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Early defects of airway mucin sialylation and of mucociliary clearance at the onset of lung pathogenesis in a pig model of cystic fibrosis

ABSTRACT: Chronic infection of the lungs by bacteria such as Pseudomonas aeruginosa plays an important role in the natural history of Cystic Fibrosis (CF). Altered mucin secretions and glycosylations are hallmarks of bacterial infections but their exact contributions to the development of chronic infection and/or inflammation remain to be established. We studied the lung environment in newborn CFTR-/- pigs, which closely mirrors the human CF phenotype at the levels of mucin glycosylation, mucociliary transport (MCT) and immune response to P. aeruginosa infections. We show an increased sialylation of mucins from the tracheal mucosa of CFTR-/- pigs, which is also associated to increased Pseudomonas aeruginosa adherence. RNA-seq analysis did not show any altered expression of inflammatory genes, nor of sialylation enzymes. CFTR-/- piglets were unable to clear P. aeruginosa from the airways, leading to increased bacteria time of residence in the airways. We propose that alterations in mucin sialylation and MCT directly contribute to the early development of a favorable environment for bacterial colonization of the CF airways in the absence of an intrinsic inflammation.

ORGANISM(S): Sus scrofa

PROVIDER: GSE99862 | GEO | 2020/06/01

REPOSITORIES: GEO

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Project description:Dysfunction of the cystic fibrosis transmembrane regulator (CFTR) in cystic fibrosis (CF) results in exaggerated and chronic inflammation as well as increased susceptibility to chronic pulmonary infections, in particular with Pseudomonas aeruginosa. Based on the concept that host immune responses do not seem to be adequate to eradicate P.aeruginosa from the lungs of CF patients and that dendritic cells (DC) play an important role in initiating and shaping adaptive immune responses, this study analyzed the role of CFTR in bone marrow-derived murine DC from CFTR knockout (CF) mice with and without exposure to P.aeruginosa. DC expressed CFTR mRNA and protein, although at much lower levels compared to whole lung. Microarray analysis of gene expression levels in DC generated from CF and wild type (WT) mice revealed significantly different expression of 16 genes in CF DC compared to WT DC. Among the genes with lower expression in CF DC was Caveolin-1, a membrane lipid raft protein. Messenger RNA and protein levels of Caveolin-1 were decreased in the CF DC compared to WT DC. Consistently, the active form of sterol-responsive element binding protein (SREBP), a negative regulator of Caveolin-1 expression, was increased in CF DC. Following exposure to P.aeruginosa, gene expression levels in CF and WT DC changed for 912 genes involved in inflammation, chemotaxis, signaling, cell cycling and apoptosis more than 1.5-fold. Among the genes that showed a different response between WT and CF DC infected with P.aeruginosa, were 3Î²-hydroxysterol-Î7 reductase (Dhcr7) and stearoyl-CoA desaturase 2 (Scd2), two enzymes involved in the lipid metabolism that are also regulated by SREBP. These results suggest that CFTR dysfunction in non-epithelial cells results in changes in the expression of genes encoding factors involved in membrane structure and lipid-metabolism. These membrane alterations in immune cells may contribute to the abnormal inflammatory and immune response characteristic of CF. Experiment Overall Design: comparison of gene expression in dendritic cells of cystic fibrosis mice without or with Pseudosmonas aeruginosa infection vs wild type dendritic cell controls

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Early defects of airway mucin sialylation and of mucociliary clearance at the onset of lung pathogenesis in a pig model of cystic fibrosis

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