Mycobacteriophages-bacteriophages infecting Mycobacterium hosts-contribute substantially to our understanding of viral diversity and evolution, provide resources for advancing Mycobacterium genetics, ...are the basis of high-impact science education programs, and show considerable therapeutic potential. Over 10,000 individual mycobacteriophages have been isolated by high school and undergraduate students using the model organism Mycobacterium smegmatis mc2155 and 2,100 have been completely sequenced, giving a high-resolution view of the phages that infect a single common host strain. The phage genomes are revealed to be highly diverse and architecturally mosaic and are replete with genes of unknown function. Mycobacteriophages have provided many widely used tools for Mycobacterium genetics including integration-proficient vectors and recombineering systems, as well as systems for efficient delivery of reporter genes, transposons, and allelic exchange substrates. The genomic insights and engineering tools have facilitated exploration of phages for treatment of Mycobacterium infections, although their full therapeutic potential has yet to be realized.
Bacteriophages are the most abundant biological entities in the biosphere, and this dynamic and old population is, not surprisingly, highly diverse genetically. Relative to bacterial genomics, phage ...genomics has advanced slowly, and a higher-resolution picture of the phagosphere is only just emerging. This view reveals substantial diversity even among phages known to infect a common host strain, but the relationships are complex, with mosaic genomic architectures generated by illegitimate recombination over a long period of evolutionary history.
The Actinobacteriophage Database (PhagesDB) is a comprehensive, interactive, database-backed website that collects and shares information related to the discovery, characterization and genomics of ...viruses that infect Actinobacterial hosts. To date, more than 8000 bacteriophages-including over 1600 with sequenced genomes-have been entered into the database. PhagesDB plays a crucial role in organizing the discoveries of phage biologists around the world-including students in the SEA-PHAGES program-and has been cited in over 50 peer-reviewed articles.
http://phagesdb.org/.
gfh@pitt.edu.
Actinobacteriophages are viruses that infect bacterial hosts in the phylum
Actinobacteria
. More than 17,000 actinobacteriophages have been described and over 3,000 complete genome sequences ...reported, resulting from large-scale, high-impact, integrated research-education initiatives such as the Science Education Alliance Phage Hunters Advancing Genomics and Evolutionary Sciences (SEA-PHAGES) program. Their genomic diversity is enormous; actinobacteriophages comprise many architecturally mosaic genomes with distinct DNA sequences. Their genome diversity is driven by the highly dynamic interactions between phages and their hosts, and prophages can confer a variety of systems that defend against attack by genetically distinct phages; phages can neutralize these defense systems by coding for counter-defense proteins. These phages not only provide insights into diverse and dynamic phage populations but also have provided numerous tools for mycobacterial genetics. A case study using a three-phage cocktail to treat a patient with a drug-resistant
Mycobacterium abscessus
suggests that phages may have considerable potential for the therapeutic treatment of mycobacterial infections.
Antibiotic resistance in bacterial pathogens presents a substantial threat to the control of infectious diseases. Development of new classes of antibiotics has slowed in recent years due to pressures ...of cost and market profitability, and there is a strong need for new antimicrobial therapies. The therapeutic use of bacteriophages has long been considered, with numerous anecdotal reports of success. Interest in phage therapy has been renewed by recent clinical successes in case studies with personalized phage cocktails, and several clinical trials are in progress. We discuss recent progress in the therapeutic use of phages and contemplate the key factors influencing the opportunities and challenges. With strong safety profiles, the main challenges of phage therapeutics involve strain variation among clinical isolates of many pathogens, battling phage resistance, and the potential limitations of host immune responses. However, the opportunities are considerable, with the potential to enhance current antibiotic efficacy, protect newly developed antibiotics, and provide a last resort in response to complete antibiotic failure.
Bacteriophage genomics Hatfull, Graham F
Current opinion in microbiology,
10/2008, Volume:
11, Issue:
5
Journal Article
Peer reviewed
Open access
The past three years have seen an escalation in the number of sequenced bacteriophage genomes with more than 500 now in the NCBI phage database, representing a more than threefold increase since ...2005. These span at least 70 different bacterial hosts, with two-thirds of the sequenced genomes of phages representing only eight bacterial hosts. Three key features emerge from the comparative analysis of these genomes. First, they span a very high degree of genetic diversity, suggesting early evolutionary origins. Second, the genome architectures are mosaic, reflecting an unusually high degree of horizontal genetic exchange in their evolution. Third, phage genomes contain a very high proportion of novel genetic sequences of unknown function, and probably represent the largest reservoir of unexplored genes. With an estimated 1031 bacterial and archael viruses in the biosphere, our view of the virosphere will draw into sharper focus as further bacteriophage genomes are characterized.
