A major goal of the overall AADCRC proposal is to define the role of the epithelial cell barrier in the pathogenesis of asthma and allergic disease and to use that information to prevent this type of disease. The present project is derived from new insights into the issue of how airway epithelial cells mediate effective host defense (especially against respiratory viruses) under one condition but inflammatory disease (especially asthma) under another. We will develop the hypothesis that the proper amplitude of interferon (IFN) signaling within airway epithelial cells is absolutely critical in determining these divergent outcomes. In support of this hypothesis, our preliminary studies suggest that: (1) the severity of the acute viral infection correlates closely with the likelihood of subsequent asthma-like disease in at least two mouse models?one with Sendai virus (SeV) and another with (unexpectedly) influenza A virus (lAV);(2) loss of IFN signaling results in more severe viral infection;(3) enhanced IFN signaling protects against viral infection;(4) the most likely cell type to mount an effective IFN response is the airway epithelial cell based on studies of bone-marrow chimeric mice;and (5) the benefit of enhanced IFN signaling is maintained when it is restricted to airway epithelial cells based on studies of transgenic mice. Furthermore, our studies of human subjects also reveal a link between IFN signaling and asthma. In this case, airway epithelial cells from asthmatic subjects exhibit a striking defect in IFN response and control of viral replication after lAV inoculation. To better understand how IFN signaling is regulated, we pursued the mechanism underlying our observations. We discovered that the master regulator of type I, II, and III IFN signaling (Stat1) forms a heretofore unrecognized transcriptional complex with two novel factors (PARP9 and DTX3L) in airway epithelial cells. This interaction proved to be essential for enhanced IFN and antiviral function. These studies thereby offer the hypothesis that restoration of proper IFN signaling would better protect against viral illness and decrease the incidence of subsequent asthma in humans as well. To further develop these insights and translate them to practical application, we have the following specific aims: (1) define the role of airway epithelial IFN signaling in protection against chronic postviral asthma using cell and mouse models using loss and gain of function approaches;and (2) define and correct the abnormality in epithelial IFN response in human asthma using well-differentiated primary-culture human airway epithelial cells, again in two complementary approaches. The studies synergize with the approach to epithelial remodeling in Project 2 and epithelial injury in Project 3 to form a novel and comprehensive approach to epithelial function in asthma and allergy.
Respiratory viral infections are among the most common causes of serious illness and are implicated as a cause of asthma. However, we currently have no specific and effective therapies that influence this type of infection or the progression to chronic lung disease. This proposal aims directly at this issue by defining a new mechanism for controlling viral infection and postviral asthma in experimental models and in humans. The proposed studies represent the next steps in the drug discovery process for these problems.
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