{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T00:01:18Z","timestamp":1793318478108,"version":"4.5.0"},"reference-count":50,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T00:00:00Z","timestamp":1763510400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>The increasing prevalence of multidrug-resistant (MDR) bacteria has reduced the effectiveness of standard antibiotics, prompting renewed interest in bacteriophage (phage) therapy as an alternative or adjunctive treatment. Phage therapy offers high specificity, self-amplification at infection sites, and minimal disruption to the gut microbiota. However, clinical implementation is challenging, due to the risk of phage resistance and uncertainties regarding optimal dosing and immune interactions.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Previously, we demonstrated that a two-phage cocktail exhibited low immunogenicity in mice and, when combined with meropenem, significantly improved clearance of ventilator-associated\n                      <jats:italic>Pseudomonas aeruginosa<\/jats:italic>\n                      pneumonia, reduced inflammation, and disrupted biofilms more effectively than either treatment alone. In the present study, we investigated the interplay between this phage cocktail and innate immune defenses using a murine respiratory infection model and human\n                      <jats:italic>in vitro<\/jats:italic>\n                      assays.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Our findings reveal that the therapeutic efficacy of phage treatment is critically dependent on the presence of neutrophils, which act synergistically with phages to achieve effective bacterial clearance, particularly when bacterial burden exceeds a defined threshold. Alveolar macrophages, however, do not significantly contribute to infection resolution\n                      <jats:italic>in vivo<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      Since neutrophils play a key-role in supporting phage-mediated\n                      <jats:italic>Pseudomonas<\/jats:italic>\n                      clearance, the efficacy of phage therapy is closely linked to the hosts immune competence \u2013 an important consideration when treating immunocompromised patients.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2025.1681461","type":"journal-article","created":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T06:36:55Z","timestamp":1763534215000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":10,"title":["Neutrophils, not macrophages, aid phage-mediated control of pulmonary Pseudomonas aeruginosa infection"],"prefix":"10.3389","volume":"16","author":[{"given":"Chantal","family":"Weissfuss","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen","family":"Hoffmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulrike","family":"Behrendt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magdalena","family":"B\u00fcrkle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shailey G.","family":"Twamley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Imke H. E.","family":"Korf","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katharina","family":"Ahrens","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine","family":"Rohde","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian M.","family":"Zobel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurent","family":"Debarbieux","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Damien","family":"Ricard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Witzenrath","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geraldine","family":"Nouailles","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,11,19]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1159\/000487515","article-title":"Pseudomonas aeruginosa and Klebsiella pneumoniae Adaptation to Innate Immune Clearance Mechanisms in the Lung","volume":"10","author":"Riquelme","year":"2018","journal-title":"J\u00a0Innate Immun"},{"key":"B2","unstructured":"WHO bacterial priority pathogens list 2024: Bacterial pathogens of public health importance to guide research, development and\u00a0strategies to prevent and control antimicrobial resistance\n          \n          \n          \n          2024"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.3390\/nu11030666","article-title":"PHAGE study: effects of supplemental bacteriophage intake on inflammation and gut microbiota in healthy adults","volume":"11","author":"Febvre","year":"2019","journal-title":"Nutrients"},{"key":"B4","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1146\/annurev-med-080219-122208","article-title":"Phage therapy for antibiotic-resistant bacterial infections","volume":"73","author":"Hatfull","year":"2022","journal-title":"Annu Rev Med"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.3390\/v10040178","article-title":"Expert opinion on three phage therapy related topics: bacterial phage resistance, phage training and prophages in bacterial production strains","volume":"10","author":"Rohde","year":"2018","journal-title":"Viruses"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1038\/s41564-024-01705-x","article-title":"Personalized bacteriophage therapy outcomes for 100 consecutive cases: a multicentre, multinational, retrospective observational study","volume":"9","author":"Pirnay","year":"2024","journal-title":"Nat Microbiol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.3390\/v9060150","article-title":"Phage-phagocyte interactions and their implications for phage application as therapeutics","volume":"9","author":"Jo\u0144czyk-Matysiak","year":"2017","journal-title":"Viruses"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcf.2020.11.017","article-title":"Phages as immunomodulators and their promising use as anti-inflammatory agents in a cftr loss-of-function zebrafish model","volume":"20","author":"Cafora","year":"2021","journal-title":"J Cystic Fibrosis: Off J Eur Cystic Fibrosis Soc"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2022.979610","article-title":"Evaluation