Even mild asthmatics experience severe exacerbations at a rate of almost one per year and those attacks can be fatal. Rhinovirus (RV) causes the majority of asthma exacerbations, which may be linked to an impaired antiviral interferon (IFN) response in asthmatics. RV is a single stranded (ss) RNA virus and is sensed by, for instance, Toll-like receptor (TLR) 7, but the role of this innate host defence pathway in regulating antiviral responses directed against RV remains unknown. RV also causes severe lower respiratory tract infections (LRTI) in infancy and RV-induced LRTI are associated with a twenty-fold greater risk of developing asthma in later life. It remains unknown whether the strong relationship between LRTI and asthma in later life is causal or a consequence arising from an impaired antiviral response.
Furthermore the molecular and cellular mechanisms of predisposing to RV-induced susceptibility and exacerbation are yet to be identified. We show in our forerunner studies that TLR7 deficiency results in exaggerated inflammatory and impaired antiviral responses that are associated with attenuated RV clearance from the lungs. TLR7 deficiency also impaired interferon regulatory factor (IRF) 7 expression a master regulator of interferon responses in virus-induced asthma exacerbation in children and promoted CCL7/MCP-3 expression a highly upregulated chemokine during RV infection and previously associated with the development of allergic airways inflammation. Our aim is to build on these observations and characterise the in-vivo role of TLR7 signalling and its downstream effector pathways (IRF7 and CCL7) in RV-induced exacerbation as well as early life RV-induced LRTI and later development of allergic airways disease. These investigations will lead to a better understanding of the link between impaired antiviral responses and asthma as well as the identification of potential therapeutic strategies to boost antiviral IFN responses and limit exaggerated RV-induced inflammation associated with exacerbations.
OVERALL HYPOTHESIS: TLR7 signalling and its downstream effector pathways play a crucial role in the generation of an effective antiviral response to RV that limits viral replication and Th2 dominated airways inflammation.