Cell-type-independent infection dynamics of clinical Pseudomonas aeruginosa isolates in human airway epithelial models.

Persistent bacterial infections pose major clinical challenges, particularly in people with cystic fibrosis (pwCF), in whom Pseudomonas aeruginosa can persist for decades despite antibiotic treatment. To investigate the host-pathogen interactions influencing infection outcomes, we modeled P. aeruginosa infection using human airway epithelial cells cultured at the air-liquid interface from both CF and non-CF donors and the BCi-NS1.1 cell line. Infection assays with reference and clinical strains revealed four distinct infection clusters based on virulence, epithelial damage, and localization, independent of model type or strain lineage. Correction of CF transmembrane conductance regulator protein (CFTR) channel function did not alter infection outcomes. Dual RNA sequencing showed conserved host inflammatory responses across models, while bacterial transcriptional profiles varied by host context, particularly in CF models. These findings demonstrate that while infection outcomes and host transcriptional responses are consistent across models, bacterial adaptation in the CF airways drives transcriptional reprogramming linked to persistence in pwCF.