CoChat
Sign Up
Cited by 41Bacteriophages and microbial interactionsImmune Response and InflammationInvertebrate Immune Response Mechanisms

Therapeutic Phages as Modulators of the Immune Response: Practical Implications

Open access
Górski, Andrzej, Międzybrodzki, Ryszard, Jończyk-Matysiak, Ewa, Kniotek, Monika, Letkiewicz, Sławomir·2023·Clinical Infectious Diseases
DOI 10.1093/cid/ciad483
Open this paper in CoChat — free accountOpen PDF

Abstract

While the medical community awaits formal proof of the efficacy of phage therapy, as is required by evidence-based medicine, existing data suggest that phages could also be applied based on their non-antibacterial action, especially phage-mediated immunomodulation. Promising avenues have been revealed by findings indicating that phages may mediate diverse actions in the immune system, while the list of phages able to dampen the aberrant immunity associated with a variety of disorders continuously grows. Here we summarize what is known in this field and possible options for the future. While available data are still scarce and preliminary, it appears that “phage repurposing” is worthy of more research, which could reveal new perspectives on applying phage therapy in contemporary medicine.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1093/cid/ciad483

Cites

1 of 1 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Studies have begun uncovering direct and indirect immunomodulatory properties of phages beyond their antimicrobial effects.

    “Studies have begun uncovering direct and indirect immunomodulatory properties of phages beyond their antimicrobial effects [21,25,74]”

    From Phage therapy in oncology: opportunities for cancer prevention and treatment (2026) · cites this paper as [74]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 66

