Microbiota, Mucus, and Modulators: Cystic Fibrosis Infection Pathogenesis in the Cystic Fibrosis Transmembrane Conductance Regulator Modulator Era.

Cystic fibrosis (CF) lung disease is a result of defective CF transmembrane conductance regulator (CFTR)-mediated ion transport, producing dehydrated mucus, impaired mucociliary clearance and an opportune environment for chronic airway infection. CF airway infections are polymicrobial airway ecosystems often dominated by CF pathogens such as Pseudomonas aeruginosa, Staphylococcus aureus, Burkholderia, Stenotrophomonas, Achromobacter, and nontuberculous mycobacteria that drive cycles of infection, inflammation, and bronchiectasis. Highly effective CFTR modulators, including elexacaftor/tezacaftor/ivacaftor, improve airway hydration and mucociliary clearance and reduce pathogen CF acquisition and density. However, even with CFTR modulator treatment, most individuals with established infection remain chronically infected, and long-term impacts of CFTR modulators on airway infection dynamics and associated clinical outcomes remain unclear. In this review, we address key gaps in understanding chronic infection in the CFTR modulator era, including changes in infection-related lung disease pathogenesis, airway-gut microbiome interactions, approaches to airway infection sampling, and implications for infection management.