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

Sonia Bastonero (1) , Yannick Le Priol (2) , Martine Armand (3) , Christophe Bernard (4) , Martine Reynaud-Gaubert , Daniel Olive (5) , Daniel Parzy (2) , Sophie de Bentzmann (4) , Christian Capo (6) , Jean-Louis Mege (6)

1 URMITE - Unité de Recherche sur les Maladies Infectieuses Tropicales Emergentes
2 IMTSSA - Institut de Médecine Tropicale du Service de Santé des Armées
3 Nutriments Lipidiques et Prévention des Maladies Métaboliques
4 LISM - Laboratoire d'ingénierie des systèmes macromoléculaires
5 CRCM / U891 Inserm - Centre de Recherche en Cancérologie de Marseille
6 URMITE - Unité de Recherche sur les Maladies Infectieuses et Tropicales Emergentes

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 ΔF508 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-1α, IL-β, IL-32, TNFSF14, LIF, CXCL1 and PLAU. In response to P. aeruginosa, genes associated with IFN-γ response to infection (CXCL10, IL-24, IFNγR2) 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-γ response was accompanied by the defective membrane expression of IFNγR2 and altered response of CF-TG cells to exogenous IFN-γ. 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.

Mots clés: Pseudomonas aeruginosa; Inflammation; Gene expression; Cystic fibrosis; Immune response; Microarrays; Cytokines; Sphingolipids

Domaines: Alimentation et Nutrition

Sonia Bastonero, Yannick Le Priol, Martine Armand, Christophe Bernard, Martine Reynaud-Gaubert, et al.. New Microbicidal Functions of Tracheal Glands: Defective Anti-Infectious Response to Pseudomonas aeruginosa in Cystic Fibrosis. PLoS ONE, 2009, 4 (4), pp.e5357. ⟨10.1371/journal.pone.0005357⟩. ⟨hal-02420126⟩