New Microbicidal Functions of Tracheal Glands: Defective Anti-Infectious Response to Pseudomonas aeruginosa in Cystic Fibrosis

被引:22
作者
Bastonero, Sonia
Le Priol, Yannick
Armand, Martine
Bernard, Christophe S.
Reynaud-Gaubert, Martine
Olive, Daniel
Parzy, Daniel
de Bentzmann, Sophie
Capo, Christian
Mege, Jean-Louis
机构
[1] Unité de Recherche sur les Maladies Infectieuses Tropicales et Emergentes, CNRS UMR 6236, Faculté de Médecine, Marseille
[2] Transcriptomic Platform, Institut de Médecine Tropicale, Service de Santé des Armées, Marseille
[3] UMR Nutriments Lipidiques et Prévention des Maladies Métaboliques, INSERM U476 INRA UMR1260, Faculté de Médecine, Marseille
[4] Laboratoire d'Ingénierie des Systèmes Macromoléculaires, CNRS-IMM-UPR 9027, Marseille
[5] Fédération des Maladies Respiratoires, Hôpital de Sainte Marguerite, Marseille
[6] Institut Paoli Calmettes, INSERM Unité 891, Centre de Recherche en Cancérologie, Marseille
来源
PLOS ONE | 2009年 / 4卷 / 04期
关键词
D O I
10.1371/journal.pone.0005357
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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 Delta F508 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-1 alpha, 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, IFN gamma R2) 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 IFN gamma R2 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 antiinfectious 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.
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页数:14
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