Special Issue "State-of-the-Art Phage Therapy Development in Europe"

A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "Bacterial Viruses".

Deadline for manuscript submissions: 31 December 2021.

Special Issue Editors

Dr. Ryszard Międzybrodzki
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Guest Editor
Bacteriophage Laboratory, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences (HIIET PAS), 53-114 Wrocław, Poland
Interests: bacteriophage; phage therapy
Dr. Nina Chanishvili
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Guest Editor
Eliava Institute of Bacteriophage, Microbiology and Virology, Tbilisi 0160, Georgia
Interests: bacteriophage research; phage therapy
Prof. Nina V. Tikunova
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Guest Editor
Institute of Chemical Biology and Fundamental Medicine, Siberian Branch, Russian Academy of Sciences, 630090 Novosibirsk, Russia
Interests: bacteriophage; phage therapy
Dr. Jean-Paul Pirnay
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Guest Editor
Laboratory for Molecular and Cellular Technology, Queen Astrid Military Hospital, 1120 Brussels, Belgium
Interests: bacteriophage; phage therapy
Prof. Petar Knezevic
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Guest Editor
Department of Biology and Ecology, University of Novi Sad Faculty of Sciences, Serbia
Interests: bacteriophage; phage therapy
Dr. Shawna McCallin
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Guest Editor
Unit of Regenerative Medicine, Department of Musculoskeletal Medicine, Service of Plastic, Reconstructive, & Hand Surgery, University Hospital of Lausanne (CHUV), 1066 Epalignes, Switzerland
Interests: bacteriophage; phage therapy

Special Issue Information

Dear Colleagues,

Phage therapy, the use of bacteriophages—the viruses of bacteria—to treat bacterial infections, has been studied since 1919, with substantial use of bacteriophages in Europe and North America. However, since the 1950s, the interest in phage therapy has slowly declined in favor of antibiotics. Today, Western countries are trying to rehabilitate phage therapy as an additional tool in the fight against antibiotic-resistant infections. Meanwhile, medicinal product development, manufacturing and marketing requirements have become significantly more stringent. However, even though bacteriophages have been classified as medicinal products in Europe, they have a number of peculiarities (e.g., target specificity and antagonistic coevolution) making them quite different from conventional medicines. This Special Issue of the journal Viruses is focused on the solutions being explored by European phage therapy stakeholders to accelerate the availability of bacteriophages for the treatment of an increasing number of desperate patients.

In this Special Issue we aim to address the topics related to:  

  • experimental and applied phage therapy;
  • host–pathogen interactions and co-evolution;
  • phage therapy in animal models;
  • principle for selection and construction of bacteriophages for therapy;
  • immune response to phage therapy;
  • case studies;
  • clinical trials.

We welcome the submission of resesearch articles, short communications and reviews.

Dr. Ryszard Międzybrodzki
Dr. Nina Chanishvili
Dr. Nina V. Tikunova
Dr. Jean-Paul Pirnay
Dr. Petar Knezevic
Dr. Shawna McCallin
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Viruses is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2200 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Published Papers (8 papers)

