title: Induction of type I interferon signaling by Pseudomonas aeruginosa is diminished in cystic fibrosis epithelial cells.
abstract: The clinical manifestations of infection in cystic fibrosis (CF) are restricted to the lung, and involve a limited number of pathogens, suggesting a specific defect in mucosal immunity. We postulated that cystic fibrosis transmembrane conductance regulator (CTFR) mutations could affect the activation of type I interferon signaling in airway epithelial cells, which function in immune surveillance and initiate the recruitment and activation of immune cells. In response to infection with Pseudomonas aeruginosa, Ifnb was induced more than 100-fold in the murine lung, and the phosphorylation of STAT1 was similarly induced by the expected TLR4/TRIF/MD2/TBK1 cascade. The stimulation by P. aeruginosa of CF (IB3) cells and control (C-38) human cell lines similarly resulted in the induction of IFN-β, but to a significantly lower extent in CF airway cells. The potential consequences of diminished type I IFN signaling were demonstrated in a murine model of P. aeruginosa pneumonia, pretreatment with polyinosinic:polycytidylic acid significantly enhanced bacterial clearance and correlated with increased numbers of mature CD11c(+)/CD86(+) dendritic cells (DCs) in the lung. Using culture supernatants from CF or control cell lines stimulated with P. aeruginosa, we similarly demonstrated the diminished activation of human monocyte-derived DCs by incubation with CF compared with normal epithelial cell culture supernatants, which was dependent on IFN-β. These observations suggest that dysfunction of the CFTR in airway epithelial cells may contribute to impaired immune surveillance in the CF airway and resultant colonization by P. aeruginosa.
authors.affiliation: Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA. asp7@columbia.edu
authors.forename: Dane
authors.initials: D
authors.lastname: Parker
authors.forename: Taylor S
authors.initials: TS
authors.lastname: Cohen
authors.forename: Morten
authors.initials: M
authors.lastname: Alhede
authors.forename: Bryan S
authors.initials: BS
authors.lastname: Harfenist
authors.forename: Francis J
authors.initials: FJ
authors.lastname: Martin
authors.forename: Alice
authors.initials: A
authors.lastname: Prince
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000276:immunology / Q000378:metabolism; D000818:Animals; D051940:B7-2 Antigen / Q000276:immunology / Q000378:metabolism; D039521:CD11c Antigen / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D003550:Cystic Fibrosis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D004847:Epithelial Cells / Q000473:pathology; D006801:Humans; D007370:Interferon Type I / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D016899:Interferon-beta / Q000235:genetics / Q000276:immunology; D051218:Lymphocyte Antigen 96 / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D010766:Phosphorylation; D011552:Pseudomonas Infections / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D011550:Pseudomonas aeruginosa / Q000276:immunology*; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000276:immunology / Q000378:metabolism
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D051940:B7-2 Antigen; D039521:CD11c Antigen; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D007370:Interferon Type I; D016899:Interferon-beta; D051218:Lymphocyte Antigen 96; D050794:STAT1 Transcription Factor; D051197:Toll-Like Receptor 4; C497965:Cd86 protein, mouse; C411728:Ly96 protein, mouse; C494080:Stat1 protein, mouse; C476286:Ticam1 protein, mouse; C493487:Tlr4 protein, mouse