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Viruses
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Bacteriophages from Biology to Therapy for the 21st Century
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Bacteriophages from Biology to Therapy for the 21st Century

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

Deadline for manuscript submissions: closed (30 April 2022) | Viewed by 22402

Special Issue Editor

Dr. Alain Dublanchet

E-Mail Website
Guest Editor
Centre Hospitalier Intercommunal de Villeneuve-Saint-Georges, Villeneuve-Saint-Georges, France
Interests: bacteriophage (phage) therapy

Special Issue Information

Dear Colleagues,

Phage therapy, a widely recognized alternative to fight bacteria, is becoming a credible medical approach to control bacterial infections in the post-antibiotic era. However, if phage therapy by itself will not solve the antibiotic resistance crisis, in the last 2 decades, the development of biotechnology has made it possible to refine the understanding of the mechanisms of attack on bacteria by bacteriophages and to discover properties so far unexplored and/or underestimated. The expanding our knowledge is a key to open the door to improved and innovative applications. For example, without being exhaustive, it is possible to improve the search for suitable phages to better use them to design specific cocktails and effective combinations of phages with antibiotics, and to predict resistance as well as to use the immune system.

This Special Issue of Viruses is devoted to exploring the future prospects for phage therapy players that could allow the use of phage therapy in a modern context. It will address topics related to:

  • Properties revealed in recent decades (relationship with immunity, phage-host interaction, etc…)
  • Efficiency of the administration methods depending the pathology (timing, doses, rate, duration, etc…)
  • Benefit and opportunity of the combination with antibiotics and their control (in vitro, in vivo, pharmacology, etc…)
  • Improved formulation (title, monophage or cocktail, etc…)
  • Indication (depending on location, chronic/acute infections, bacteria sp., etc…)
  • Principles and value of personalized/individualized therapeutic
  • Practical organization (creation of specialized centers, biobanks, multidisciplinary group, etc…
  • Production, regulatory, etc…

Dr. Alain Dublanchet
Guest Editor

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 submissions that pass pre-check are 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 2600 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.

Keywords

  • bacteriophage (phage) therapy
  • alternative therapy
  • innovation
  • combined modality therapy
  • phage biobank
  • regulatory framework
  • coordination group

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Published Papers (7 papers)

