Host–Pathogen Interactions in Cystic Fibrosis Lung Disease: Adaptation, Persistence, and Clinical Implications of Pseudomonas aeruginosa

Cystic fibrosis (CF) lung disease is characterized by chronic infection and progressive airway damage, driven by interactions between epithelial dysfunction, immune dysregulation, and microbial adaptation. Defective cystic fibrosis transmembrane conductance regulator (CFTR) function disrupts airway hydration and mucociliary clearance, creating a microenvironment that facilitates infection, particularly with Pseudomonas aeruginosa (P. aeruginosa). Within this environment, P. aeruginosa undergoes adaptive changes, including biofilm formation and metabolic reprogramming, which support long-term survival in the airway. Concurrently, host immune responses become dysregulated, with ineffective bacterial clearance and sustained neutrophil-dominated inflammation contributing to tissue injury. These processes establish a self-reinforcing cycle that drives disease progression. Importantly, early infection represents a critical therapeutic window during which bacterial populations remain more amenable to eradication before irreversible airway remodeling occurs. Delayed intervention promotes transition to a more treatment-refractory state and accelerates disease progression. Despite the clinical benefits of CFTR modulators, airway damage and established infections often remain. The relative contributions and interactions of epithelial dysfunction, immune dysregulation, and bacterial adaptation in sustaining chronic infection remain incompletely defined, representing a key knowledge gap. In this context, this review aims to integrate current evidence on host–pathogen co-adaptation in CF lung disease, with a particular focus on P. aeruginosa, and highlight emerging therapeutic strategies.