In cystic fibrosis (CF) airways, the dysfunctional Cl^- secretion (due to mutations in the Cftr gene) alters the mucociliary clearance and favors bacterial infections causing progressive lung damage. We previously showed that the ability of CF airway epithelia to repair is less efficient, than in healthy controls, due to the CFTR defect and bacterial infections, in particular with P. aeruginosa (PA) and S. aureus (SA). Our work also unveiled that the CFTR rescue by modulators enhances airway repair, but their efficacy is dampened by infection. Our goal is thus to identify new therapeutic strategies, interfering with bacterial virulence, to improve the efficacy of CFTR-directed treatments and favor the repair of infected airways.

Using patient-derived samples from our Biobank, including primary airway cells and living tissues from CF lung explants, exposed to virulence factors (VirF) from PA and SA cultures, we are investigating CFTR expression/function as well as epithelial injury and repair.

We first dissected how CFTR function regulates epithelial repair processes. We also identified which VirF from PA (elastase) and SA (?-, ?-hemolysin) are responsible for the deleterious impact of infection. Importantly, we identified new approaches, interfering with bacterial virulence, which prevented their negative effect. We have also data supporting that airway epithelial integrity could be further improved by combined treatments, including CFTR and K⁺ channel modulators.

Altogether, these precision strategies, combining treatments targeting both bacterial virulence and ion channels, may favor the functional integrity of damaged CF lung tissues from CF patients harboring various types of mutations.