Cystic fibrosis: better understanding of the causes of chronic bacterial infection
Cystic fibrosis is caused by genetic mutations in the CFTR gene. This genetic disorder is associated with airway surface dehydration, the formation of bacterial docking stations and an increase in epithelial barrier permeability, which together promote life-threatening chronic bacterial infections. Exploring the potential interactions among these distinct alterations may unveil new therapeutic avenues for addressing cystic fibrosis.
A cascade of cellular events links the airway dehydration to altered barrier function
Over the past few years, researchers in the laboratory of Prof. Marc Chanson have deciphered how docking stations favouring bacterial infections are formed on the surface of the dehydrated cystic fibrosis airway epithelium. In collaboration with the laboratory of Prof. Aurélien Roux from the Faculty of Sciences, they have now discovered that the presence of these docking stations, which are characterized by the persistent expression of the β1-integrin receptor, plays an active role in the loss of airway barrier function. Their experiments on an in vitro model of human lung cells showed that the presence of docking stations induces a cascade of cellular events including the degradation of the YAP1 protein (Figure below). The absence of this protein disrupts the junctions between cells, further weakening the airway barrier and increasing susceptibility to infection.
In contrast to healthy airways (left panel), the presence of bacterial docking stations (blue aggregates) in cystic fibrosis airways (right panel) induces the degradation of the YAP1 protein, leading to the disruption of cell junctions (yellow and dark blue dots) and reduced integrity of the epithelium barrier, thus increasing the susceptibility to infection by opportunistic bacteria (green elements). © adapted from the graphical abstract in Simonin et al. 2024.
What’s next ?
Understanding these molecular mechanisms not only sheds light on the cellular mechanisms that favour bacterial infections but also opens up promising avenues for targeted therapeutic interventions to preserve airway integrity and improve the quality of life of people with cystic fibrosis. The researchers are now trying to find a way to stop the degradation of the YAP1 protein in order to restore the protective barrier function of the airway epithelium.