Extracellular vesicles secreted by primary human bronchial epithelial cells reduce Pseudomonas aeruginosa burden and inflammation in Cystic Fibrosis mouse lung

Cystic Fibrosis (CF) results in a reduction in the volume of airway surface liquid, increased accumulation of viscous mucus, persistent antibiotic resistant lung infections that cause chronic inflammation and a decline in lung function. More than fifty percent of adults with CF are chronically colonized by Pseudomonas aeruginosa ( P. aeruginosa), the primary reason for morbidity and mortality in people with CF (pwCF). Although highly effective modulator therapy (HEMT) is an important part of disease management in CF, HEMT does not eliminate P. aeruginosa or lung inflammation. Thus, new treatments are required to reduce lung infection and inflammation in CF. In a previous in vitro study we demonstrated that primary human bronchial epithelial cells (HBEC) secrete extracellular vesicles (EVs) that block the ability of P. aeruginosa to form biofilms by reducing the abundance of several proteins necessary for biofilm formation as well as enhancing the sensitivity of P. aeruginosa to beta-lactam antibiotics. In this study using a CF mouse model of P. aeruginosa infection we demonstrate that intratracheal administration of EVs secreted by HBEC reduced P. aeruginosa lung burden and several pro-inflammatory cytokines including IFN-γ, TNF-α, and MIP-1β in bronchoalveolar fluid (BALF), even in the absence of antibiotics. Moreover, EVs decreased neutrophils in BALF. Thus, EVs secreted by HBEC reduce the lung burden of P. aeruginosa, decrease inflammation and reduce neutrophils in a CF mouse model. These results suggest that HBEC via the secretion of EVs may play an important role in the immune response to P. aeruginosa lung infection.