VIRAL-ALLERGEN INTERACTIONS: INSIGHTS INTO THE ORIGINS OF ALLERGIC ASTHMA.

Abstract

<p>Asthma is a chronic immune-inflammatory disease of the airways, characterized by reversible airflow obstruction and airway hyperresponsiveness (AHR), and is associated with the development of airway remodeling. While our understanding of the pathophysiology of allergic asthma has increased remarkably in the last few decades, the origins of the disease remain elusive. Indeed, studies indicate that the prevalence of allergic asthma, has increased dramatically over the last 30 years. Within this context, a number of environmental factors including respiratory viral infections have been associated with the onset of this disease but causal evidence is lacking. The work presented in this thesis examines the interactions between a respiratory viral infection, specifically influenza A, and the common aeroallergen house dust mite (HDM) in an experimental murine model. To this end, we investigated the impact of an acute influenza A infection on the exposure to a subclinical dose of HDM (Chapter 2) and addressed potential underlying immune mechanisms using a global, genomic approach (Chapter 3). Our data demonstrate an enhancement of immune inflammatory responses to HDM and reveals multiple immune pathways by which influenza A may enhance the response to subsequent allergen exposure. Collectively these immune pathways are capable of lowering the threshold of HDM responsiveness. Lastly, as allergic asthma develops in most instances during infancy, we investigated the impact of an influenza A infection on allergen responses in infant mice (Chapter 4). In this setting, acute influenza A infection subverts constitutive allergen hyporesponsiveness thus resulting in sensitization, airway inflammation and, ultimately, structural and functional alterations persisting into adulthood.</p>