The role of STATs in the interaction of virus and type 2 cytokines in airway epithelial cells

Respiratory virus infection, mainly rhinovirus (RV), is the leading cause of asthma exacerbations. Airway epithelial cells (AECs) are the primary site of viral infection and replication and therefore key to the host antiviral immune response. Asthma is an inflammatory airway disease, and AECs are exposed to inflammatory cytokines including type 2 cytokines IL-4 and IL-13, which is involved in pathological processes that drives asthma. In asthma, the interaction of molecular signalling pathways in AECs stimulated by type 2 cytokines and virus infection regulate airway inflammation and determine disease outcome. However, the mechanism involved in the interplay between type 2 inflammation and antiviral response in asthma remains unclear. This thesis investigates the effect of type 2 cytokines on antiviral response in primary bronchial epithelial cells (pBECs) from asthmatics via the JAK-STAT signalling pathway. To establish a pivotal role for STATs in mediating the response to respiratory viruses, in chapter 3, transcriptome profiles in pBECs with RV, influenza virus (IV) or coronavirus (CoV) infection were analysed. The results revealed that the genes involved in JAK-STAT signalling pathway were commonly induced in pBEC response to different respiratory viruses, and this signalling is delayed in asthma. In chapter 4, viral load and STAT1, STAT6 expression and phosphorylation were characterised in RV-infected pBECs in the presence of IL-4/IL-13 to determine the effect of type 2 cytokines on virus replication and virus-induced JAK-STAT signalling. Despite predicted that type 2 cytokines would suppress virus induced IFN, I observed the opposite outcomes: increased type I/III IFN expression associated with increased viral load in the presence of type 2 cytokines. However despite increased IFNs, type 2 cytokines inhibited RV-induced STAT1 expression and phosphorylation, leading to attenuated antiviral response and increased virus replication in pBECs from asthmatics. To confirm this in chapter 5, immune gene signatures were measured in pBECs with IL-4/IL-13 treatment, RV infection or the combination of RV infection with IL-4/IL-13 from asthmatics. The results identified that type 2 cytokines negatively regulate RV induced IFN-mediated signalling by suppressing STAT1 expression, and revealed both type 2 cytokines and RV infection contributed to the expression of genes involved in antigen presentation by epithelial cells such as MHC class II. In summary, STAT signalling in response to type 2 cytokines and virus infection in pBECs was well characterised, which provided a new insight into the mechanisms underlying the interaction between type 2 inflammation and antiviral response in airway epithelium, by identifying reduced STAT1 expression and activation as the potential molecular cause of defective antiviral immunity in asthma.