title: How mutant CFTR may contribute to Pseudomonas aeruginosa infection in cystic fibrosis.
abstract: Patients with cystic fibrosis (CF) have a pronounced hypersusceptibility (80 to 90%) to Pseudomonas aeruginosa infection. We hypothesized that airway epithelial cell ingestion of bacteria followed by cellular desquamation may protect the lung from infection, and epithelial cells expressing mutant forms of the cystic fibrosis transmembrane conductance regulator (CFTR) may be defective in this function. We found that transformed human airway epithelial cells homozygous for the delta F508 allele of CFTR were significantly defective in uptake of P. aeruginosa compared with the same cell line complemented with the wild-type allele of CFTR. Partial membrane expression of the delta F508 CFTR protein occurs in cells grown at 26 degrees C, and under these conditions uptake of P. aeruginosa occurred at levels comparable to cells with a wild-type allele of CFTR. Epithelial cell ingestion assays using isogenic bacterial strains differing in lipopolysaccharide (LPS) phenotype, along with inhibition studies, identified the LPS-core oligosaccharide as the bacterial ligand for epithelial cell invasion. Inhibition of epithelial cell ingestion of P. aeruginosa in a neonatal mouse lung infection model led to increased levels of bacteria in the lungs 24 and 48 h after infection. Defective epithelial cell internalization of P. aeruginosa may be a critical factor in hypersusceptibility of CF patients to chronic lung infections.
authors.affiliation: Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115-5899, USA.
authors.forename: G B
authors.initials: GB
authors.lastname: Pier
authors.forename: M
authors.initials: M
authors.lastname: Grout
authors.forename: T S
authors.initials: TS
authors.lastname: Zaidi
authors.forename: J B
authors.initials: JB
authors.lastname: Goldberg
mesh_terms: D000818:Animals; D001422:Bacterial Adhesion; D002461:Cell Line, Transformed; D003550:Cystic Fibrosis / Q000150:complications / Q000235:genetics* / Q000382:microbiology*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics* / Q000502:physiology; D004198:Disease Susceptibility; D004848:Epithelium / Q000378:metabolism / Q000382:microbiology; D006801:Humans; D051379:Mice; D017354:Point Mutation; D011552:Pseudomonas Infections / Q000150:complications / Q000382:microbiology*; D011550:Pseudomonas aeruginosa / Q000235:genetics / Q000502:physiology*; D012137:Respiratory System / Q000378:metabolism / Q000382:microbiology; D012141:Respiratory Tract Infections / Q000150:complications / Q000382:microbiology*
chemical_list: C505032:CFTR protein, human; D019005:Cystic Fibrosis Transmembrane Conductance Regulator