Exploring the Role of Pseudomonas aeruginosa Elastase in Lung Epithelial Barrier Dysfunction: Advancing toward Antivirulence Therapies

Pseudomonas aeruginosa, a major
cause of pulmonary infections, poses significant clinical challenges
due to its virulence and rising antimicrobial resistance. We investigated
the role of LasB, a key virulence factor and elastase of P. aeruginosa, in disrupting the lung epithelial
barrier. LasB cleaves the junctional protein E-cadherin, alters Claudin-4
localization, and reduces levels of immunomodulatory cytokines including
GM-CSF and G-CSF. Using bronchial and alveolar cell models, we demonstrate
that LasB induces dose-dependent barrier damage in both systems. Transcriptomic
analysis reveals widespread gene expression changes, including the
upregulation of DUSP2 and FGFBP1 associated with stress signaling and immune modulation. LasB inhibitors
mitigate barrier disruption and partially restore cytokine levels.
In a live bacterial infection model, LasB inhibition supports antibiotic
treatment, enhancing bacterial clearance and preserving epithelial
integrity. These findings establish LasB as a pivotal factor in P. aeruginosa pathogenesis and highlight the therapeutic
potential of antivirulence strategies targeting LasB as promising
adjuncts to conventional antibiotics.