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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 <jats:italic>Pseudomonas aeruginosa<\/jats:italic> phages and human airway epithelial cells (AECs) derived from a person with cystic fibrosis (CF), 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.<\/jats:p>","DOI":"10.1371\/journal.pbio.3002566","type":"journal-article","created":{"date-parts":[[2024,4,23]],"date-time":"2024-04-23T17:37:59Z","timestamp":1713893879000},"page":"e3002566","update-policy":"https:\/\/doi.org\/10.1371\/journal.pbio.corrections_policy","source":"Crossref","is-referenced-by-count":31,"title":["Lytic bacteriophages induce the secretion of antiviral and proinflammatory cytokines from human respiratory epithelial cells"],"prefix":"10.1371","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5246-4718","authenticated-orcid":true,"given":"Paula F.","family":"Zamora","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas G.","family":"Reidy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine R.","family":"Armbruster","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daria","family":"Van Tyne","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul E.","family":"Turner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan L.","family":"Koff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4767-6238","authenticated-orcid":true,"given":"Jennifer M.","family":"Bomberger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2024,4,23]]},"reference":[{"key":"pbio.3002566.ref001","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1146\/annurev-med-080219-122208","article-title":"Phage Therapy for Antibiotic-Resistant Bacterial Infections.","volume":"73","author":"GF Hatfull","year":"2022","journal-title":"Annu Rev Med."},{"key":"pbio.3002566.ref002","first-page":"15","article-title":"Current Clinical Landscape and Global Potential of Bacteriophage Therapy.","author":"NM Hitchcock","year":"2023","journal-title":"Viruses."},{"key":"pbio.3002566.ref003","doi-asserted-by":"crossref","first-page":"e3002119","DOI":"10.1371\/journal.pbio.3002119","article-title":"Translating phage therapy into the clinic: Recent accomplishments but continuing challenges","volume":"21","author":"A Petrovic Fabijan","year":"2023","journal-title":"PLoS Biol"},{"key":"pbio.3002566.ref004","doi-asserted-by":"crossref","DOI":"10.3390\/v14061170","article-title":"A Thorough Synthesis of Phage Therapy Unit Activity in Poland-Its History, Milestones and International Recognition.","volume":"14","author":"M Zaczek","year":"2022","journal-title":"Viruses"},{"key":"pbio.3002566.ref005","doi-asserted-by":"crossref","first-page":"1056","DOI":"10.3389\/fmicb.2020.01056","article-title":"Phage Therapy in Poland\u2014a Centennial Journey to the First Ethically Approved Treatment Facility in Europe.","volume":"11","author":"M Zaczek","year":"2020","journal-title":"Front Microbiol"},{"key":"pbio.3002566.ref006","unstructured":"Organization WH. 2022. 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