Mammalian cells internalize bacteriophages and use them as a resource to enhance cellular growth and survival
Open accessAbstract
There is a growing appreciation that the direct interaction between bacteriophages and the mammalian host can facilitate diverse and unexplored symbioses. Yet the impact these bacteriophages may have on mammalian cellular and immunological processes is poorly understood. Here, we applied highly purified phage T4, free from bacterial by-products and endotoxins to mammalian cells and analyzed the cellular responses using luciferase reporter and antibody microarray assays. Phage preparations were applied in vitro to either A549 lung epithelial cells, MDCK-I kidney cells, or primary mouse bone marrow derived macrophages with the phage-free supernatant serving as a comparative control. Highly purified T4 phages were rapidly internalized by mammalian cells and accumulated within macropinosomes but did not activate the inflammatory DNA response TLR9 or cGAS-STING pathways. Following 8 hours of incubation with T4 phage, whole cell lysates were analyzed via antibody microarray that detected expression and phosphorylation levels of human signaling proteins. T4 phage application led to the activation of AKT-dependent pathways, resulting in an increase in cell metabolism, survival, and actin reorganization, the last being critical for macropinocytosis and potentially regulating a positive feedback loop to drive further phage internalization. T4 phages additionally down-regulated CDK1 and its downstream effectors, leading to an inhibition of cell cycle progression and an increase in cellular growth through a prolonged G1 phase. These interactions demonstrate that highly purified T4 phages do not activate DNA-mediated inflammatory pathways but do trigger protein phosphorylation cascades that promote cellular growth and survival. We conclude that mammalian cells are internalizing bacteriophages as a resource to promote cellular growth and metabolism.
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Phages can translocate into tumors and interact with mammalian cells, potentially affecting tumor signaling and stress pathways.
“Increasing evidence suggests that phages can translocate into tumors and interact with mammalian cells, potentially affecting tumor signaling and stress pathways [27,28]”
From Phage therapy in oncology: opportunities for cancer prevention and treatment (2026) · cites this paper as [27]
The Abstract and Discussion report that T4 phages enter mammalian cells in vitro and alter AKT- and CDK1-related signaling. They do not show phages translocating into tumors or establish effects on signaling or stress pathways within tumors; the Discussion explicitly notes that the experiments used cell lines rather than tumors. (LLM, conf=0.88)
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Bacteriophage defends murine gut from Escherichia coli invasion via mucosal adherence
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Bacteriophages: A Challenge for Antimicrobial Therapy
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Human bladder organoids model urinary tract infection and bacteriophage therapyPreprint
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A novel miniaturized filamentous phagemid as a gene delivery vehicle to target mammalian cells
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Phage-Microbiota Crosstalk: Implications for Central Nervous System Disorders
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Transcriptomic analysis of phage-mammalian cell interaction reveals diverse phage immunobarcodes
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Phage therapy in oncology: opportunities for cancer prevention and treatment
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Breaking down barriers to improve phage therapy delivery
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Connecting the dots between phage pharmacokinetics, pharmacodynamics and immune interactions
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Phage therapy: from basic biology to clinical application
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- Authors
- Bichet, M. C., Adderley, J., Avellaneda-Franco, L., Magnin-Bougma, I., Torriero-Smith, N., Gearing, L. J., Deffrasnes, C., David, C., Pepin, G., Gantier, M. P., Lin, R. C., Patwa, R., Moseley, G. W., Doerig, C., & Barr, J. J.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- RMIT University (AU)
- Monash University (AU)
- Hudson Institute of Medical Research (AU)
- Westmead Institute for Medical Research (AU)
- Corresponding author
- Barr, Jeremy J.
- ORCID
- Venue
- PLOS Biology
- Publisher
- Public Library of Science (PLoS)
- Published
- 2023-10-26
- Volume
- 21
- Issue
- 10
- Pages
- e3002341
- ISSN
- 1544-9173 (ISSN-L)
- 1545-7885
- PMC
- PMC10602308
- OpenAlex
- W4387954451
- Cited by
- 47
- References
- 91
- Citations by year
- 2026: 19 · 2025: 16 · 2024: 11 · 2023: 1
- FWCI
- 7.59
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS Biology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- Australian Research Council (DE170100525)
- National Health and Medical Research Council (1156588, 1125704)
- Perpetual (2018HIG00007)
- Topics
- Physical Sciences › Environmental Science › Ecology › Bacteriophages and microbial interactions
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Keywords
- bacteriophage T4, macropinocytosis, Akt signaling, CDK1, cell cycle regulation, G1 phase, actin reorganization, cellular metabolism, cell survival, TLR9, cGAS-STING
- MeSH terms
- Animals, Antibodies, Cell Cycle, DNA, Humans, Mammals, Bacteriophage T4, Mice
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