title: Effects ofPseudomonas aeruginosaon CFTR chloride secretion and the host immune response.
abstract: In the healthy lung the opportunistic pathogen,Pseudomonas aeruginosa, is rapidly eliminated by mucociliary clearance, a process that is dependent on the activity of the CFTR anion channel that, in concert with a number of other transport proteins, regulates the volume and composition of the periciliary surface liquid. This fluid layer is essential to enable cilia to clear pathogens from the lungs. However, in cystic fibrosis (CF), mutations in theCFTRgene reduce Cl-and [Formula: see text] secretion, thereby decreasing periciliary surface liquid volume and mucociliary clearance of bacteria. In CF this leads to persistent infection with the opportunistic pathogen,P. aeruginosa, which is the cause of reduced lung function and death in ~95% of CF patients. Others and we have conducted studies to elucidate the effects ofP. aeruginosaon wild-type and Phe508del-CFTR Cl-secretion as well as on the host immune response. These studies have demonstrated that Cif (CFTR inhibitory factor), a virulence factor secreted byP. aeruginosa, is associated with reduced lung function in CF and induces the ubiquitination and degradation of wt-CFTR as well as TAP1, which plays a key role in viral and bacterial antigen presentation. Cif also enhances the degradation of Phe508del-CFTR that has been rescued by ORKAMBI, a drug approved for CF patients homozygous for the Phe508del-CFTR mutation, thereby reducing drug efficacy. This review is based on the Hans Ussing Distinguished Lecture at the 2016 Experimental Biology Meeting given by the author.
authors.affiliation: Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire Bruce.A.Stanton@Dartmouth.edu.
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Stanton
mesh_terms: D002713:Chlorine / Q000276:immunology*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000276:immunology*; D006801:Humans; D018928:Immunity, Mucosal / Q000276:immunology; D015640:Ion Channel Gating / Q000276:immunology; D018448:Models, Immunological; D009079:Mucociliary Clearance / Q000276:immunology; D018410:Pneumonia, Bacterial / Q000276:immunology* / Q000382:microbiology; D011552:Pseudomonas Infections / Q000276:immunology* / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000276:immunology*; D020545:Respiratory Mucosa / Q000276:immunology*
chemical_list: C505032:CFTR protein, human; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D002713:Chlorine
keywords: CFTR; ORKAMBI; Pseudomonas aeruginosa; cystic fibrosis; outer membrane vesicles