A major goal of this AADCRC proposal is to understand how the innate and adaptive immune responses? contribute to asthma In this Project, we concentrate on the innate response of airway epithelial cells and the? special role of Stat1 signaling. We particularly develop the hypothesis that epithelial Statl signaling is a? critical early step in defense against respiratory viruses and can thereby also regulate virus-inducible asthma? traits in the short and long terms. Thus, loss of epithelial (versus immune) cell function for Stat1 is associated? with exquisite sensitivity to respiratory viral infection. In the case of Sendai virus (SeV) infection, loss of Stat1? gives rise to severe neutrophilic inflammation in mice that resembles severe RSV bronchiolitis in infancy. In? the case of hMPV infection, loss of Stat1 allows for a striking eosinophilic inflammation and mucous cell? metaplasia that may resemble hMPV infection in children with associated asthma symptoms. In contrast to? Statl deficiency, a modification of Statl (designated Stat1-CC) that increases IFN responsiveness can? increase viral clearance and improve outcome from infection. In the case of SeV, infection also causes? delayed but then permanent switch to asthma traits (i.e., airway hyperreactivity and mucous cell metaplasia),? and Stat1-CC protects against this long-term consequence as well. Moreover, these benefits appear? achievable even when Stat1-CC expression is restricted to ciliated airway epithelial cells, the predominant? site of viral replication. We therefore submit that epithelial Stat1 signaling is the first line of defense against? infection by asthmagenic viruses and that compromise of this defense leads to more severe infection and in? turn to a greater likelihood of developing acute and chronic asthmatic phenotypes. By contrast, we propose? that modifying this epithelial system to enhance IFN efficacy can decrease the severity of viral infection and? the likelihood of developing an asthmatic response. Thus, a proper balance of the Stat1 system is required to? optimize host defense and minimize airway inflammation. To further develop this concept, we aim to: (i)? Define the role of epithelial Stat1 signaling in acute and chronic responses to viral infection in a mouse? model that focuses on the epithelial requirement for endogenous Stat1 as well as the benefit of epithelial? Statl-CC in defense against infection with SeV and hMPV and the subsequent development of asthma traits,? (ii) Define the role of epithelial Stat1 signaling after virus-induced wheezing in early childhood and after? established asthma in adulthood.
This aim will prospectively characterize the acute and chronic response to? hMPV infection in children and the behavior of epithelial Stat1 signaling in this setting and will re-visit the? issue of epithelial Stat1 signaling in adult asthma with attention to Stat1/Stat2 activation of type I IFN? signaling. This Project will also collaborate with Project 2 and 3 in studies of complement component and? inhibitory receptor signaling in T cells to gain a more complete analysis of the antiviral response and how it? relates to the development of asthma.
Showing the most recent 10 out of 84 publications
