Airway epithelial control of Pseudomonas aeruginosa infection in cystic fibrosis

Abstract

Defective expression or function of the cystic fibrosis transmembrane conductance regulator (CFTR) underlies the hypersusceptibility of cystic fibrosis (CF) patients to chronic airway infections, particularly with Pseudomonas aeruginosa. CFTR is involved in the specific recognition of P. aeruginosa, thereby contributing to effective innate immunity and proper hydration of the airway surface layer (ASL). In CF, the airway epithelium fails to initiate an appropriate innate immune response, allowing the microbe to bind to mucus plugs that are then not properly cleared because of the dehydrated ASL. Recent studies have identified numerous CFTR-dependent factors that are recruited to the epithelial plasma membrane in response to infection and that are needed for bacterial clearance, a process that is defective in CF patients hypersusceptible to infection with this organism.

Figure 1

Visualization of P. aeruginosa in the tracheal epithelium 4 h after infection with an LPS-smooth, non-mucoid isolate. In mice with WT-CFTR (a–d), the uninfected epithelium shows mixtures of ciliated and non-ciliated cells in a firm layer, whereas in the P. aeruginosa-infected epithelium the organisms are seen entering the tracheal epithelial cells, usually with one of the polar ends being taken into an obvious membrane invagination. In transgenic CFTR-knockout-mice (e–h), the infected tracheal epithelial surface looks only modestly disrupted, with no bacterial cells observed bound or entering the epithelial cells. When sections are treated to preserve the mucus (g,h), the bacteria seen in the CF epithelium are primarily entrapped within or on the mucus material.

Figure 2

Schematic overview of airway epithelial response to Pseudomonas aeruginosa infection. On an intact mucosal surface (a), some P. aeruginosa cells bind to CFTR, initiating a rapid, regulated inflammatory response to eliminate infecting organisms and restore tissue homeostasis. On a CF mucosal surface (b), failure to produce functional CFTR in the plasma membrane prevents initiation of the proper, desirable and coordinated host inflammatory response and instead elicits dysregulated inflammation, particularly when bacteria become trapped in mucus plugs.