Etude du rôle de la phospholipase A2 sécrétée de type IIA dans la mucoviscidose : modulation de son expression par Pseudomonas aeruginosa

摘要

The type IIA secretory phospholipase A2 (sPLA2-IIA) is a host defense protein endowed with antibacterial activity, especially against Gram positive bacteria. Cystic fibrosis (CF) is a genetic disease due to mutations of Cftr gene. In the lungs, CFTR mutation favored bacterial colonization by bacterial pathogens, of which S. aureus and P. aeruginosa are the most isolated. These two bacterial species sequentially colonized airways of CF patients: S. aureus is predominant in young patients and P. aeruginosa in adults. But the mechanisms involved in this switch of bacterial prevalence are still unknown. In this work we showed that sPLA2-IIA levels were increased in lungs of CF patients compared to lungs of non-CF patients and that sPLA2-IIA levels increased with age of patients. sPLA2-IIA recovered from CF patients expectorations was active and killed specifically S. aureus. Using animal models of lung infection, we demonstrated the selectivity of sPLA2-IIA against S. aureus and that P. aeruginosa induced sPLA2-IIA expression, the latter contributed to S . aureus elimination from the airways. Finally, we identified epithelial cells as a major source of sPLA2-IIA in CF airways. In these cells, P. aeruginosa induced sPLA2-IIA expression through injection of ExoS toxin and activation of KLF2 transcription factor. Taken together, these results indicate that i) P. aeruginosa-induced sPLA2-IIA expression in CF airways participated to S. aureus elimination and ii) a bacteria eliminate another bacteria by manipulating host innate immunity.