of phages and liposomes as combination therapy to counteract Pseudomonas aeruginosa infection in wild-type and CFTR-null models","volume":"13","author":"Cafora","year":"2022","journal-title":"Front Microbiol"},{"key":"B10","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1016\/j.chom.2017.06.018","article-title":"Synergy between the host immune system and bacteriophage is essential for successful phage therapy against an acute respiratory pathogen","volume":"22","author":"Roach","year":"2017","journal-title":"Cell Host Microbe"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2014.11.001","article-title":"The 3 major types of innate and adaptive cell-mediated effector immunity","volume":"135","author":"Annunziato","year":"2015","journal-title":"J Allergy Clin Immunol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.3390\/pathogens9010006","article-title":"The role of pseudomonas aeruginosa lipopolysaccharide in bacterial pathogenesis and physiology","volume":"9","author":"Huszczynski","year":"2019","journal-title":"Pathog (Basel Switzerland)"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.3390\/pathogens6010010","article-title":"Interactions between neutrophils and pseudomonas aeruginosa in cystic fibrosis","volume":"6","author":"Rada","year":"2017","journal-title":"Pathog (Basel Switzerland)"},{"key":"B14","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1038\/s41392-022-01056-1","article-title":"Pseudomonas aeruginosa: pathogenesis, virulence factors, antibiotic resistance, interaction with host, technology advances and emerging therapeutics","volume":"7","author":"Qin","year":"2022","journal-title":"Signal Transduction Targeted Ther"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1007\/s12275-011-1512-4","article-title":"Antibacterial efficacy of lytic Pseudomonas bacteriophage in normal and neutropenic mice models","volume":"49","author":"Tiwari","year":"2011","journal-title":"J Microbiol (Seoul Korea)"},{"key":"B16","doi-asserted-by":"publisher","first-page":"5725","DOI":"10.1038\/s41467-025-61268-1","article-title":"Macrophage-induced reduction of bacteriophage density limits the efficacy of in vivo pulmonary phage therapy","volume":"16","author":"Zborowsky","year":"2025","journal-title":"Nat Commun"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtbi.2017.06.037","article-title":"Modeling the synergistic elimination of bacteria by phage and the innate immune system","volume":"429","author":"Leung","year":"2017","journal-title":"J Theor Biol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2022.110825","article-title":"Combination of in vivo phage therapy data with in silico model highlights key parameters for pneumonia treatment efficacy","volume":"39","author":"Delattre","year":"2022","journal-title":"Cell Rep"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.3390\/pharmaceutics14020427","article-title":"Phages against pathogenic bacterial biofilms and biofilm-based infections: A review","volume":"14","author":"Liu","year":"2022","journal-title":"Pharmaceutics"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0124280","article-title":"Strain specific phage treatment for staphylococcus aureus infection is influenced by host immunity and site of infection","volume":"10","author":"Pincus","year":"2015","journal-title":"PloS One"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1012793","article-title":"Multi-strain phage induced clearance of bacterial infections","volume":"21","author":"Marchi","year":"2025","journal-title":"PloS Comput Biol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.3390\/v15081726","article-title":"Human neutrophil response to pseudomonas bacteriophage PAK_P1, a therapeutic candidate","volume":"15","author":"Roach","year":"2023","journal-title":"Viruses"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1305923110","article-title":"Bacteriophage adhering to mucus provide a non-host-derived immunity","volume":"110","author":"Barr","year":"2013","journal-title":"Proc Natl Acad Sci United States America"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.2217\/fmb-2017-0049","article-title":"Phages and immunomodulation","volume":"12","author":"G\u00f3rski","year":"2017","journal-title":"Future Microbiol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1128\/mbio.01874-17","article-title":"Bacteriophage transcytosis provides a mechanism to cross epithelial cell layers","volume":"8","author":"Nguyen","year":"2017","journal-title":"MBio"},{"key":"B26","doi-asserted-by":"publisher","first-page":"285","DOI":"10.1016\/j.chom.2019.01.008","article-title":"Expansion of bacteriophages is linked to aggravated intestinal inflammation and colitis","volume":"25","author":"Gogokhia","year":"2019","journal-title":"Cell Host Microbe"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1016\/j.coviro.2021.04.010","article-title":"Immune-bacteriophage interactions in inflammatory bowel diseases","volume":"49","author":"Gogokhia","year":"2021","journal-title":"Curr Opin Virol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.3390\/v13071241","article-title":"Influence of caudovirales phages on humoral immunity in mice","volume":"13","author":"Chechushkov","year":"2021","journal-title":"Viruses"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.3390\/v15020387","article-title":"Repetitive Exposure to Bacteriophage Cocktails against Pseudomonas aeruginosa or Escherichia coli Provokes Marginal Humoral Immunity in Na\u00efve Mice","volume":"15","author":"Weissfuss","year":"2023","journal-title":"Viruses"},{"key":"B30","doi-asserted-by":"publisher","first-page":"4500","DOI":"10.1038\/s41467-025-59806-y","article-title":"Adjunctive phage therapy improves antibiotic treatment of ventilator-associated-pneumonia with Pseudomonas aeruginosa","volume":"16","author":"Weissfuss","year":"2025","journal-title":"Nat Commun"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1093\/ismejo\/wraf065","article-title":"Phage-phage competition and biofilms affect