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, a ubiquitous environmental fungus, and its presence is associated with accelerated lung function decline. Half of the patients infected with Aspergillus are <18 years of age. The observation that CF patients are more susceptible to A. fumigatus infection even after lung transplantation suggests that CF immune cells are intrinsically impaired in their antifungal activity. CFTR expression has been demonstrated in cells of the innate and adaptive immune system and has shown to be critical for normal function. In vitro studies have demonstrated that CF phagocytes display reduced killing activity against typical CF bacterial pathogens as Pseudomonas aeruginosa and Burkholderia cepacia. Others have reported defects in a number of host immune mechanisms including the release of antimicrobial peptides, intracellular alkalization and diminished production of hypochlorous acid. Little attention has been paid to the role of A. fumigatus and other filamentous fungi in the pathogenesis of non-ABPA (allergic bronchopulmonary aspergillosis) respiratory disease in CF, despite their frequent recovery in respiratory samples. It has become more apparent however, that A. fumigatus may play an important role in chronic lung disease in CF. 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 [1,2]. 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 . The abnormal function of CFTR correlates with impaired degranulation of antimicrobial proteins. More specifically, Pohl et al demonstrated that CF PMN release less secondary and tertiary granule components compared with healthy PMN and that activation of the low-molecular-mass GTP-binding protein Rab27a, involved in the regulation of granule trafficking, is defective. When CF patients (harbouring the G551D mutation) were treated with ivacaftor, resulting in normalised PMN ion levels, an increased activation of Rab27, increased degranulation and increase bacterial killing was observed . These combined results indicate that CFTR defective PMN are intrinsically impaired in crucial immune pathways. Brunel, S.F., et al. Aspergillus induced superoxide production by CF phagocytes associates with disease severity. Eur Resp J Open Research 2018; in press. Brunel, S., et al. Live imaging of antifungal activity by human primary neutrophils and monocytes in response to A. fumigatus. J. Vis. Exp. April 19, 122 (2017). Barnaby, R., et al. Lumacaftor (VX-809) restores the ability of CF macrophages to phagocytose and kill Pseudomonas aeruginosa. Am. J. Physiol. Cell. Mol. Physiol. 314, L432–L438 (2018). Pohl, K., et al. A neutrophil intrinsic impairment affecting Rab27a and degranulation in cystic fibrosis is corrected by CFTR potentiator therapy. Blood 124, 999–1009 (2014).
Full conference title:
- ISHAM 20th (2018)