Grant: Operating Grant

Asthma affects over 300 million people worldwide and is the most prevalent chronic disease in children. The prevalence of asthma in Canada currently stands at ~12% in children and over 6% in adults; it is the leading cause of absenteeism from school and the third leading cause of work loss. Allergic Asthma (AA) represents over 2/3 of all cases of asthma.The last 30 years have delivered astounding progress of many facets of the pathogenesis (how it works) of this disease. In stark contrast, elucidation of its origins, i.e. its etiology (why it occurs), remains elusive. This is a central issue because deciphering the conditions underlying the onset of AA may be fundamental for the design of primary prevention strategies. Programming of allergen responsiveness, i.e. sensitization versus tolerance, largely occurs within the first 2 years of life. We propose that environmental exposure to commensal bacteria (good microbes) within this interval is essential to develop components of the immune system of the lung that facilitate allergen tolerance. Conversely, exposure to pathogenic bacteria (bad microbes) will subvert the naturally pro-tolerant lung environment in early life, permit sensitization and imprint long-lasting features of asthma. We will use a murine experimental system to study the precise evolution of immune responses in the normal lung as well as responsiveness to house dust mite, the most prevalent aeroallergen worldwide, from birth to adulthood (8 weeks). We will, then, determine the impact that distinct microbial exposures have on these responses. Lastly, we will investigate specific cellular and molecular mechanisms that we think are important to program tolerance to aeroallergens in early life, i.e. the first 2-3 weeks of life in mice. A number of studies will take advantage of mice bred in a fully sterile facility (germ free mice), the only one in Canada and one the very few in the world.