmatic children. In the first aim, using primary cells from children with asthma we will test our hypothesis that polymorphisms in genes coding for viral sensors, and/or key steps in signal transduction pathways upstream of IFN responses, contribute to heterogeneity in IFN I/III responses to HRV infection by AECs from asthmatic children. In the second aim, we will prospectively follow a cohort of asthmatic children to test our hypothesis that deficient AEC IFN I/III responses to HRV are associated with a greater incidence of viral-triggered exacerbations in AEC donors. In the final aim, we will test our hypothesis that excessively high IFN I/III responses by asthmatic AECs to HRV are associated with lung function decline among AEC donors, and we will interrogate potential mechanisms whereby excessively high IFN I/III responses may promote proliferation and activation of lung stromal cells. The studies conducted in my research program and unique resource of primary airway epithelial cells from clinically well characterized asthmatic children provide an exceptional training environment for young investigators dedicated to a career in mechanistic patient-oriented research to learn translational research techniques to investigate the role of the airway epithelium in pediatric lung diseases and viral infection.
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