bioRxiv Science⌕ Search

Biology subjects

Chanson, M.

Publications and source records attributed to Chanson, M..

2 recordsLinked to original sources

Adaptation of Pseudomonas aeruginosa to the lung allograft environment in cystic fibrosis lung transplant recipients

Lung transplantation (LT) is the ultimate treatment option for patients suffering from end stage cystic fibrosis (CF). Most LT-patients, colonized pre-LT by Pseudomonas aeruginosa witness colonization of their non-CF allograft within a few days or weeks post-LT, thereby compromising graft and life expectancy. How P. aeruginosa isolates adapted for years to the specific CF lung environment efficiently colonize and survive in the non-CF allograft environment remains unclear. To address this question, we collected sequential isolates from CF LT-recipients and non-CF LT-recipients and performed phenotypic and genetic analyses of pairs of early and late isolates from LT-patients. We found evidence for mutations compatible with a switch from biofilm to planktonic lifestyle as well as loss of mucoid phenotypes. Hypermutators, characteristic of chronic CF-adapted isolates, were also found in four LT-patients. Their persistence in the non-CF allograft environment suggests a continuous seeding from the sinuses. Our results suggest that in CF LT-recipients efficient colonisation by P. aeruginosa of the allograft implies both adaptation and continuous seeding from the sinuses to the lower respiratory tract.

microbiology↗

Akt Drives TGF-beta-induced Over-secretion of DKK1 and Impairment of Cystic Fibrosis Airway Epithelium Polarity

Epithelial polarity is fundamental in maintaining barrier integrity and tissue protection. In cystic fibrosis (CF), apicobasal polarity of the airway epithelium is lost, resulting in increased apical fibronectin deposition and enhanced susceptibility to bacterial infections. Here we show that CFTR mutation in primary human airway epithelial cells (HAECs) and CFTR knockdown in a HAEC line promote the overexpression and over-secretion of TGF-{beta}1 and DKK1 when cultured at air-liquid interface (ALI). These dynamic changes result in hyperactivation of the TGF-{beta} pathway and inhibition of the Wnt pathway through degradation of {beta}-catenin leading to imbalanced proliferation and polarization. The abnormal interplay between TGF-{beta} and Wnt signaling pathways is further enhanced by aberrant Akt signaling. Pharmacological manipulation of TGF-{beta}, Wnt, and Akt pathways restored polarization of the CF epithelium. Our data shed new insights into the signaling pathways that fine-tune apicobasal polarization and also highlight new therapeutic strategies in preventing infections in CF HAECs.

cell biology↗