  1. Borysowski J, Przybylski M, Międzybrodzki R, et al. The effects of bacteriophages on the expression of genes involved in antimicrobial immunity. Postepy Hig Med Dosw 2019; 73:414-20.
  2. Borysowski J, Przybylski M, Międzybrodzki R, et al. The effects of T4 and A5/80 phages on the expression of immunologically important genes in differentiated Caco-2 cells. Postepy Hig Med Dosw 2020; 74:371-6.
  3. Miernikiewicz P, Dąbrowska K, Piotrowicz A, et al. T4 phage and its head surface proteins do not stimulate inflammatory mediator production. PLoS One 2013; 8: e71036.
  4. Febvre HP, Rao S, Gindin M. PHAGE study: effects of supplemental bacterio- phage intake on inflammation and gut microbiota in healthy adults. Nutrients 2019; 11:666.
  5. Khan Mirzaei M, Haileselassie Y, Navis M, et al. Morphologically distinct Escherichia coli bacteriophages differ in their efficacy and ability to stimulate cy- tokine release in vitro. Front Microbiol 2016; 7:437.
  6. Dufour N, Delattre R, Chevallereau A, et al. Phage therapy of pneumonia is not associated with an overstimulation of the inflammatory response com- pared to antibiotic treatment in mice. Antimicrob Agents Chemother 2019; 63:e00379-19.
  7. Borysowski J, Wierzbicki P, Kłosowska D, et al. The effects of T4 and A3/R phage preparations on whole-blood monocyte and neutrophil respiratory burst. Viral Immunol 2010; 23:541-4.
  8. Borysowski J, Międzybrodzki R, Wierzbicki P, et al. A3r phage and Staphylococcus aureus lysate do not induce neutrophil degranulation. Viruses 2017; 9:36.
  9. Bocian K, Borysowski J, Zarzycki M, et al. The effects of T4 and A3/R bacterio- phages on differentiation of human myeloid dendritic cells. Front Microbiol 2016; 7:1267.
  10. Pincus NB, Reckhow JD, Saleem D, et al. Strain specific phage treatment for Staphylococcus aureus infection is influenced by host immunity and site of infec- tion. PLoS One 2015; 10:e0124280.
  11. Freyberger HR, He Y, Roth AL, et al. Effects of Staphylococcus aureus bacterio- phage K on expression of cytokines and activation markers by human dendritic cells in vitro. Viruses 2018; 10:617.
  12. Zhang L, Hou X, Sun L, et al. Staphylococcus aureus bacteriophage suppresses LPS-induced inflammation in MAC-T bovine mammary epithelial cells. Front Microbiol 2018; 9:1614.
  13. Van Belleghem JD, Clement F, Merabishvili M, et al. Pro-and anti-inflammatory responses of peripheral blood mononuclear cells induced by Staphylococcus aure- us and Pseudomonas aeruginosa phages. Sci Rep 2017; 7:8004.
  14. Roach DR, Chollet-Martin S, Noël B, et al. Human neutrophil response to Pseudomonas bacteriophages. BioRxiv 786905 [preprint]. September 30, 2019. Available from: https://doi.org/10.1101/786905 · DOI
  15. Trend S, Chang BJ, O'Dea M, et al. Use of a primary epithelial cell screening tool to investigate phage therapy in cystic fibrosis. Front Pharmacol 2018; 9:1330.
  16. Shiley JR, Comfort KK, Robinson JB. Immunogenicity and antimicrobial effec- tiveness of Pseudomonas aeruginosa specific bacteriophage in a human lung in vi- tro model. Appl Microbiol Biotechnol 2017; 101:7977-85.
  17. Cafora M, Brix A, Forti F, et al. Phages as immunomodulators and their promis- ing use as anti-inflammatory agents in a cftr loss-of-function zebrafish model. J Cyst Fibros 2021; 20:1046-52.
  18. Cafora M, Deflorian G, Forti F, et al. Phage therapy against Pseudomonas aerugi- nosa infections in a cystic fibrosis zebrafish model. Sci Rep 2019; 9:1527.
  19. Chen Y, Sun E, Yang L, et al. Therapeutic application of bacteriophage PHB02 and its putative depolymerase against Pasteurella multocida capsular type A in mice. Front Microbiol 2018; 9:1678.
  20. Xue Y, Zhai S, Wang Z, et al. The Yersinia phage X1 administered orally efficiently protects a murine chronic enteritis model against Yersinia enterocolitica infection. Front Microbiol 2020; 11:351.
  21. Schubert BD, Ku H, Kabwe M, et al. Effects of Klebsiella pneumoniae bacterio- phages on IRAK3 knockdown/knockout THP-1 monocyte cell lines. Viruses 2022; 14:2582.
  22. Grabowski Ł, Pierzynowska K, Kosznik-Kwaśnicka K, et al. Sex-dependent differ- ences in behavioral and immunological responses to antibiotic and bacteriophage administration in mice. Front Immunol 2023; 14:1133358.
  23. Górski A, Międzybrodzki R, Jończyk-Matysiak E, et al. Phage-specific diverse ef- fects of bacterial viruses on the immune system. Future Microbiol 2019; 14: 1171-4.
  24. Górski A, Dąbrowska K, Świtała-Jeleń K, et al. New insights into the possible role of bacteriophages in host defense and disease. Med Immunol 2003; 2:2.
  25. Górski A, Weber-Dąbrowska B. The potential role of endogenous bacteriophages in controlling invading pathogens. Cell Mol Life Sci 2005; 62:511-9.
  26. Górski A, Ważna E, Dąbrowska BW, et al. Bacteriophage translocation. FEMS Immunol Med Microbiol 2006; 46:313-9.
  27. Barr JJ. A bacteriophages journey through the human body. Immunol Rev 2017; 279:106-22.
  28. Van Belleghem JD, Dabrowska K, Vaneechoutte M, et al. Interactions between bacteriophage, bacteria, and the mammalian immune system. Viruses 2018; 11: 10.
  29. Bichet MC, Chin WH, Richards W, et al. Bacteriophage uptake by mammalian cell layers represents a potential sink that may impact phage therapy. iScience 2021; 24:102287.
  30. Wahida A, Tang F, Barr JJ. Rethinking phage-bacteria-eukaryotic relationships and their influence on human health. Cell Host Microbe 2021; 29:681-8.
  31. Hodyra-Stefaniak K, Miernikiewicz P, Drapała J, et al. Mammalian host-versus-phage immune response determines phage fate in vivo. Sci Rep 2015; 5:14802.
  32. Kaźmierczak Z, Majewska J, Milczarek M, et al. Circulation of fluorescently la- belled phage in a murine model. Viruses 2021; 13:297.