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Research

23 pages, 4985 KiB  
Article
Administration of Bacteriophages via Nebulization during Mechanical Ventilation: In Vitro Study and Lung Deposition in Macaques
by Sandrine Le Guellec, Jeoffrey Pardessus, Elsa Bodier-Montagutelli, Guillaume L’Hostis, Emilie Dalloneau, Damien Piel, Hakim Chouky Samaï, Antoine Guillon, Elvir Mujic, Emmanuelle Guillot-Combe, Stephan Ehrmann, Eric Morello, Jérôme Gabard, Nathalie Heuzé-Vourc’h, Cindy Fevre and Laurent Vecellio
Viruses 2023, 15(3), 602; https://doi.org/10.3390/v15030602 - 22 Feb 2023
Cited by 10 | Viewed by 3572
Abstract
Bacteriophages have been identified as a potential treatment option to treat lung infection in the context of antibiotic resistance. We performed a preclinical study to predict the efficacy of delivery of bacteriophages against Pseudomonas aeruginosa (PA) when administered via nebulization during mechanical ventilation [...] Read more.
Bacteriophages have been identified as a potential treatment option to treat lung infection in the context of antibiotic resistance. We performed a preclinical study to predict the efficacy of delivery of bacteriophages against Pseudomonas aeruginosa (PA) when administered via nebulization during mechanical ventilation (MV). We selected a mix of four anti-PA phages containing two Podoviridae and two Myoviridae, with a coverage of 87.8% (36/41) on an international PA reference panel. When administered via nebulization, a loss of 0.30–0.65 log of infective phage titers was measured. No difference between jet, ultrasonic and mesh nebulizers was observed in terms of loss of phage viability, but a higher output was measured with the mesh nebulizer. Interestingly, Myoviridae are significantly more sensitive to nebulization than Podoviridae since their long tail is much more prone to damage. Phage nebulization has been measured as compatible with humidified ventilation. Based on in vitro measurement, the lung deposition prediction of viable phage particles ranges from 6% to 26% of the phages loaded in the nebulizer. Further, 8% to 15% of lung deposition was measured by scintigraphy in three macaques. A phage dose of 1 × 109 PFU/mL nebulized by the mesh nebulizer during MV predicts an efficient dose in the lung against PA, comparable with the dose chosen to define the susceptibility of the strain. Full article
(This article belongs to the Special Issue Bacteriophages from Biology to Therapy for the 21st Century)
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34 pages, 5115 KiB  
Article
The Isolation and Characterization of a Broad Host Range Bcep22-like Podovirus JC1
by Carly M. Davis, Marta K. Ruest, Jamie H. Cole and Jonathan J. Dennis
Viruses 2022, 14(5), 938; https://doi.org/10.3390/v14050938 - 29 Apr 2022
Cited by 10 | Viewed by 3774
Abstract
Bacteriophage JC1 is a Podoviridae phage with a C1 morphotype, isolated on host strain Burkholderia cenocepacia Van1. Phage JC1 is capable of infecting an expansive range of Burkholderia cepacia complex (Bcc) species. The JC1 genome exhibits significant similarity and synteny to Bcep22-like phages [...] Read more.
Bacteriophage JC1 is a Podoviridae phage with a C1 morphotype, isolated on host strain Burkholderia cenocepacia Van1. Phage JC1 is capable of infecting an expansive range of Burkholderia cepacia complex (Bcc) species. The JC1 genome exhibits significant similarity and synteny to Bcep22-like phages and to many Ralstonia phages. The genome of JC1 was determined to be 61,182 bp in length with a 65.4% G + C content and is predicted to encode 76 proteins and 1 tRNA gene. Unlike the other Lessieviruses, JC1 encodes a putative helicase gene in its replication module, and it is in a unique organization not found in previously analyzed phages. The JC1 genome also harbours 3 interesting moron genes, that encode a carbon storage regulator (CsrA), an N-acetyltransferase, and a phosphoadenosine phosphosulfate (PAPS) reductase. JC1 can stably lysogenize its host Van1 and integrates into the 5′ end of the gene rimO. This is the first account of stable integration identified for Bcep22-like phages. JC1 has a higher global virulence index at 37 °C than at 30 °C (0.8 and 0.21, respectively); however, infection efficiency and lysogen stability are not affected by a change in temperature, and no observable temperature-sensitive switch between lytic and lysogenic lifestyle appears to exist. Although JC1 can stably lysogenize its host, it possesses some desirable characteristics for use in phage therapy. Phage JC1 has a broad host range and requires the inner core of the bacterial LPS for infection. Bacteria that mutate to evade infection by JC1 may develop a fitness disadvantage as seen in previously characterized LPS mutants lacking inner core. Full article
(This article belongs to the Special Issue Bacteriophages from Biology to Therapy for the 21st Century)
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10 pages, 2486 KiB  
Article
Identification and Characterization of vB_PreP_EPr2, a Lytic Bacteriophage of Pan-Drug Resistant Providencia rettgeri
by Jaime L. Mencke, Yunxiu He, Andrey A. Filippov, Mikeljon P. Nikolich, Ashton T. Belew, Derrick E. Fouts, Patrick T. McGann, Brett E. Swierczewski, Derese Getnet, Damon W. Ellison and Katie R. Margulieux
