The interplay between epithelial-derived type-2 inflammation and rhinovirus infection in asthma

Rhinovirus (RV) infections are a key driver of asthma exacerbations. The airway epithelium is the main site of RV infection which orchestrates innate immune responses to limit viral replication. However, the airway epithelium in some individuals with asthma has a dysregulated antiviral response to RV infection which promotes type-2 inflammation. This thesis contains investigations into different RV-induced epithelial mediators which drive asthma exacerbations. The role of IL-25, CCL17, CCL22, interferon (IFN)-β, and IFN-λ are characterised in the host response to RV utilizing a combination of in vitro and in vivo approaches. In chapter 3, transcriptional regulation of airway epithelial cells (AEC) during RV infection was investigated for the chemokines CCL17 and CCL22. STAT6 was identified as crucial for RV-induced CCL17, but dampened CCL22 secretion during models of allergic inflammation. Silencing STAT6 through siRNA enhanced CCL22 secretion from AEC. In chapter 4, regulation of RV-induced IL-25 was examined at an epithelial cell level. IL-25 was shown to negatively regulate antiviral immunity in AECs from both healthy donors and donors with asthma. AECs cultured from donors with asthma maintained the deficient IFN phenotype observed in individuals with asthma, and IL-25 blockade with a monoclonal antibody (mAb) ameliorated virus induced IFN expression. In chapter 5, the regulation of virus-induced epithelial-derived mediators and type-2 innate lymphoid cells (ILC2) was investigated. Human ILC2 express the IFN-λ receptor IFNLR1 upon stimulation with IL-25 or IFN-β. Inversely, IFN-β reduced expression of its receptor IFNAR1 on ILC2. Both IFN-β and IFN-λ were required to reduce the frequencies of IL-13+ and IL-5+ ILC2 when cultured in the presence of IL-25. In summary, multiple approaches from investigating transcriptional regulation in AECs or treatment with an IL-25 mAb, to applying AEC-derived mediators on ILC2 were used to identify RV-induced regulation of mucosal immunity. These approaches identified limitations in our current understanding of how viral infections exacerbate individuals with asthma. Finally, they demonstrated how a novel IL-25 mAb could be used to simultaneously suppress type-2 inflammation and enhance the hosts anti-viral response during viral infection/asthma exacerbation.