Anti-inflammatory activity of Pseudomonas aeruginosa DEV phage in cystic fibrosis models.

Abstract

Cystic fibrosis is caused by biallelic mutations in the gene encoding the CFTR conductor channel. The recent approval of the Elexacaftor-Tezacaftor-Ivacaftor (ETI) therapy has marked a milestone in the management of this disease, alleviating respiratory and digestive symptoms. However, this treatment has no impact on the increased susceptibility to bacterial infections. In this scenario, phage therapy, viruses capable of selectively targeting and killing bacteria, is an emerging option. In the exploration of phages as therapeutic agents, a crucial consideration is their interaction with host cells, especially the immune system. In a previous study, we established the anti-inflammatory effect of four selected phages using the cftr loss-of-function (LoF) zebrafish embryos. In this study, we dissected the interactions of one of them, i.e. the phage DEV, with two cell types crucial in the context of cystic fibrosis: bronchial epithelial cells carrying biallelic CFTR F508del mutation (CuFi-1) and macrophages chemically CFTR inhibited. DEV administration to both human cell types showed anti-inflammatory effects by decreasing the expression of pro-inflammatory cytokines. We further demonstrated that, when in contact with CuFi-1 cells, DEV is internalized and degraded through the lysosomal compartment. In zebrafish, we showed that DEV interacts with tissue-resident macrophages and, in turn, reduces neutrophil recruitment toward the inflammation site. This information sheds light on a previously undocumented aspect of phage therapy as a modulator of the immune response, inducing anti-inflammatory effects. This could be particularly noteworthy within the context of excessive inflammation observed in the airways of individuals with cystic fibrosis.