Specialized pro-resolving mediators regulate in vitro human airway epithelial resistance to Aspergillus fumigatus

Cystic fibrosis (CF) is caused by mutations in the CFTR gene resulting in alterations in the immune functions of the airway epithelium, including reduced biosynthesis of the specialized pro-resolving lipid mediators (SPMs). Aspergillus fumigatus is the most isolated filamentous fungus in patients with CF. This study explore whether specialized pro-resolving lipid mediators (SPMs) regulate the barrier function of airway epithelium in vitro during colonization by A. fumigatus. We have shown that mature A. fumigatus hyphae disrupt tight junctions in primary cultures of nasal epithelium from CF and non-CF patients, as well as in a CF bronchial epithelial cell line. However, these cellular models mount an immune response to resist the fungus. We found that epithelial vulnerability is strongly dependent on its initial level of differentiation and integrity at the time of fungal inoculation. Indeed, while highly differentiated and non-CF epithelia exhibit a strong resistance against A. fumigatus and a significant reduction in fungal load and hyphal growth, less differentiated epithelia have a limited capacity to maintain their structure and contain fungal growth. Furthermore, we have demonstrated the role of several SPMs that stimulate the innate immune response of the airway epithelium by preventing tight junction disruption induced by A. fumigatus colonization and decreasing fungal galactomannan secretion. Moreover, SPMs increase hBD2 transcription in highly differentiated nasal primary cultures from non-CF subjects, but not in those from CF patients, and these lipid mediators reduced the production of pro-inflammatory cytokines induced by fungal colonization. Overall, our data suggest that the reduction of SPMs in patients with CF could contribute to the difficulty of eradicating A. fumigatus. and this could open novel therapeutic perspectives to treat this disease.