Exploring the role of early life respiratory infection in asthma

© 2017 Dr. Meaghan FitzPatrickThe underlying cause of asthma is yet to be determined. Asthma is presently the most common chronic disease affecting children, and it is becoming clear that disease originates in early life and as a result of complex synergistic interactions of various environmental exposures. There has been increasing interest in the role of neonatal infections; with evidence emerging that asymptomatic pneumococcal colonisation is a strong predictor of future asthma, which can be exacerbated by viral infection. It is therefore paramount that appropriate models of disease are developed in order to elucidate these complex immunological interactions that have profound pathogenic potential during this window of lung development. Importantly, small airways dysfunction is present in the majority of asthmatics, and remains relatively undertreated by existing therapy, contributing considerably to the severity of disease. The lung slice technique is a powerful in vitro tool that can be used to explore airway and vascular pharmacology, offering a unique experimental link between cell-based assays and in vivo experimentation. Methodological studies compared airway reactivity in lung slices in varying experimental conditions, and application of the lung slice technique to characterize reactivity following acute respiratory infection in vivo, permitting application of this technique within the rest of this thesis. Utilising novel mouse models of asthma, parameters of bronchial reactivity, lung immunity and structural changes were assessed in adulthood following exposures in infancy, elucidating key mechanisms driving the deleterious effects caused by early life exposures. Using a mouse model of neonatal respiratory co-infection, the effect of early life co-infection with Streptococcus pneumoniae (SP) and influenza A virus (IAV) on mouse lung health, immunity and structure in adulthood was investigated. Co-infection caused a significant increase in central airway resistance that was not associated with conventional airway remodelling such as mucus overproduction, smooth muscle thickening or epithelial leakage. Airways hyperresponsiveness (AHR) was not maintained in lung slices in vitro. An increase in hysteresivity was observed in both IAV and co-infected mice. Hence, it is possible that co-infection in infancy is causing distinct structural changes that contribute to ventilation heterogeneity, which persists into adulthood. A novel model of early life co-infection combined with house dust mite (HDM) aeroallergen challenge was developed and characterised. Neonatal co-infection in the background of HDM sensitisation resulted in chronic lung colonisation, exacerbated neutrophilic inflammation, increased mucin production and increased AHR. Hence, pneumococcal colonisation does not protect against allergic airways disease which is predominately driven by mechanisms that are independent of TH2 immunity. This study identified SAA, IL-17A and G-CSF as molecular markers for this phenotype, which parallels features of more severe asthma. Taken together, the strong neutrophilic/TH17/SAA signal, accompanied by AHR and mucus hyper-secretion generated in the present study in early life co-infection plus HDM group suggests this model may be capturing key features of severe, steroid insensitive asthma, providing novel insight into clinically relevant pathology. Ultimately, this model presents a unique opportunity to develop new treatment strategies to circumvent a highly relevant cause of childhood asthma