HDAC6 inhibition reduces Pseudomonas aeruginosa adherence and internalization in cystic fibrosis epithelial cells via microtubule stabilization

Pseudomonas aeruginosa is a common opportunistic pathogen that causes chronic lung infections in individuals with cystic fibrosis. Despite advances in therapies that restore cystic fibrosis transmembrane conductance regulator function, persistent colonization of the airway remains a major clinical challenge. Reduced clearance of P. aeruginosa from the cystic fibrosis airway has been associated with the increased activity of histone deacetylase 6 (HDAC6), a cytoplasmic deacetylase that decreases microtubule acetylation and stability. In this study, we investigated the role of HDAC6 in modulating interactions between P. aeruginosa and cystic fibrosis airway epithelial cells. Pharmacologic inhibition of HDAC6 significantly reduced bacterial adherence in both mouse and human cystic fibrosis epithelial cells. Genetic deletion of HDAC6 produced similar effects, while knockout of a microtubule-stabilizing protein increased bacterial adherence, mimicking the cystic fibrosis phenotype. HDAC6 inhibition also reduced bacterial internalization, although to a lesser extent compared to adherence. These results suggest that microtubule destabilization contributes to the enhanced colonization of cystic fibrosis airways by P. aeruginosa . Targeting host microtubule regulatory pathways, particularly by inhibiting HDAC6, may represent a promising host-directed strategy to limit early bacterial attachment and reduce the risk of chronic infection in cystic fibrosis.