Targeting HuR-Vav3 mRNA interaction prevents Pseudomonas aeruginosa adhesion to the cystic fibrosis airway epithelium

Cystic fibrosis (CF) is characterized by chronic bacterial infections leading to progressive bronchiectasis and respiratory failure. Pseudomonas aeruginosa (Pa) is the predominant opportunistic pathogen infecting the CF airways. The guanine nucleotide exchange factor Vav3 plays a critical role in Pa...

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Bibliographic Details
Published in:JCI insight 2023-02, Vol.8 (3)
Main Authors: Badaoui, Mehdi, Sobolewski, Cyril, Luscher, Alexandre, Bacchetta, Marc, Köhler, Thilo, van Delden, Christian, Foti, Michelangelo, Chanson, Marc
Format: Article
Language:English
Subjects:
Cell biology
Cystic Fibrosis - genetics
Cystic Fibrosis - metabolism
Epithelium - metabolism
Fibronectins - metabolism
Humans
Infectious disease
Life Sciences
Proto-Oncogene Proteins c-vav - genetics
Proto-Oncogene Proteins c-vav - metabolism
Pseudomonas aeruginosa - genetics
Pseudomonas aeruginosa - immunology
Respiratory System - metabolism
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Summary:Cystic fibrosis (CF) is characterized by chronic bacterial infections leading to progressive bronchiectasis and respiratory failure. Pseudomonas aeruginosa (Pa) is the predominant opportunistic pathogen infecting the CF airways. The guanine nucleotide exchange factor Vav3 plays a critical role in Pa adhesion to the CF airways by inducing luminal fibronectin deposition that favors bacteria trapping. Here we report that Vav3 overexpression in CF is caused by upregulation of the mRNA-stabilizing protein HuR. We found that HuR accumulates in the cytoplasm of CF airway epithelial cells and that it binds to and stabilizes Vav3 mRNA. Interestingly, disruption of the HuR-Vav3 mRNA interaction improved the CF epithelial integrity, inhibited the formation of the fibronectin-made bacterial docking platforms, and prevented Pa adhesion to the CF airway epithelium. These findings indicate that targeting HuR represents a promising antiadhesive approach in CF that can prevent initial stages of Pa infection in a context of emergence of multidrug-resistant pathogens.
ISSN:2379-3708
2379-3708
DOI:10.1172/jci.insight.161961