The Role of Airway Epithelial Cell Endoplasmic Reticulum Stress in Viral-Induced Asthma Exacerbations

Respiratory viral infections are important drivers of asthma exacerbations, associated with significant morbidity and mortality. Viral infections alter the airway environment, hijacking host cell translational machinery and leading to the upregulation of cellular processes such as the unfolded protein response (UPR), an ER (endoplasmic reticulum) stress pathway. Activation of UPR acts to alleviate ER stress and downstream inflammatory signalling either through restoration of protein homeostasis or initiation of apoptosis. Many viruses can manipulate UPR to promote their own replication whilst disrupting cell protein homeostasis. Importantly, the mechanisms and consequences of respiratory viral infection and the role of ER stress in airway epithelial cells have yet to be fully elucidated. We hypothesised that respiratory viruses, rhinovirus (RV, a major cause of asthma exacerbations) and respiratory syncytial virus (RSV, which causes bronchiolitis, a severe childhood illness) modulate the UPR to promote viral replication. Understanding how these viruses perturb ER stress will allow us to target virus-induced ER stress for therapeutic intervention.
The ability of RV and RSV to modulate inflammatory and ER stress pathways in primary and lifespan extended bronchial epithelial cells was explored. Both RV and RSV stimulated inflammatory and antiviral secretory responses, though these differed somewhat in magnitude between the two viruses. Mock infection with viral control, control antigen, had profound effects on UPR marker expression whilst RV and RSV induced only modest changes in UPR signalling. Pre-treatment with two ER stress inducers modified virus-induced inflammatory and antiviral responses and viral replication in a virus-specific fashion, limiting RSV replication but promoting RV replication. Furthermore, the extent to which RSV induced inflammatory cytokine release and ER stress was also investigated in primary bronchial epithelial cells from asthmatic donors. No differences were observed in inflammatory or antiviral responses or UPR marker expression following RSV infection between cells from healthy or asthmatic donors. Pre-treatment with ER stress inducer thapsigargin decreased RSV-induced antiviral secretory responses but had no effect on viral replication in the low donor numbers available.
These data suggest that further work is required to fully elucidate respiratory virus-induced UPR signalling, however, induction of ER stress may be a potential therapeutic target in viral-induced asthma exacerbations.