Chapter 2 - Phage as a Modulator of Immune Responses: Practical Implications for Phage Therapy

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Abstract

Although the natural hosts for bacteriophages are bacteria, a growing body of data shows that phages can also interact with some populations of mammalian cells, especially with cells of the immune system. In general, these interactions include two main aspects. The first is the phage immunogenicity, that is, the capacity of phages to induce specific immune responses, in particular the generation of specific antibodies against phage antigens. The other aspect includes the immunomodulatory activity of phages, that is, the nonspecific effects of phages on different functions of major populations of immune cells involved in both innate and adaptive immune responses. These functions include, among others, phagocytosis and the respiratory burst of phagocytic cells, the production of cytokines, and the generation of antibodies against nonphage antigens. The aim of this chapter is to discuss the interactions between phages and cells of the immune system, along with their implications for phage therapy. These topics are presented based on the results of experimental studies and unique data on immunomodulatory effects found in patients with bacterial infections treated with phage preparations.

Section snippets

Background

The vast majority of studies on phage biology have traditionally focused on the interactions of bacteriophages with bacterial cells. However, bacteriophages can also interact with some populations of mammalian cells, especially with immune cells. In fact, the first studies on the interactions between bacteriophages and immune cells were conducted by Felix d'Herelle shortly after the discovery of phages (d'Herelle, 1922). Since then, a considerable body of experimental data has accumulated to

Anti-phage humoral responses

Antiviral antibodies are one of the main components of antiviral immune responses. In the case of pathogenic viruses, these antibodies can exhibit four main activities: virus neutralization, antibody-dependent cellular cytotoxicity, antibody-dependent cell-mediated virus inhibition, and phagocytosis (Forthal and Moog, 2009).

Antibodies that were examined in the vast majority of studies on phage immunogenicity are neutralizing antibodies. Essentially, these are defined as antibodies that bind

Effects of phages on phagocytic cells

The activity of phagocytic cells constitutes one of the essential functions of antibacterial immune responses (Silva 2010). Investigating phage interactions with major populations of phagocytic cells may thus verify whether phages could eliminate bacteria in vivo not only by direct bactericidal activity, but also by activating phagocytic cells. Furthermore, interactions between endogenous phages (known to be present in very large numbers within normal microflora; Górski and Weber-Dąbrowska 2005

Phage Virion Inactivation by Immune Cells

Inchley (1969) showed that the majority of T4 phage particles are cleared rapidly from the circulation of mice by cells of the reticuloendothelial system of the liver and, to a lesser extent, of the spleen. However, experiments performed on nonimmune germ-free mice demonstrated that it is the spleen rather than the liver that clears most of the phage particles from the blood regardless of the route of phage administration (Geier et al., 1973). Interestingly, both studies consistently showed

Concluding Remarks

The aim of this chapter was to update and summarize existing knowledge on phage effects on the immune system. Evidently, such a report should be helpful in fully understanding the possible mechanisms of action of phage therapy and for appropriate planning of clinical trials, which would take into account different aspects of possible interactions of phages with the human organism. In this context, two questions are of paramount importance, namely: How does the immune system react to the

Acknowledgments

This work was supported by the European Regional Development Fund within the Operational Program Innovative Economy, 2007-2013, Priority axis 1. Research and Development of ModernTechnologies, Measure 1.3 Support for R&D projects for entrepreneurs carried out by scientific entities, Submeasure 1.3.1 Development projects as project No. POIG 01.03.01-02-003/08 entitled “Optimization of the production and characterization of bacteriophage preparations for therapeutic use”, by statutory funds from

References (87)

  • H.M. Krisch et al.

    The immense journey of bacteriophage T4: From d'Hérelle to Delbrück and then to Darwin and beyond

    Res. Microbiol.

    (2008)
  • H. Kumar et al.

    Toll-like receptors and innate immunity

    Biochem. Biophys. Res. Commun.

    (2009)
  • H. Langbeheim et al.

    Cellular immune responses toward MS-2 phage and a synthetic fragment of its coat protein

    Cell. Immunol.

    (1978)
  • R. Międzybrodzki et al.

    Bacteriophage preparation inhibition of reactive oxygen species generation by endotoxin-stimulated polymorphonuclear leukocytes

    Virus Res.

    (2008)
  • T.J. Molenaar et al.

