Grant: Doctoral: Vanier Canada Graduate Scholarships

Cystic fibrosis (CF) is one of the most common genetic diseases in Europe and North America. In CF, there are mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR), which results in defective chloride transport in cells, creating fertile ground for infection with chronic opportunistic pathogens. Up to 80% of CF patients become infected with Pseudomonas aeruginosa bacterium, which causes a decline in lung function. Many CF patients experience recurrent episodes of rapid impairment in lung function, called "pulmonary exacerbations", requiring medical attention and hospitalization. While overt activation of the immune system (i.e. inflammation) that responds to pathogens in the lungs is considered to be a key driver of the decline in lung function, the precise mechanisms in the context of CF have remained unclear. The aim of this project is to identify the most toxic inflammatory signaling mechanisms that result in the rupture and death of host cells during stable disease and pulmonary exacerbations of CF patients. To do so, I will use P. aeruginosa that is isolated from CF patients' sputum during pulmonary exacerbations and stable disease to evaluate their ability to activate different inflammatory responses upon interacting with various types of immune cells. I will also use normal cells and cells with a CFTR gene mutation to determine the mutation's impact on inflammatory cell death signaling during infection. Finally, due to the potential association between viral infections and pulmonary exacerbations, I will delineate this impact in a mouse model. Ultimately, this work will shed light on the mechanisms behind pulmonary exacerbations based on pathogen and patient factors, leading to the identification of new potential therapeutic targets and approaches for patient management. In doing so, these new therapies could greatly impact the CF patient population by helping preserve lung function and significantly improving their quality of life.