  33. Jończyk-Matysiak E, Weber-Dąbrowska B, Owczarek B, et al. Phage-phagocyte interactions and their implications for phage application as therapeutics. Viruses 2017; 9:150.
  34. Roach DR, Leung CY, Henry M, et al. Synergy between the host immune system and bacteriophage is essential for successful phage therapy against an acute respi- ratory pathogen. Cell Host Microbe 2017; 22:38-47.e4.
  35. Górski A, Międzybrodzki R, Łobocka M, et al. Phage therapy: what have we learned? Viruses 2018; 10:288.
  36. Jończyk-Matysiak E, Łusiak-Szelachowska M, Kłak M, et al. The effect of bacter- iophage preparations on intracellular killing of bacteria by phagocytes. J Immunol Res 2015; 2015:482863.
  37. Møller-Olsen C, Ho SFS, Shukla RD, et al. Engineered K1F bacteriophages kill in- tracellular Escherichia coli K1 in human epithelial cells. Sci Rep 2018; 8:17559.
  38. Shan J, Ramachandran A, Thanki AM, et al. Bacteriophages are more virulent to bacteria with human cells than they are in bacterial culture; insights from HT-29 cells. Sci Rep 2018; 8:5091.
  39. Chu Y, Meng Q, Yu J, et al. Strain-level dynamics reveal regulatory roles in atopic eczema by gut bacterial phages. Microbiol Spectr 2023; 11:e0455122.
  40. Choi Y, Hosseindoust A, Ha SH, et al. Effects of dietary supplementation of bac- teriophage cocktail on health status of weanling pigs in a non-sanitary environ- ment. J Anim Sci Biotechnol 2023; 14:64.
  41. Przerwa A, Zimecki M, Świtała-Jeleń K, et al. Effects of bacteriophages on free radical production and phagocytic functions. Med Microbiol Immunol 2006; 195:143-50.
  42. Międzybrodzki R, Świtała-Jeleń K, Fortuna W, et al. Bacteriophage preparation inhibition of reactive oxygen species generation by endotoxin-stimulated poly- morphonuclear leukocytes. Virus Res 2008; 131:233-42.
  43. Grabowski Ł, Węgrzyn G, Węgrzyn A, Podlacha M. Highly different effects of phage therapy and antibiotic therapy on immunological responses of chickens in- fected with Salmonella enterica serovar Typhimurium. Front Immunol 2022; 13: 956833.
  44. Ghanaim AM, Foaad MA, Gomaa EZ, et al. Bacteriophage therapy as an alterna- tive technique for treatment of multidrug-resistant bacteria causing diabetic foot infection. Int Microbiol 2023; 26:343-59.
  45. Bao H, Zhang H, Zhou Y, et al. Dysbiosis and intestinal inflammation caused by Salmonella Typhimurium in mice can be alleviated by preadministration of a lytic phage. Microbiol Res 2022; 260:127020.
  46. Perea L, Rodríguez-Rubio L, Nieto JC, et al. Bacteriophages immunomodulate the response of monocytes. Exp Biol Med (Maywood) 2021; 246:1263-8.
  47. Mendes BG, Duan Y, Schnabl B. Immune response of an oral Enterococcus faecalis phage cocktail in a mouse model of ethanol-induced liver disease. Viruses 2022; 14:490.
  48. Guglielmi G. Do bacteriophage guests protect human health? Science 2017; 358: 982-3.
  49. Taglialegna A. Infection marks gut commensals. Nat Rev Microbiol 2023; 21: 413-413.
  50. Johansen J, Atarashi K, Arai Y, et al. Centenarians have a diverse gut virome with the potential to modulate metabolism and promote healthy lifespan. Nat Microbiol 2023; 8:1064-78.
  51. Peterson LW, Artis D. Intestinal epithelial cells: regulators of barrier function and immune homeostasis. Nat Rev Immunol 2014; 14:141-53.
  52. Górski A, Jończyk-Matysiak E, Lusiak-Szelachowska M, et al. Bacteriophages tar- geting intestinal epithelial cells: a potential novel form of immunotherapy. Cell Mol Life Sci 2018; 75:589-95.
  53. Nguyen S, Baker K, Padman BS, et al. Bacteriophage transcytosis provides a mech- anism to cross epithelial cell layers. mBio 2017; 8:e01874-17.
  54. Żaczek M, Górski A, Skaradzińska A, et al. Phage penetration of eukaryotic cells: practical implications. Future Virol 2020; 14:745-60.
  55. Górski A, Bollyky PL, Przybylski M, et al. Perspectives of phage therapy in non- bacterial infections. Front Microbiol 2019; 9:3306.
  56. Trend S, Fonceca AM, Ditcham WG, et al. The potential of phage therapy in cystic fibrosis: essential human-bacterial-phage interactions and delivery considerations for use in Pseudomonas aeruginosa-infected airways. J Cyst Fibros 2017; 16:663-70.
  57. Chen N, Bai T, Wang S, et al. New insights into the role and therapeutic potential of heat shock protein 70 in bovine viral diarrhea virus infection. Microorganisms 2023; 11:1473.
  58. Van Eden W, Jansen MAA, Ludwig I, et al. The enigma of heat shock proteins in immune tolerance. Front Immunol 2017; 8:1599.
  59. Górski A, Międzybrodzki R, Żaczek M, Borysowski J. Phages in the fight against COVID-19? Future Microbiol 2020; 15:1095-100.
  60. Górski A, Borysowski J, Międzybrodzki R. Sepsis, phages, and COVID-19. Pathogens 2020; 9:844.
  61. Górski A, Międzybrodzki R, Jończyk-Matysiak E, et al. Perspectives of phage-eukaryotic cell interactions to control Epstein-Barr virus infections. Front Microbiol 2018; 9:630.
  62. Dery KJ, Kadono K, Hirao H, et al. Microbiota in organ transplantation: an im- munological and therapeutic conundrum? Cell Immunol 2020; 351:104080.
  63. Dery KJ, Górski A, Międzybrodzki R, et al. Therapeutic perspectives and mecha- nistic insights of phage therapy in allotransplantation. Transplantation 2021; 105: 1449-58.
  64. Górski A, Jończyk-Matysiak E, Międzybrodzki R, et al. Phage transplantation in allotransplantation: possible treatment in graft-versus-host disease? Front Immunol 2018; 9:941.
  65. Górski A, Jończyk-Matysiak E, Łusiak-Szelachowska M, et al. Phage therapy in al- lergic disorders? Exp Biol Med (Maywood) 2018; 243:534-7.
  66. Megremis S, Constantinides B, Xepapadaki P, et al. Respiratory eukaryotic virome expansion and bacteriophage deficiency characterize childhood asthma. Sci Rep 2023; 13:8319.

