Bacteriophage diversity, dynamics, function, and exploitation

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Bacteriophages are the most numerous biological entities on the planet. The phage population is enormously dynamic, replacing itself through infection and reproduction every few days, and may be more than three billion years old. Not surprisingly, they are enormously diverse genetically, although this diversity remains ill-defined and only an extremely small part of the phage population has been genomically explored. Bacteriophages play prominent roles in the environment, in human health, and in biotechnology. They are implicated in many bacterial diseases by coding for toxins, and modulate bacterial physiology in a variety of ways. Their diversity is generated in part by the highly dynamic microbial community in which there is enormous selective pressure for bacteria to survive the constant onslaught of viral infections, and for the phages to co-evolve by mutating to infect new bacterial hosts or evolving counter-defense systems that overcome resistance. Among the defense systems that bacteria use to fight off phage infection are restriction- modification and CRISPR-Cas systems, both of which have played revolutionary roles in biotechnology and genome engineering. The huge impact of these derives in part from their extraordinary efficiency and specificity, the consequences of three billion years of highly dynamic evolution. The growing problem of widespread antibiotic resistance by bacterial pathogens presents a substantial global health risk. Addressing this requires innovative strategies for new therapeutic approaches, and an aggressive search for new antimicrobial agents. The prospects of bacteriophage therapy have been contemplated for nearly 100 years, but has not found widespread use in the US. Diseases caused by pathogens in the phylum Actinobacteria, including tuberculosis and NTM infections of Cystic Fibrosis patients, are notable public health challenges, but any prospects for therapeutic phage interventions requires an understanding of the determinants of phage host range and the mechanisms and specificity of phage resistance. A large collection of over 13,000 phages infecting Actinobacterial hosts, 2,500 of which are completely sequenced, provide a powerful resource for investigating phage diversity, phage genome evolution, phage host range, bacterial-phage dynamics, and genetic and clinical tools for tuberculosis and NTM infections. Many of these phages are temperate, and code for defense systems that are prophage-expressed and inhibit the infection of lysogens by different (i.e. heterotypic) phages. These defense systems are highly varied and most of the genes do not have bioinformatically predicted functions. Defense is often specific for a few subset of the phages, but the mechanisms of targeting is not known. The characterization of phage diversity, evolution, dynamics, and resistance will facilitate the development of new diagnostic, preventative, and therapeutic approaches for bacterial infections.