Vav3 Mediates Pseudomonas aeruginosa Adhesion to the Cystic Fibrosis Airway Epithelium

Mehdi Badaoui,Alice Zoso,Tahir Idris,Marc Bacchetta,Juliette Simonin,Sylvain Lemeille,Bernhard Wehrle-Haller,Marc Chanson

doi:10.1016/j.celrep.2020.107842

Abstract

Pseudomonas aeruginosa (Pa) represents the leading cause of airway infection in cystic fibrosis (CF). Early airways colonization can be explained by enhanced adhesion of Pa to the respiratory epithelium. RNA sequencing (RNA-seq) on fully differentiated primary cultures of airway epithelial cells from CF and non-CF donors predict that VAV3, β1 INTEGRIN, and FIBRONECTIN genes are significantly enriched in CF. Indeed, Vav3 is apically overexpressed in CF, associates with active β1 integrin luminally exposed, and increases fibronectin deposition. These luminal microdomains, rich in fibronectin and β1 integrin and regulated by Vav3, mediate the increased Pa adhesion to the CF epithelium. Interestingly, Vav3 inhibition normalizes the CF-dependent fibronectin and β1-integrin ectopic expression, improves the CF epithelial integrity, and prevents the enhanced Pa trapping to the CF epithelium. Through its capacity to promote a luminal complex with active β1 integrin and fibronectin that favors bacteria trapping, Vav3 may represent a new target in CF.

Highlights

Cystic fibrosis (CF) is an autosomal recessive genetic disease caused by mutations in the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) gene that encodes for a chloride (ClÀ) channel
RNA sequencing (RNA-seq) on fully differentiated primary cultures of airway epithelial cells from CF and nonCF donors predict that VAV3, b1 INTEGRIN, and FIBRONECTIN genes are significantly enriched in CF
Vav3 inhibition normalizes the CF-dependent fibronectin and b1-integrin ectopic expression, improves the CF epithelial integrity, and prevents the enhanced Pseudomonas aeruginosa (Pa) trapping to the CF epithelium

Summary

Introduction

Cystic fibrosis (CF) is an autosomal recessive genetic disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene that encodes for a chloride (ClÀ) channel. The deletion of phenylalanine in position 508 (F508del-CFTR), which impairs CFTR trafficking to the plasma membrane, represents the most common mutation in the Caucasian population (Farrell, 2008; Castellani et al, 2008). Defective CFTR mainly impairs ClÀ transport, which leads to several phenotypic manifestations that affect the respiratory system. The respiratory failure and mostly the airway bacterial colonization by opportunistic pathogens determine the prognosis of the disease (Stoltz et al, 2015). Pseudomonas aeruginosa (Pa) represents the leading cause of the airway infection. Despite the effort to make the antibiotics therapy against Pa more widespread, the CF Foundation reported in 2017 that 30% of the European CF population and 45.7% of the American CF population are infected by Pa (CF Foundation [CFF] Patient Registry Annual Data Report, 2017; http://www.cff.org)

Results

Discussion

Conclusion