Grant: Project Grant

Patients with the genetic disease cystic fibrosis have chronic lung disease that leads to chronic symptoms, and ultimately respiratory failure and early death at a median age of 32. This chronic lung disease is characterized by severe inflammation that destroys the lung and chronic bacterial infections of the airways. The bacterium Pseudomonas aeruginosa is the main pathogen and causes severe chronic lung infections lasting years to decades. A large part of the lung inflammation is determined by the bacterial infection. During this chronic infection, P. aeruginosa very commonly develops mutations in a gene called lasR that profoundly change the behavior of bacteria. CF patients who are infected with these P. aeruginosa variants with lasR mutations appear to have worse lung function. However, we do not understand how this happens. Our group has observed in preliminary studies that these P. aeruginosa lasR variants cause an exaggerated inflammatory response in experimental conditions with human cell cultures and animal infection models. In this project, we will perform experiments with human lung cells and mice to understand how lasR variants cause exaggerated inflammation. Our studies will help us understand how the genetic changes of the bacteria P. aeruginosa during chronic infection in CF patients cause greater lung inflammation, thus contributing to the progression of lung disease. These findings will bring important knowledge on how to better identify P. aeruginosa infections that cause the worst disease in CF patients and better target antimicrobial treatments.