The role of TRAIL-regulated signalling pathways and TLR7 in rhinovirus-induced exacerbation of allergic airways disease

Research Doctorate - Doctor of Philosophy (PhD)Asthma is a chronic inflammatory disease of the airways, associated with debilitating reversible airflow obstruction. The majority of healthcare costs from asthma-related hospitalisations are attributed to exacerbations by respiratory viruses, with rhinoviruses (RV) being the most commonly detected. This thesis presents original research papers detailing investigations to elucidate the mechanisms underlying RV-induced exacerbations of allergic airways disease (AAD). The first manuscript (see Chapter 2) details the elucidation of a novel TRAIL signalling pathway where the TRAIL-regulated gene product Midline-1 (MID1), which inhibits protein phosphatase 2A (PP2A), was found to promote AAD through increased homing of myeloid dendritic cells (mDCs) to the airway via CCL20 release. Notably, inhibition of MID1 or reactivation of PP2A abolished airway hyperresponsiveness (AHR) and attenuated airways inflammation and mucus hypersecretion in mouse models of AAD and RV-induced exacerbation. The second manuscript (see Chapter 3) investigates the importance of Toll-like receptor (TLR) 7-elicited interferon (IFN) responses during RV infection in an asthmatic setting. We show that following exposure to house dust mite (HDM), mice deficient in TLR7 display exaggerated eosinophilic inflammation and attenuated anti-viral responses when challenged with RV. TLR7 expression in the lungs of mice was found to be suppressed by interleukin-(IL)-5-induced eosinophilia, while human asthmatics with eosinophilic but not neutrophilic airways inflammation also showed reduced TLR7 and IFN expression. The third manuscript (see Chapter 4) revisits established therapeutic agents, long-acting β₂ agonists (LABAs), in light of recently described interactions with PP2A. This study extends those findings by reporting that administration of salmeterol, or other β₂ agonists, protected mice against HDM- and RV-induced lung inflammation as effectively as the corticosteroid dexamethasone. Salmeterol but not dexamethasone mediated this via increased PP2A activity, the inflammatory phenotype recapitulated when PP2A was targeted by siRNA. Taken together, these studies have identified new targets for the therapeutic intervention of asthma and RV-induced exacerbation