Asthma and allergic rhinitis are currently understood as closely related, inflammatory diseases of the respiratory track, most often starting early in life and having a chronic, non-predictable, course. The major focus in mechanistic and animal model research in this respect has been that of an immunological imbalance between Th1 and Th2 cytokine responses, and/or defective T-cell mediated regulation, leading to allergen sensitization and persistent eosinophilic inflammation. More recently, pathological features of asthma, collectively called airway remodelling, have attracted attention, suggesting a defect in epithelial repair that is augmented in the context of Th2 inflammation.
However, there are several features of the disease that cannot be explained from the above model: a considerable part of the disease burden and symptoms in asthma do not depend upon allergen exposure, but are rather caused by other stimuli such as exercise, pollution or infection. Mechanisms and mediators of inflammation induced by these triggers are notably different and probably independent from allergen-induced inflammation. The effect of such factors in rhinitis is even less understood.
Furthermore, despite considerable efforts and numerous well-designed studies, it has proved difficult to predict the persistence or not of clinical symptoms, with acceptable sensitivity and specificity, or identify risk factors other than atopy and current disease severity, suggesting that the natural history of the disease may be continuously developing in relation to ongoing exposures.
The contribution of respiratory viruses has been well established in respect to triggering acute exacerbations of asthma, RVs being by far the commonest pathogen involved. In regard to asthma and/or allergy development, respiratory syncytial virus causing severe bronchiolitis has been frequently implicated, but causality has been just as frequently challenged.
Recently however, it has become evident that RV is a stronger risk factor in this respect, although causality cannot be still confirmed. Much less is known about the mechanisms that mediate asthma and rhinitis persistence and how these may be affected by infection. RV induces production of growth factors that promote airway remodelling, and this is augmented in an atopic environment. Disease exacerbations may increase the chances for a subsequent infection and/or exacerbation. In a recently described mouse model, a single viral infection resulted, in addition to the acute effects typically described, in development of chronic inflammation. However, exposure to respiratory infectious agents and subsequent symptoms are very frequent events, affecting all individuals, so in humans additional factors should account for persistence of the inflammatory response.
PreDicta will evaluate the hypothesis that repeated infections may reprogram the immune responses towards a chronic inflammation pattern. Several key areas will be investigated including the role of emerging respiratory viruses, such as RV-C, and concurrent bacterial colonization in inflammatory responses, the role of repeated infections in clinical asthma persistence, the involvement of repeated RV infections in allergen sensitization, the function of respiratory epithelium in T cell differentiation and function, the molecular basis for defective type I IFN production and impaired viral clearance, the interactions between viruses and bacteria in the respiratory mucosa, the interplay of T cell-dendritic cell-epithelial cells in immune regulation and tolerance, and the importance of lipid mediators in the resolution of airway inflammation.