Viruses 2022, 14(4), 708; https://doi.org/10.3390/v14040708 - 29 Mar 2022
Cited by 6 | Viewed by 2323
Abstract
Providencia rettgeri is an emerging opportunistic Gram-negative pathogen with reports of increasing antibiotic resistance. Pan-drug resistant (PDR) P. rettgeri infections are a growing concern, demonstrating a need for the development of alternative treatment options which is fueling a renewed interest in bacteriophage (phage) [...] Read more.
Providencia rettgeri is an emerging opportunistic Gram-negative pathogen with reports of increasing antibiotic resistance. Pan-drug resistant (PDR) P. rettgeri infections are a growing concern, demonstrating a need for the development of alternative treatment options which is fueling a renewed interest in bacteriophage (phage) therapy. Here, we identify and characterize phage vB_PreP_EPr2 (EPr2) with lytic activity against PDR P. rettgeri MRSN 845308, a clinical isolate that carries multiple antibiotic resistance genes. EPr2 was isolated from an environmental water sample and belongs to the family Autographiviridae, subfamily Studiervirinae and genus Kayfunavirus, with a genome size of 41,261 base pairs. Additional phenotypic characterization showed an optimal MOI of 1 and a burst size of 12.3 ± 3.4 PFU per bacterium. EPr2 was determined to have a narrow host range against a panel of clinical P. rettgeri strains. Despite this fact, EPr2 is a promising lytic phage with potential for use as an alternative therapeutic for treatment of PDR P. rettgeri infections. Full article
(This article belongs to the Special Issue Bacteriophages from Biology to Therapy for the 21st Century)
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12 pages, 1461 KiB  
Article
Insights into Gene Transcriptional Regulation of Kayvirus Bacteriophages Obtained from Therapeutic Mixtures
by Sara Arroyo-Moreno, Colin Buttimer, Francesca Bottacini, Nina Chanishvili, Paul Ross, Colin Hill and Aidan Coffey
Viruses 2022, 14(3), 626; https://doi.org/10.3390/v14030626 - 17 Mar 2022
Cited by 6 | Viewed by 2711
Abstract
Bacteriophages (phages) of the genus Kayvirus of Staphylococcus aureus are promising agents for therapeutic applications. In this study, we isolated Kayvirus phages, SAM1 and SAM2, from the Fersisi commercial phage cocktail (George Eliava Institute, Tbilisi, Georgia), which exhibits high sequence homology with phage [...] Read more.
Bacteriophages (phages) of the genus Kayvirus of Staphylococcus aureus are promising agents for therapeutic applications. In this study, we isolated Kayvirus phages, SAM1 and SAM2, from the Fersisi commercial phage cocktail (George Eliava Institute, Tbilisi, Georgia), which exhibits high sequence homology with phage K (≥94%, BLASTn). We found that phages SAM1 and SAM2 infected 95% and 86% of 21 MRSA of differing sequence types (MLST, SCCmec type) obtained from the Irish National MRSA collection, respectively. We conducted differential transcriptomic analysis by RNA-Seq on phage SAM1 during host infection, showing differential expression of its genes at different points during host infection. This analysis also allowed the identification of potentially adverse outcomes in the application of these phages to target MRSA as therapy. The interaction of phage SAM1 on the host caused the upregulation of prophage genes. Additionally, phage infection was found to cause the slight upregulation of host genes implicated in virulence factors relating to hemolysins, immune evasion, and adhesion, but also the downregulation of genes associated with enterotoxins. The findings of this study give further insights into the biology of kayviruses and their use as therapeutics. Full article
(This article belongs to the Special Issue Bacteriophages from Biology to Therapy for the 21st Century)
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14 pages, 2551 KiB  
Article
Immune Response of an Oral Enterococcus faecalis Phage Cocktail in a Mouse Model of Ethanol-Induced Liver Disease
by Beatriz Garcia Mendes, Yi Duan and Bernd Schnabl
Viruses 2022, 14(3), 490; https://doi.org/10.3390/v14030490 - 27 Feb 2022
Cited by 7 | Viewed by 2400
Abstract
Cytolysin-positive Enterococcus faecalis (E. faecalis) cause more severe alcohol-associated hepatitis, and phages might be used to specifically target these bacteria in a clinical trial. Using a humanized mouse model of ethanol-induced liver disease, the effect of cytolytic E. faecalis phage treatment [...] Read more.
Cytolysin-positive Enterococcus faecalis (E. faecalis) cause more severe alcohol-associated hepatitis, and phages might be used to specifically target these bacteria in a clinical trial. Using a humanized mouse model of ethanol-induced liver disease, the effect of cytolytic E. faecalis phage treatment on the intestinal and liver immune response was evaluated. The observed immune response was predominantly anti-inflammatory and tissue-restoring. Besides, live phages could be readily recovered from the serum, spleen, and liver following oral gavage in ethanol-fed mice. We also isolated 20 new phages from the sewage water; six of them exhibited a relatively broad host range. Taken together, the oral administration of cytolytic E. faecalis phages leads to the translocation of phages to the systemic circulation and appears to be safe, following chronic-binge ethanol administration. A cocktail of three phages covers the majority of tested cytolysin-positive E. faecalis strains and could be tested in a clinical trial. Full article