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Research

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Article
Are Bordetella bronchiseptica Siphoviruses (Genus Vojvodinavirus) Appropriate for Phage Therapy—Bacterial Allies or Foes?
Viruses 2021, 13(9), 1732; https://doi.org/10.3390/v13091732 (registering DOI) - 31 Aug 2021
Abstract
Bordetella bronchiseptica is a respiratory animal pathogen that shows growing resistance to commonly used antibiotics, which has necessitated the examination of new antimicrobials, including bacteriophages. In this study, we examined the previously isolated and partially characterized B. bronchiseptica siphoviruses of the genus Vojvodinavirus [...] Read more.
Bordetella bronchiseptica is a respiratory animal pathogen that shows growing resistance to commonly used antibiotics, which has necessitated the examination of new antimicrobials, including bacteriophages. In this study, we examined the previously isolated and partially characterized B. bronchiseptica siphoviruses of the genus Vojvodinavirus (LK3, CN1, CN2, FP1 and MW2) for their ability to inhibit bacterial growth and biofilm, and we examined other therapeutically important properties through genomic analysis and lysogeny experiments. The phages inhibited bacterial growth at a low multiplicity of infection (MOI = 0.001) of up to 85% and at MOI = 1 for >99%. Similarly, depending on the phages and MOIs, biofilm formation inhibition ranged from 65 to 95%. The removal of biofilm by the phages was less efficient but still considerably high (40–75%). Complete genomic sequencing of Bordetella phage LK3 (59,831 bp; G + C 64.01%; 79 ORFs) showed integrase and repressor protein presence, indicating phage potential to lysogenize bacteria. Lysogeny experiments confirmed the presence of phage DNA in bacterial DNA upon infection using PCR, which showed that the LK3 phage forms more or less stable lysogens depending on the bacterial host. Bacterial infection with the LK3 phage enhanced biofilm production, sheep blood hemolysis, flagellar motility, and beta-lactam resistance. The examined phages showed considerable anti-B. bronchiseptica activity, but they are inappropriate for therapy because of their temperate nature and lysogenic conversion of the host bacterium. Full article
(This article belongs to the Special Issue State-of-the-Art Phage Therapy Development in Europe)
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Article
Characterization of Anti-Bacterial Effect of the Two New Phages against Uropathogenic Escherichia coli
Viruses 2021, 13(7), 1348; https://doi.org/10.3390/v13071348 - 12 Jul 2021
Viewed by 556
Abstract
Urinary tract infections (UTIs) are among the events that most frequently need medical intervention. Uropathogenic Escherichia coli are frequently their causative agents and the infections are sometimes complicated by the presence of polyresistant nosocomial strains. Phage therapy is a tool that has good [...] Read more.
Urinary tract infections (UTIs) are among the events that most frequently need medical intervention. Uropathogenic Escherichia coli are frequently their causative agents and the infections are sometimes complicated by the presence of polyresistant nosocomial strains. Phage therapy is a tool that has good prospects for the treatment of these infections. In the present study, we isolated and characterized two bacteriophages with broad host specificity against a panel of local uropathogenic E. coli strains and combined them into a phage cocktail. According to genome sequencing, these phages were closely related and belonged to the Tequatrovirus genus. The newly isolated phages showed very good activity on a panel of local clinical E. coli strains from urinary tract infections. In the form of a two-phage cocktail, they were active on E. coli strains belonging to phylogroups B2 and D, with relatively lower activity in B1 and no response in phylogroup A. Our study is a preliminary step toward the establishment of a national phage bank containing local, well-characterized phages with therapeutic potential for patients in Slovakia. Full article
(This article belongs to the Special Issue State-of-the-Art Phage Therapy Development in Europe)
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Article
Investigation of Salmonella Phage–Bacteria Infection Profiles: Network Structure Reveals a Gradient of Target-Range from Generalist to Specialist Phage Clones in Nested Subsets
Viruses 2021, 13(7), 1261; https://doi.org/10.3390/v13071261 - 28 Jun 2021
Viewed by 663
Abstract
Bacteriophages that lyse Salmonella enterica are potential tools to target and control Salmonella infections. Investigating the host range of Salmonella phages is a key to understand their impact on bacterial ecology, coevolution and inform their use in intervention strategies. Virus–host infection networks have [...] Read more.
Bacteriophages that lyse Salmonella enterica are potential tools to target and control Salmonella infections. Investigating the host range of Salmonella phages is a key to understand their impact on bacterial ecology, coevolution and inform their use in intervention strategies. Virus–host infection networks have been used to characterize the “predator–prey” interactions between phages and bacteria and provide insights into host range and specificity. Here, we characterize the target-range and infection profiles of 13 Salmonella phage clones against a diverse set of 141 Salmonella strains. The environmental source and taxonomy contributed to the observed infection profiles, and genetically proximal phages shared similar infection profiles. Using in vitro infection data, we analyzed the structure of the Salmonella phage–bacteria infection network. The network has a non-random nested organization and weak modularity suggesting a gradient of target-range from generalist to specialist species with nested subsets, which are also observed within and across the different phage infection profile groups. Our results have implications for our understanding of the coevolutionary mechanisms shaping the ecological interactions between Salmonella phages and their bacterial hosts and can inform strategies for targeting Salmonella enterica with specific phage preparations. Full article
(This article belongs to the Special Issue State-of-the-Art Phage Therapy Development in Europe)
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Article
Influence of Caudovirales Phages on Humoral Immunity in Mice
Viruses 2021, 13(7), 1241; https://doi.org/10.3390/v13071241 - 26 Jun 2021
Viewed by 527
Abstract
Bacteriophages are promising antibacterial agents. Although they have been recognized as bacterial viruses and are considered to be non-interacting with eukaryotic cells, there is growing evidence that phages may have a significant impact on the immune system via interactions with macrophages, neutrophils, and [...] Read more.
Bacteriophages are promising antibacterial agents. Although they have been recognized as bacterial viruses and are considered to be non-interacting with eukaryotic cells, there is growing evidence that phages may have a significant impact on the immune system via interactions with macrophages, neutrophils, and T-cell polarization. In this study, the influence of phages of podovirus, siphovirus, and myovirus morphotypes on humoral immunity of CD-1 mice was investigated. In addition, tissue distribution of the phages was tested in these mice. No common patterns were found either in the distribution of phages in mice or in changes in the levels of cytokines in the sera of mice once injected with phages. Importantly, pre-existing IgM-class antibodies directed against capsid proteins of phages with myovirus and siphovirus morphotypes were identified in mice before immunization. After triple immunization of CD1-mice with phages without any adjuvant, levels of anti-phage serum polyclonal IgG antibodies increased. Immunogenic phage proteins recognized by IgM and/or IgG antibodies were identified using Western blot analysis and mass spectrometry. In addition, mice serum collected after immunization demonstrated neutralizing properties, leading to a substantial decrease in infectivity of investigated phages with myovirus and siphovirus morphotypes. Moreover, serum samples collected before administration of these phages exhibited some ability to reduce the phage infectivity. Furthermore, Proteus phage PM16 with podovirus morphotype did not elicit IgM or IgG antibodies in immunized mice, and no neutralizing activities against PM16 were revealed in mouse serum samples before and after immunization. Full article
(This article belongs to the Special Issue State-of-the-Art Phage Therapy Development in Europe)
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Article
Characterization of Salmonella Isolates from Various Geographical Regions of the Caucasus and Their Susceptibility to Bacteriophages
Viruses 2020, 12(12), 1418; https://doi.org/10.3390/v12121418 - 10 Dec 2020
Cited by 2 | Viewed by 1211
Abstract
Non-typhoidal Salmonella present a major threat to animal and human health as food-borne infectious agents. We characterized 91 bacterial isolates from Armenia and Georgia in detail, using a suite of assays including conventional microbiological methods, determining antimicrobial susceptibility profiles, matrix assisted laser desorption/ionization-time [...] Read more.
Non-typhoidal Salmonella present a major threat to animal and human health as food-borne infectious agents. We characterized 91 bacterial isolates from Armenia and Georgia in detail, using a suite of assays including conventional microbiological methods, determining antimicrobial susceptibility profiles, matrix assisted laser desorption/ionization-time of flight (MALDI-TOF) mass spectrometry, serotyping (using the White-Kauffmann-Le Minor scheme) and genotyping (repetitive element sequence-based PCR (rep-PCR)). No less than 61.5% of the isolates were shown to be multidrug-resistant. A new antimicrobial treatment strategy is urgently needed. Phage therapy, the therapeutic use of (bacterio-) phages, the bacterial viruses, to treat bacterial infections, is increasingly put forward as an additional tool for combatting antibiotic resistant infections. Therefore, we used this representative set of well-characterized Salmonella isolates to analyze the therapeutic potential of eleven single phages and selected phage cocktails from the bacteriophage collection of the Eliava Institute (Georgia). All isolates were shown to be susceptible to at least one of the tested phage clones or their combinations. In addition, genome sequencing of these phages revealed them as members of existing phage genera (Felixounavirus, Seunavirus, Viunavirus and Tequintavirus) and did not show genome-based counter indications towards their applicability against non-typhoidal Salmonella in a phage therapy or in an agro-food setting. Full article
(This article belongs to the Special Issue State-of-the-Art Phage Therapy Development in Europe)
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Review

