Macrophage-induced reduction of bacteriophage density limits the efficacy of in vivo pulmonary phage therapy
Abstract The rise of antimicrobial resistance leads to renewed interest in evaluating phage therapy. In murine models highly effective treatment of acute pneumonia caused by Pseudomonas aeruginosa relies on the synergistic antibacterial activity of bacteriophages with neutrophils. Here, we show that...
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| Format: | Article |
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Nature Portfolio
2025-07-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-61268-1 |
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| author | Sophia Zborowsky Jérémy Seurat Quentin Balacheff Solène Ecomard Céline Mulet Chau Nguyen Ngoc Minh Marie Titécat Emma Evrard Rogelio A. Rodriguez-Gonzalez Jacopo Marchi Joshua S. Weitz Laurent Debarbieux |
| author_facet | Sophia Zborowsky Jérémy Seurat Quentin Balacheff Solène Ecomard Céline Mulet Chau Nguyen Ngoc Minh Marie Titécat Emma Evrard Rogelio A. Rodriguez-Gonzalez Jacopo Marchi Joshua S. Weitz Laurent Debarbieux |
| author_sort | Sophia Zborowsky |
| collection | DOAJ |
| description | Abstract The rise of antimicrobial resistance leads to renewed interest in evaluating phage therapy. In murine models highly effective treatment of acute pneumonia caused by Pseudomonas aeruginosa relies on the synergistic antibacterial activity of bacteriophages with neutrophils. Here, we show that depletion of alveolar macrophages (AM) shortens the survival of adult male mice without boosting the P. aeruginosa load in the lungs. Unexpectedly, upon bacteriophage treatment, pulmonary levels of P. aeruginosa are significantly lower in AM-depleted than in immunocompetent mice. To explore potential mechanisms underlying the benefit of AM-depletion in treated mice, we develop a mathematical model of bacteriophage, bacteria, and innate immune system dynamics. Simulations from the model fitted to data suggest that AM reduce bacteriophage density in the lungs. We experimentally confirm that the in vivo decay of bacteriophage is faster in immunocompetent compared to AM-depleted animals and that AM phagocytize therapeutic bacteriophage. These findings demonstrate the involvement of feedback between bacteriophage, bacteria, and the immune system in shaping the outcomes of phage therapy in clinical settings. |
| format | Article |
| id | doaj-art-1e023007cdab4a97b2b7df1522cd75ad |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-1e023007cdab4a97b2b7df1522cd75ad2025-08-20T03:03:41ZengNature PortfolioNature Communications2041-17232025-07-0116111210.1038/s41467-025-61268-1Macrophage-induced reduction of bacteriophage density limits the efficacy of in vivo pulmonary phage therapySophia Zborowsky0Jérémy Seurat1Quentin Balacheff2Solène Ecomard3Céline Mulet4Chau Nguyen Ngoc Minh5Marie Titécat6Emma Evrard7Rogelio A. Rodriguez-Gonzalez8Jacopo Marchi9Joshua S. Weitz10Laurent Debarbieux11Institut Pasteur, Université Paris Cité, CNRS UMR6047, Bacteriophage Bacterium HostInstitut de Biologie, Ecole Normale SupérieureInstitut Pasteur, Université Paris Cité, CNRS UMR6047, Bacteriophage Bacterium HostInstitut Pasteur, Université Paris Cité, CNRS UMR6047, Bacteriophage Bacterium HostInstitut Pasteur, Université Paris Cité, CNRS UMR6047, Bacteriophage Bacterium HostInstitut Pasteur, Université Paris Cité, CNRS UMR6047, Bacteriophage Bacterium HostUniversité de Lille, INSERM, CHU Lille, U1286-INFINITE-Institute for Translational Research in InflammationInstitut Pasteur, Université Paris Cité, CNRS UMR6047, Bacteriophage Bacterium HostSchool of Biological Sciences, Georgia Institute of TechnologySchool of Biological Sciences, Georgia Institute of TechnologyInstitut de Biologie, Ecole Normale SupérieureInstitut Pasteur, Université Paris Cité, CNRS UMR6047, Bacteriophage Bacterium HostAbstract The rise of antimicrobial resistance leads to renewed interest in evaluating phage therapy. In murine models highly effective treatment of acute pneumonia caused by Pseudomonas aeruginosa relies on the synergistic antibacterial activity of bacteriophages with neutrophils. Here, we show that depletion of alveolar macrophages (AM) shortens the survival of adult male mice without boosting the P. aeruginosa load in the lungs. Unexpectedly, upon bacteriophage treatment, pulmonary levels of P. aeruginosa are significantly lower in AM-depleted than in immunocompetent mice. To explore potential mechanisms underlying the benefit of AM-depletion in treated mice, we develop a mathematical model of bacteriophage, bacteria, and innate immune system dynamics. Simulations from the model fitted to data suggest that AM reduce bacteriophage density in the lungs. We experimentally confirm that the in vivo decay of bacteriophage is faster in immunocompetent compared to AM-depleted animals and that AM phagocytize therapeutic bacteriophage. These findings demonstrate the involvement of feedback between bacteriophage, bacteria, and the immune system in shaping the outcomes of phage therapy in clinical settings.https://doi.org/10.1038/s41467-025-61268-1 |
| spellingShingle | Sophia Zborowsky Jérémy Seurat Quentin Balacheff Solène Ecomard Céline Mulet Chau Nguyen Ngoc Minh Marie Titécat Emma Evrard Rogelio A. Rodriguez-Gonzalez Jacopo Marchi Joshua S. Weitz Laurent Debarbieux Macrophage-induced reduction of bacteriophage density limits the efficacy of in vivo pulmonary phage therapy Nature Communications |
| title | Macrophage-induced reduction of bacteriophage density limits the efficacy of in vivo pulmonary phage therapy |
| title_full | Macrophage-induced reduction of bacteriophage density limits the efficacy of in vivo pulmonary phage therapy |
| title_fullStr | Macrophage-induced reduction of bacteriophage density limits the efficacy of in vivo pulmonary phage therapy |
| title_full_unstemmed | Macrophage-induced reduction of bacteriophage density limits the efficacy of in vivo pulmonary phage therapy |
| title_short | Macrophage-induced reduction of bacteriophage density limits the efficacy of in vivo pulmonary phage therapy |
| title_sort | macrophage induced reduction of bacteriophage density limits the efficacy of in vivo pulmonary phage therapy |
| url | https://doi.org/10.1038/s41467-025-61268-1 |
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