Mycobacteriophages are viruses that infect mycobacterial hosts, such as Mycobacterium tuberculosis and Mycobacterium smegmatis 1. Because the discovery and genomic characterization of ...mycobacteriophages has been the focus of integrated research and education programs, including the Phage Hunters Integrating Research and Education (PHIRE) and the Howard Hughes Medical Institute Science Education Alliance Phage Hunters Advancing Genomics and Evolutionary Science (HHMI SEA-PHAGES), thousands of phages have been isolated using a single host strain, M. smegmatis mc2155, over 500 of which have been completely sequenced 2-5. ...mutants can be readily isolated from some phages that expand their host range to infect these other strains 12. ...the observed phage diversity can be explained by assuming that wherever broad and diverse ranges of hosts are present, the phages can rapidly dance across the microbial landscape, using the hosts as "stepping-stones."
Innovations in science education are desperately needed to find ways to engage and interest students early in their undergraduate careers. Exposing students to authentic research experiences is ...highly beneficial, but finding ways to include all types of students and to do this at large scale is especially challenging. An attractive solution is the concept of an inclusive research education community (iREC) in which centralized research leadership and administration supports multiple institutions, including diverse groups of schools and universities, faculty and students. The Science Education Alliance Phage Hunters Advancing Genomics and Evolutionary Sciences (SEA-PHAGES) programme is an excellent example of an iREC, in which students explore viral diversity and evolution through discovery and genomic analysis of novel bacteriophages. The SEA-PHAGES programme has proven to be sustainable, to be implemented at large scale, and to enhance student persistence in science, as well as to produce substantial research advances. Discovering a new virus with the potential for new biological insights and clinical applications is inherently exciting. Who wouldn't want to discover a new virus?
Increasing antimicrobial resistance rates have revitalized bacteriophage (phage) research, the natural predators of bacteria discovered over 100 years ago. In order to use phages therapeutically, ...they should (1) preferably be lytic, (2) kill the bacterial host efficiently, and (3) be fully characterized to exclude side effects. Developing therapeutic phages takes a coordinated effort of multiple stakeholders. Herein, we review the state of the art in phage therapy, covering biological mechanisms, clinical applications, remaining challenges, and future directions involving naturally occurring and genetically modified or synthetic phages.
Phage therapy has undergone a revitalization in the last 7 years, and a growing number of clinical trials are underway. This review provides a comprehensive view on the state of the art in phage therapy, covering biological mechanisms, clinical applications, remaining challenges, and future directions.
Non-tuberculous mycobacterium (NTM) infections are often clinically challenging, with lengthy antibiotic regimens that fail to resolve the infections with few good outcomes remaining. ...Mycobacteriophages—viruses that infect
Mycobacterium
hosts—show promise as therapeutic agents for NTM infections and have been used in 20 compassionate use cases. Favorable outcomes were observed in many but not all cases, although the phages show exceptional safety profiles and no evidence of phage resistance was observed, even when only a single phage was administered. Phage-specific antibodies are commonly present following intravenous administration and are often neutralizing for the phage in vitro. However, phage neutralization does not consistently correlate with poor treatment outcomes and may not be a therapeutic limitation in all patients, even when immunocompetent. Currently, the therapeutic potential of phages is substantially limited by the great variation in phage susceptibility and a relatively small repertoire of therapeutically useful phages. As many as 45% of clinical isolates can have a smooth colony morphotype, and phages that both efficiently infect and kill these strains have yet to be described. In contrast, ~ 75% of rough strains are susceptible to and killed by one or more phages and therapeutic options can be considered on a compassionate use basis. Although therapies must currently be personalized, elucidating the determinants of phage host specificity, expanding the useful phage repertoire, and identifying the key determinants of clinical outcomes will reveal their full therapeutic potential.
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