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.
Shafiei et al. (Fri,) studied this question.