    Uptake and processing of modified bacteriophage M13 in mice: Implications for phage display

    Virology

    (2002)
  • K.B. Schwarz

    Oxidative stress during viral infection: A review

    Free Radic. Biol. Med.

    (1996)
  • A.V. Sokoloff et al.

    The interactions of peptides with the innate immune system studied with use of T7 phage peptide display

    Mol. Ther.

    (2000)
  • A.S. Srivastava et al.

    Immunological factors that affect the in vivo fate of T7 phage in the mouse

    J. Virol Methods

    (2004)
  • V.M. Victor et al.

    Immune cells: Free radical and antioxidants in sepsis

    Int. Immunopharmacol.

    (2004)
  • C.L. Vitiello et al.

    An amino acid substitution in a capsid protein enhances phage survival in mouse circulatory system more than a 1000-fold

    Virus Res.

    (2005)
  • B. Weber-Dąbrowska et al.

    Effect of phage therapy on the turnover and function of peripheral neutrophils

    FEMS Immunol. Med. Microbiol.

    (2002)
  • M. Yanagida

    Identification of some antigenic precursors of bacteriophage T4

    J. Mol. Biol.

    (1972)
  • R. Aronow et al.

    Electron microscopy of in vitro endocytosis of T2 phage by cells from rabbit peritoneal exudate

    J. Exp. Med.

    (1964)
  • A.G. Baker

    Staphylococcus bacteriophage lysate: Topical and parenteral use in allergic patients

    Pa Med. J.

    (1963)
  • A. Bateman et al.

    A member of the immunoglobulin superfamily in bacteriophage T4

    Virus Genes

    (1997)
  • A.E. Bogden et al.

    The concept of induction and elicitation as an immunotherapeutic approach

    Natl. Cancer Inst. Monogr.

    (1978)
  • J. Borysowski et al.

    The effects of T4 and A3/R phage preparations on whole-blood monocyte and neutrophil respiratory burst

    Viral Immunol.

    (2010)
  • A. Bruttin et al.

    Human volunteers receiving Escherichia coli phage T4 orally: A safety test of phage therapy

    Antimicrob. Agents Chemother.

    (2005)
  • L. Chang et al.

    Rapid flow cytometric assay for the assessment of natural killer cell activity

    J. Immunol. Methods

    (1993)
  • J.R. Clark et al.

    Bacterial viruses as human vaccines? Expert Rev

    Vaccines

    (2004)
  • K. Dabrowska et al.

    Antitumor activity of bacteriophages in murine experimental cancer models caused possibly by inhibition of beta3 integrin signaling pathway

    Acta Virol.

    (2004)
  • K. Dabrowska et al.

    Possible association between phages, Hoc protein, and the immune system

    Arch. Virol.

    (2006)
  • K. Dabrowska et al.

    Hoc protein regulates the biological effects of T4 phage in mammals

    Arch. Microbiol.

    (2007)
  • J.H. Dean et al.

    The relative proliferation index as a more sensitive parameter for evaluating lymphoproliferative responses of cancer patients to mitogens and alloantigens

    Int. J. Cancer

    (1977)
  • J.H. Dean et al.

    In vitro human reactivity to staphylococcal phage lysate

    J. Immunol.

    (1975)
  • F. d'Herelle

    Opsonic power of the lysins

  • H.J. Esber et al.

    Specific and nonspecific immune resistance enhancing activity of staphage lysate

    J. Immunopharmacol.

    (1981)
  • U. Ferrini et al.

    Polymorphonuclear leucocyte stimulation measured by phage inactivation

    Int. Arch. Allergy Appl. Immunol.

    (1989)
  • D.N. Forthal et al.

    Fc receptor-mediated antiviral antibodies

    Curr. Opin. HIV AIDS

    (2009)
  • M.R. Geier et al.

    Fate of bacteriophage lambda in non-immune germ-free mice

    Nature

    (1973)
  • A. Górski et al.

    The potential role of endogenous bacteriophages in controlling invading pathogens

    Cell. Mol. Life Sci.

    (2005)
  • C.H. Hung et al.

    Experimental phage therapy in treating Klebsiella pneumonia-mediated liver abscesses and bacteremia in mice

    Antimicrob. Agents Chemother.

    (2011)
  • C.J. Inchley

    The activity of mouse Kupffer cells following intravenous injection of T4 bacteriophage

    Clin. Exp. Immunol.

    (1969)
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