interactions between two virulent bacteriophages and Pseudomonas aeruginosa","volume":"19","author":"B\u00fcrkle","year":"2025","journal-title":"ISME J"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.3390\/v14010033","article-title":"Preclinical Assessment of Bacteriophage Therapy against Experimental Acinetobacter baumannii Lung Infection","volume":"14","author":"Wienhold","year":"2021","journal-title":"Viruses"},{"key":"B33","doi-asserted-by":"publisher","first-page":"287","DOI":"10.1186\/s13054-018-2224-5","article-title":"Delay in antibiotic therapy results in fatal disease outcome in murine pneumococcal pneumonia","volume":"22","author":"Berger","year":"2018","journal-title":"Crit Care (London England)"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1111\/j.1462-2920.2012.02719.x","article-title":"Pseudomonas aeruginosa population structure revisited under environmental focus: impact of water quality and phage pressure","volume":"14","author":"Selezska","year":"2012","journal-title":"Environ Microbiol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2180-10-301","article-title":"Characterization of JG024, a pseudomonas aeruginosa PB1-like broad host range phage under simulated infection conditions","volume":"10","author":"Garbe","year":"2010","journal-title":"BMC Microbiol"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.17.1.208","article-title":"The use of lead citrate at high pH as an electron-opaque stain in electron microscopy","volume":"1","author":"Reynolds, Edward","year":"1963","journal-title":"J Cell Biol"},{"key":"B37","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1189\/jlb.0407247","article-title":"Use of Ly6G-specific monoclonal antibody to deplete neutrophils in mice","volume":"83","author":"Daley","year":"2008","journal-title":"J Leukocyte Biol"},{"key":"B38","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1007\/978-1-60327-360-2_13","article-title":"Liposomes for specific depletion of macrophages from organs and tissues","volume":"605","author":"van Rooijen","year":"2010","journal-title":"Methods Mol Biol (Clifton N.J.)"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.02970-14","article-title":"Anti-pseudomonas aeruginosa igY antibodies induce specific bacterial aggregation and internalization in human polymorphonuclear neutrophils","volume":"83","author":"Thomsen","year":"2015","journal-title":"Infection Immun"},{"key":"B40","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1164\/rccm.202308-1403OC","article-title":"A bispecific monoclonal antibody targeting psl and pcrV enhances neutrophil-mediated killing of pseudomonas aeruginosa in patients with bronchiectasis","volume":"210","author":"Long","year":"2024","journal-title":"Am J Respir Crit Care Med"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00501-09","article-title":"Inescapable need for neutrophils as mediators of cellular innate immunity to acute Pseudomonas aeruginosa pneumonia","volume":"77","author":"Koh","year":"2009","journal-title":"Infection Immun"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00217.2001","article-title":"Activation of type II alveolar epithelial cells during acute endotoxemia","volume":"282","author":"Sunil","year":"2002","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1172\/JCI170501","article-title":"Alveolar macrophages in tissue homeostasis, inflammation, and infection: evolving concepts of therapeutic targeting","volume":"133","author":"Malainou","year":"2023","journal-title":"J Clin Invest"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00055.2006","article-title":"Alveolar macrophages contribute to alveolar barrier dysfunction in ventilator-induced lung injury. American Journal of Physiology","volume":"291","author":"Frank","year":"2006","journal-title":"Lung Cell Mol Physiol"},{"key":"B45","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1165\/rcmb.2008-0170OC","article-title":"Macrophages directly contribute to the exaggerated inflammatory response in cystic fibrosis transmembrane conductance regulator-\/- mice","volume":"40","author":"Bruscia","year":"2009","journal-title":"Am J Respir Cell Mol Biol"},{"key":"B46","doi-asserted-by":"publisher","first-page":"346","DOI":"10.1007\/s00284-024-03875-7","article-title":"Immunomodulation in non-traditional therapies for methicillin-resistant staphylococcus aureus (MRSA) management","volume":"81","author":"Subbarayudu","year":"2024","journal-title":"Curr Microbiol"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1128\/aac.01429-23","article-title":"Host immunity involvement in the outcome of phage therapy against hypervirulent Klebsiella pneumoniae infections","volume":"68","author":"Tang","year":"2024","journal-title":"Antimicrobial Agents Chemotherapy"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1183\/16000617.0029-2024","article-title":"Phage therapy: breathing new tactics into lower respiratory tract infection treatments","volume":"33","author":"Vaezi","year":"2024","journal-title":"Eur Respir Review: an Off J Eur Respir Soc"},{"key":"B49","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1186\/s41073-016-0007-6","article-title":"Sex and Gender Equity in Research: rationale for the SAGER guidelines and recommended use","volume":"1","author":"Heidari","year":"2016","journal-title":"Res Integrity Peer Rev"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1128\/iai.00283-22","article-title":"Sex and gender differences in bacterial infections","volume":"90","author":"Dias","year":"2022","journal-title":"Infection Immun"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1681461\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T06:36:56Z","timestamp":1763534216000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1681461\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,19]]},"references-count":50,"alternative-id":["10.3389\/fimmu.2025.1681461"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2025.1681461","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,19]]},"article-number":"1681461"}}