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Review
The Safety and Toxicity of Phage Therapy: A Review of Animal and Clinical Studies
Viruses 2021, 13(7), 1268; https://doi.org/10.3390/v13071268 - 29 Jun 2021
Viewed by 958
Abstract
Increasing rates of infection by antibiotic resistant bacteria have led to a resurgence of interest in bacteriophage (phage) therapy. Several phage therapy studies in animals and humans have been completed over the last two decades. We conducted a systematic review of safety and [...] Read more.
Increasing rates of infection by antibiotic resistant bacteria have led to a resurgence of interest in bacteriophage (phage) therapy. Several phage therapy studies in animals and humans have been completed over the last two decades. We conducted a systematic review of safety and toxicity data associated with phage therapy in both animals and humans reported in English language publications from 2008–2021. Overall, 69 publications met our eligibility criteria including 20 animal studies, 35 clinical case reports or case series, and 14 clinical trials. After summarizing safety and toxicity data from these publications, we discuss potential approaches to optimize safety and toxicity monitoring with the therapeutic use of phage moving forward. In our systematic review of the literature, we found some adverse events associated with phage therapy, but serious events were extremely rare. Comprehensive and standardized reporting of potential toxicities associated with phage therapy has generally been lacking in the published literature. Structured safety and tolerability endpoints are necessary when phages are administered as anti-infective therapeutics. Full article
(This article belongs to the Special Issue State-of-the-Art Phage Therapy Development in Europe)
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Other

