Biosciences Research Seminar - Aspergillus infections in cystic fibrosis

Cystic fibrosis (CF), caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) in epithelial cells is the most common inherited life-limiting disease in North European people and affecting 90,000 people worldwide. Progressive lung damage caused by recurrent infection and persistent inflammation is the major determinant of survival with a median age of death at 29 years. Approximately 50% of CF patients are infected with Aspergillus fumigatus, and its presence is associated with accelerated lung function decline.

CFTR expression has been demonstrated in cells of the innate and adaptive immune system and has shown to be critical for normal host immune mechanisms against bacteria. Research delineating the role of CFTR-deficient phagocytes in Aspergillus persistence and infection in the CF lung, has only recently received attention. We have recently shown that although human CF phagocytes are capable of efficiently kill A. fumigatus, this is at a cost of excessive reactive oxygen species (ROS). The excessive amounts of ROS induced by A. fumigatus in CF neutrophils are significantly correlated to disease severity in terms of clinical exacerbations and lung function. Our data suggest that the hyperinflammatory response upon exposure to A. fumigatus by CF phagocyte may well be contributing to progressive lung disease. In vitro studies have demonstrated that restoring the CFTR function, leads to improved immune mechanisms such as phagocytosis and bacterial killing. We are currently assessing ways to dampen the hyperinflammatory responses induced by A. fumigatus with the aim to improve the management of Aspergillus infection in people with cystic fibrosis.