title: New microbicidal functions of tracheal glands: defective anti-infectious response to Pseudomonas aeruginosa in cystic fibrosis.
abstract: Tracheal glands (TG) may play a specific role in the pathogenesis of cystic fibrosis (CF), a disease due to mutations in the cftr gene and characterized by airway inflammation and Pseudomonas aeruginosa infection. We compared the gene expression of wild-type TG cells and TG cells with the cftr DeltaF508 mutation (CF-TG cells) using microarrays covering the whole human genome. In the absence of infection, CF-TG cells constitutively exhibited an inflammatory signature, including genes that encode molecules such as IL-1alpha, IL-beta, IL-32, TNFSF14, LIF, CXCL1 and PLAU. In response to P. aeruginosa, genes associated with IFN-gamma response to infection (CXCL10, IL-24, IFNgammaR2) and other mediators of anti-infectious responses (CSF2, MMP1, MMP3, TLR2, S100 calcium-binding proteins A) were markedly up-regulated in wild-type TG cells. This microbicidal signature was silent in CF-TG cells. The deficiency of genes associated with IFN-gamma response was accompanied by the defective membrane expression of IFNgammaR2 and altered response of CF-TG cells to exogenous IFN-gamma. In addition, CF-TG cells were unable to secrete CXCL10, IL-24 and S100A8/S100A9 in response to P. aeruginosa. The differences between wild-type TG and CF-TG cells were due to the cftr mutation since gene expression was similar in wild-type TG cells and CF-TG cells transfected with a plasmid containing a functional cftr gene. Finally, we reported an altered sphingolipid metabolism in CF-TG cells, which may account for their inflammatory signature. This first comprehensive analysis of gene expression in TG cells proposes a protective role of wild-type TG against airborne pathogens and reveals an original program in which anti-infectious response was deficient in TG cells with a cftr mutation. This defective response may explain why host response does not contribute to protection against P. aeruginosa in CF.
authors.affiliation: Unité de Recherche sur les Maladies Infectieuses Tropicales et Emergentes, CNRS UMR 6236, Faculté de Médecine, Marseille, France.
authors.forename: Sonia
authors.initials: S
authors.lastname: Bastonero
authors.forename: Yannick
authors.initials: Y
authors.lastname: Le Priol
authors.forename: Martine
authors.initials: M
authors.lastname: Armand
authors.forename: Christophe S
authors.initials: CS
authors.lastname: Bernard
authors.forename: Martine
authors.initials: M
authors.lastname: Reynaud-Gaubert
authors.forename: Daniel
authors.initials: D
authors.lastname: Olive
authors.forename: Daniel
authors.initials: D
authors.lastname: Parzy
authors.forename: Sophie
authors.initials: S
authors.lastname: de Bentzmann
authors.forename: Christian
authors.initials: C
authors.lastname: Capo
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Mege
mesh_terms: D001426:Bacterial Proteins / Q000378:metabolism; D002478:Cells, Cultured; D003550:Cystic Fibrosis / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics; D016207:Cytokines / Q000235:genetics; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D011550:Pseudomonas aeruginosa / Q000378:metabolism / Q000472:pathogenicity; D013107:Sphingolipids / Q000378:metabolism; D014132:Trachea / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology
chemical_list: D001426:Bacterial Proteins; C505032:CFTR protein, human; D016207:Cytokines; D018836:Inflammation Mediators; D013107:Sphingolipids; D019005:Cystic Fibrosis Transmembrane Conductance Regulator