Lytic bacteriophages induce the secretion of antiviral and proinflammatory cytokines from human respiratory epithelial cells

Phage therapy is a therapeutic approach to treat multidrug resistant infections that employs lytic bacteriophages (phages) to eliminate bacteria. Despite the abundant evidence for its success as an antimicrobial in Eastern Europe, there is scarce data regarding its effects on the human host. Here, we aimed to understand how lytic phages interact with cells of the airway epithelium, the tissue site that is colonized by bacterial biofilms in numerous chronic respiratory disorders. Using a panel of Pseudomonas aeruginosa phages and human airway epithelial cells derived from a person with cystic fibrosis, we determined that interactions between phages and epithelial cells depend on specific phage properties as well as physiochemical features of the microenvironment. Although poor at internalizing phages, the airway epithelium responds to phage exposure by changing its transcriptional profile and secreting antiviral and proinflammatory cytokines that correlate with specific phage families. Overall, our findings indicate that mammalian responses to phages are heterogenous and could potentially alter the way that respiratory local defenses aid in bacterial clearance during phage therapy. Thus, besides phage receptor specificity in a particular bacterial isolate, the criteria to select lytic phages for therapy should be expanded to include mammalian cell responses. We sought to determine whether respiratory epithelial cells can sense and respond to purified lytic phages. We conducted RNA sequencing of RNA derived from phage-treated CF AECs. To enrich for phage-positive cells, CFBE41o- cells were exposed to fluorescently labeled OMKO1, LPS-5, PSA04, and PSA34 for 24 h and were then subjected to cell sorting using flow cytometry.