Cited by

Sorted by citations

Authors
Górski, A., Międzybrodzki, R., Jończyk-Matysiak, E., Kniotek, M., & Letkiewicz, S.
Affiliations
  • Medical University of Warsaw (PL)
  • Bacteriophage Laboratory, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences (HIIET PAS) , Wrocław , Poland
  • Jan Długosz University (PL)
Corresponding author
Międzybrodzki, Ryszard
ORCID
Venue
Clinical Infectious Diseases
Publisher
Oxford University Press (OUP)
Published
2023-11-01
Volume
77
Issue
Supplement_5
Pages
S433-S439
ISSN
  • 1058-4838 (ISSN-L)
  • 1537-6591
DOI
10.1093/cid/ciad483
OpenAlex
W4388466159
Cited by
41
References
1
Citations by year
2026: 21 · 2025: 13 · 2024: 7
FWCI
6.63
Type
journal article
Language
en
Open access
Licence
academic.oup.com/pages/standard-publication-reuse-rights (vor)
Locations
  • Clinical Infectious Diseases (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • European Society of Clinical Microbiology and Infectious Diseases
  • Warszawski Uniwersytet Medyczny
  • Agencja Badań Medycznych
  • European Regional Development Fund
Topics
  • Physical Sciences › Environmental Science › Ecology › Bacteriophages and microbial interactions
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
  • Life Sciences › Immunology and Microbiology › Immunology › Invertebrate Immune Response Mechanisms
Keywords
phage therapy, bacteriophages, autoimmunity, immunomodulation
MeSH terms
Bacteriophages, Humans, Immunity, Immunomodulation

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review