Current therapies prevent only ~40% of asthma exacerbations. These figures are in the context of clinical trials - real life asthma exacerbations are even less likely to be prevented.

The vast majority of asthma exacerbations therefore continue to occur despite use of the best available current therapies. When exacerbations do occur, treatment options are limited and have developed little in recent years. Treatment involves increasing doses of inhaled bronchodilators and systemic/oral corticosteroids - more of the same drugs that failed to prevent the exacerbation occurring in the first place. Further these treatments do not address the cause of the exacerbations, nor specific mechanisms involved in their pathogenesis. Current preventive and therapeutic strategies are thus of limited efficacy and development of new approaches is urgently needed. This requires understanding the mechanisms of asthma exacerbations so that targets for development of novel approaches to prevention/therapy can be identified. Virus infections are the major precipitants of exacerbations of asthma: Respiratory virus infections are detected in at least 80% of acute exacerbations in children and adults. Rhinoviruses (RV) are numerically the most important viruses implicated, accounting for 2/3 of infections detected. RV infection is therefore the greatest single precipitant of acute exacerbation of both diseases. For this reason we believe it important to study RV infections for the exacerbation work proposed. The airway epithelium is the site of RV infection and is now the focus of research seeking to develop better treatments for asthma attacks: This has led a number of key findings to support this line of investigation. First, there is an abnormality in the bronchial epithelium itself. In this context, we and others have provided key evidence showing that epithelial cells from asthmatics have inherited and/or acquired phenotypic differences that predispose them to abnormal differentiation and repair and these appear early in disease development. Another finding is that asthmatic epithelium can exhibit abnormal immune responses to RV infection including deficient anti-viral immunity and exaggerated expression of mediators that can up-regulate type-2 immunity. This is important because activation of type-2 immunity is an important driver of pulmonary inflammation during an asthma exacerbation. Epithelial regulation of type-2 immunity: Most children and around 50% of adults have allergic asthma. Type-2 immunity is upregulated in allergic asthma and is defined by production of IL-4, IL-5, IL9 and IL-13. These cytokines drive the pathological processes that underpin disease. However it is still unclear how viral infection of airway epithelium activates type-2 immunity to cause an exacerbation. We have recently published studies reporting epithelial expressed type-2 activating cytokines IL-25 and IL-33 are increased and associated with disease severity in human experimental RV asthma exacerbations studies.

We hypothesize that infection of asthmatic BECs generates an immune mediator milieu involving IL-25 and IL-33 that overcomes control by corticosteroids and activates type-2 immunity leading to increased airways inflammation and worsening of asthma symptoms.

We therefore aim to delineate the mechanisms that regulate expression of IL-25 and IL-33 during RV infection of bronchial epithelium.

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