(This article belongs to the Special Issue Bacteriophages from Biology to Therapy for the 21st Century)
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12 pages, 2384 KiB  
Article
Campylobacter jejuni Developed the Resistance to Bacteriophage CP39 by Phase Variable Expression of 06875 Encoding the CGPTase
by Yuanyue Tang, Jie Li, Yuexuan Wang, Zhaojun Song, Hangning Ying, Linghua Kong, Xin’an Jiao and Jinlin Huang
Viruses 2022, 14(3), 485; https://doi.org/10.3390/v14030485 - 26 Feb 2022
Cited by 3 | Viewed by 2383
Abstract
Bacteriophage (phage) is regarded as an antimicrobial alternative for Campylobacter in food production. However, the development of phage resistance to the host is a main concern for the phage application. This study characterized the phage CP39 and investigated the phage resistance of CP39 [...] Read more.
Bacteriophage (phage) is regarded as an antimicrobial alternative for Campylobacter in food production. However, the development of phage resistance to the host is a main concern for the phage application. This study characterized the phage CP39 and investigated the phage resistance of CP39 in Campylobacter jejuni NCTC12662. We determined that phage CP39 belonged to the Myoviridae family by the WGS and phylogenetic analysis. Phage CP39 was confirmed as a capsular polysaccharide (CPS)-dependent phage by primary C. jejuni phage typing. It was further confirmed that the phage could not be adsorbed by the acapsular mutant ΔkpsM but showed the same lytic ability in both the wild-type strain NCTC 12662 and the ΔmotA mutant lacking motile flagella filaments. We further determined that the 06875 gene encoding CDP-glycerol:poly (glycerophosphate) glycerophosphotransferase (CGPTase) in the CPS loci was related to phage CP39 adsorption by SNP analysis and observed a rapid development of phage resistance in NCTC 12662 during the phage infection. Furthermore, we observed a high mutation frequency of 06875 (32%), which randomly occurred in nine different sites in the gene according to colony PCR sequencing. The mutation of the 06875 gene could cause the phase variable expression of non-functional protein and allow the bacteria against the phage infection by modifying the CPS. Our study confirmed the 06875 gene responsible for the CPS-phage adsorption for the first time and demonstrated the phase variable expression as a main mechanism for the bacteria to defend phage CP39. Our study provided knowledge for the evolutionary adaption of bacteria against the bacteriophage, which could add more information to understand the phage resistance mechanism before applying in the industry. Full article
(This article belongs to the Special Issue Bacteriophages from Biology to Therapy for the 21st Century)
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16 pages, 3361 KiB  
Article
Phenotypic and Genomic Comparison of Klebsiella pneumoniae Lytic Phages: vB_KpnM-VAC66 and vB_KpnM-VAC13
by Olga Pacios, Laura Fernández-García, Inés Bleriot, Lucia Blasco, Antón Ambroa, María López, Concha Ortiz-Cartagena, Felipe Fernández Cuenca, Jesús Oteo-Iglesias, Álvaro Pascual, Luis Martínez-Martínez, Pilar Domingo-Calap and María Tomás
Viruses 2022, 14(1), 6; https://doi.org/10.3390/v14010006 - 21 Dec 2021
Cited by 9 | Viewed by 4271
Abstract
Klebsiella pneumoniae is a human pathogen that worsens the prognosis of many immunocompromised patients. Here, we annotated and compared the genomes of two lytic phages that infect clinical strains of K. pneumoniae (vB_KpnM-VAC13 and vB_KpnM-VAC66) and phenotypically characterized vB_KpnM-VAC66 (time of adsorption of [...] Read more.
Klebsiella pneumoniae is a human pathogen that worsens the prognosis of many immunocompromised patients. Here, we annotated and compared the genomes of two lytic phages that infect clinical strains of K. pneumoniae (vB_KpnM-VAC13 and vB_KpnM-VAC66) and phenotypically characterized vB_KpnM-VAC66 (time of adsorption of 12 min, burst size of 31.49 ± 0.61 PFU/infected cell, and a host range of 20.8% of the tested strains). Transmission electronic microscopy showed that vB_KpnM-VAC66 belongs to the Myoviridae family. The genomic analysis of the phage vB_KpnM-VAC66 revealed that its genome encoded 289 proteins. When compared to the genome of vB_KpnM-VAC13, they showed a nucleotide similarity of 97.56%, with a 93% of query cover, and the phylogenetic study performed with other Tevenvirinae phages showed a close common ancestor. However, there were 21 coding sequences which differed. Interestingly, the main differences were that vB_KpnM-VAC66 encoded 10 more homing endonucleases than vB_KpnM-VAC13, and that the nucleotidic and amino-acid sequences of the L-shaped tail fiber protein were highly dissimilar, leading to different three-dimensional protein predictions. Both phages differed significantly in their host range. These viruses may be useful in the development of alternative therapies to antibiotics or as a co-therapy increasing its antimicrobial potential, especially when addressing multidrug resistant (MDR) pathogens. Full article
(This article belongs to the Special Issue Bacteriophages from Biology to Therapy for the 21st Century)
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