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Study Protocol
Bacteriophage Therapy for Difficult-to-Treat Infections: The Implementation of a Multidisciplinary Phage Task Force (The PHAGEFORCE Study Protocol)
Viruses 2021, 13(8), 1543; https://doi.org/10.3390/v13081543 - 05 Aug 2021
Viewed by 679
Abstract
In times where only a few novel antibiotics are to be expected, antimicrobial resistance remains an expanding global health threat. In case of chronic infections caused by therapy-resistant pathogens, physicians have limited therapeutic options, which are often associated with detrimental consequences for the [...] Read more.
In times where only a few novel antibiotics are to be expected, antimicrobial resistance remains an expanding global health threat. In case of chronic infections caused by therapy-resistant pathogens, physicians have limited therapeutic options, which are often associated with detrimental consequences for the patient. This has resulted in a renewed interest in alternative strategies, such as bacteriophage (phage) therapy. However, there are still important hurdles that currently impede the more widespread implementation of phage therapy in clinical practice. First, the limited number of good-quality case series and clinical trials have failed to show the optimal application protocol in terms of route of administration, frequency of administration, treatment duration and phage titer. Second, there is limited information on the systemic effects of phage therapy. Finally, in the past, phage therapy has been applied intuitively in terms of the selection of phages and their combination as parts of phage cocktails. This has led to an enormous heterogeneity in previously published studies, resulting in a lack of reliable safety and efficacy data for phage therapy. We hereby present a study protocol that addresses these scientific hurdles using a multidisciplinary approach, bringing together the experience of clinical, pharmaceutical and molecular microbiology experts. Full article
(This article belongs to the Special Issue State-of-the-Art Phage Therapy Development in Europe)
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Case Report
A Case of Phage Therapy against Pandrug-Resistant Achromobacter xylosoxidans in a 12-Year-Old Lung-Transplanted Cystic Fibrosis Patient
Viruses 2021, 13(1), 60; https://doi.org/10.3390/v13010060 - 05 Jan 2021
Cited by 5 | Viewed by 1317
Abstract
Bacteriophages are a promising therapeutic strategy among cystic fibrosis and lung-transplanted patients, considering the high frequency of colonization/infection caused by pandrug-resistant bacteria. However, little clinical data are available regarding the use of phages for infections with Achromobacter xylosoxidans. A 12-year-old lung-transplanted cystic [...] Read more.
Bacteriophages are a promising therapeutic strategy among cystic fibrosis and lung-transplanted patients, considering the high frequency of colonization/infection caused by pandrug-resistant bacteria. However, little clinical data are available regarding the use of phages for infections with Achromobacter xylosoxidans. A 12-year-old lung-transplanted cystic fibrosis patient received two rounds of phage therapy because of persistent lung infection with pandrug-resistant A. xylosoxidans. Clinical tolerance was perfect, but initial bronchoalveolar lavage (BAL) still grew A. xylosoxidans. The patient’s respiratory condition slowly improved and oxygen therapy was stopped. Low-grade airway colonization by A. xylosoxidans persisted for months before samples turned negative. No re-colonisation occurred more than two years after phage therapy was performed and imipenem treatment was stopped. Whole genome sequencing indicated that the eight A. xylosoxidans isolates, collected during phage therapy, belonged to four delineated strains, whereby one had a stop mutation in a gene for a phage receptor. The dynamics of lung colonisation were documented by means of strain-specific qPCRs on different BALs. We report the first case of phage therapy for A. xylosoxidans lung infection in a lung-transplanted patient. The dynamics of airway colonization was more complex than deduced from bacterial culture, involving phage susceptible as well as phage resistant strains. Full article
(This article belongs to the Special Issue State-of-the-Art Phage Therapy Development in Europe)
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Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Evaluation of the therapeutic potential of Aeromonas hydrophila phage AhMtk13a on simulated Aeromonas infection in Danio rerio

Principle for selection and construction of bacteriophages for therapy

Evaluation of stability of phages in different solutions suitable for production of magistral preparations

Phage therapy of patients with paraprosthetic infection

Phage therapy trial to eradicate LA-MRSA from healthy carrier pigs

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