The role of pseudomonal proteases in inflammation in CF

Chronic Pseudomonas aeruginosa infections are a major complication in individuals with cystic fibrosis (CF), contributing to persistent airway inflammation and progressive lung damage. A critical factor in this adaptation from acute to chronic infection is the secretion of bacterial proteases, yet their precise impact on host immune responses remains incompletely understood.

In her study, Merel Wauters, PhD student at the Ghent University Hospital investigated how P. aeruginosa proteases modulate cytokine activity using a dual approach. First, recombinant cytokines were directly exposed to cell-free bacterial supernatants. In addition she used an organotypic 3D lung epithelial model cultured under physiologically relevant conditions, including synthetic CF sputum medium and clinical CF isolates.

Interestingly, several key pro-inflammatory cytokines, including IL-8, IL-6, and TNF-α, were strongly degraded by protease-producing isolates. In the 3D lung model, bacterial supernatants significantly reduced cytokine release, indicating that proteases primarily degrade cytokines rather than trigger inflammatory signaling. A subsequent comparative proteomics analysis identified an upregulation of several extracellular proteases, with elastase B (LasB) emerging as the most prominent candidate. Functional assays using a LasB-deficient mutant confirmed its significant contribution to cytokine degradation, accounting for five of the seven cytokines affected. Nevertheless, residual degradation observed in the mutant indicated that additional proteases also contribute to this activity.

In conclusion, P. aeruginosa proteases suppress host immune responses by degrading cytokines, thereby dampening inflammation in a 3D lung model. While LasB plays a central role, other proteases contribute, underscoring the multifactorial nature of protease-mediated immune modulation in CF lung disease.