A bacteriophage (or phage) is a virus that infects bacteria or archaea. After infection, the phage replicates within the cytoplasm of the infected bacterium or archaeon.
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Bacterial CRISPR-Cas systems utilize sequence-specific RNA-guided nucleases to defend against bacteriophage infection. As a countermeasure, numerous phages are known that produce proteins to block the function of class 1 CRISPR-Cas systems. However, currently no proteins are known to inhibit the widely used class 2 CRISPR-Cas9 system. To find these inhibitors, we searched cas9-containing bacterial genomes for the co-existence of a CRISPR spacer and its target, a potential indicator for CRISPR inhibition. This analysis led to the discovery of four unique type II-A CRISPR-Cas9 inhibitor proteins encoded by Listeria monocytogenes prophages. More than half of L. monocytogenes strains with cas9 contain at least one prophage-encoded inhibitor, suggesting widespread CRISPR-Cas9 inactivation. Two of these inhibitors also blocked the widely used Streptococcus pyogenes Cas9 when assayed in Escherichia coli and human cells. These natural Cas9-specific “anti-CRISPRs” present tools that can be used to regulate the genome engineering activities of CRISPR-Cas9.
Benjamin J. Rauch, Melanie R. Silvis, Judd F. Hultquist, Christopher S. Waters, Michael J. McGregor, Nevan J. Krogan, and Joseph Bondy-Denomy: (2017). "Inhibition of CRISPR-Cas9 with Bacteriophage Proteins". Cell 168 (1-2): 150–158.e10. ISSN 00928674. DOI:10.1016/j.cell.2016.12.009.Bacteriophage (phage) therapy, i.e., the use of viruses that infect bacteria as antimicrobial agents, is a promising alternative to conventional antibiotics. Indeed, resistance to antibiotics has become a major public health problem after decades of extensive usage. However, one of the main questions regarding phage therapy is the possible rapid emergence of phage-resistant bacterial variants, which could impede favourable treatment outcomes. Experimental data has shown that phage-resistant variants occurred in up to 80% of studies targeting the intestinal milieu and 50% of studies using sepsis models. Phage-resistant variants have also been observed in human studies, as described in three out of four clinical trials that recorded the emergence of phage resistance. On the other hand, recent animal studies suggest that bacterial mutations that confer phage-resistance may result in fitness costs in the resistant bacterium, which, in turn, could benefit the host. Thus, phage resistance should not be underestimated and efforts should be made to develop methodologies for monitoring and preventing it.
Frank Oechslin: (2018). "Resistance Development to Bacteriophages Occurring during Bacteriophage Therapy". Viruses 10 (7): 351. ISSN 1999-4915. DOI:10.3390/v10070351.Increasing reports of antimicrobial resistance and limited new antibiotic discoveries and development have fuelled innovation in other research fields and led to a revitalization of bacteriophage (phage) studies in the Western world. Phage therapy mainly utilizes obligately lytic phages to kill their respective bacterial hosts, while leaving human cells intact and reducing the broader impact on commensal bacteria that often results from antibiotic use. Phage therapy is rapidly evolving and has resulted in cases of life-saving therapeutic use and multiple clinical trials. However, one of the biggest challenges this antibiotic alternative faces relates to regulations and policy surrounding clinical use and implementation beyond compassionate cases. This review discusses the multi-drug resistant Gram-negative pathogens of highest critical priority and summarizes the current state-of-the-art in phage therapy targeting these organisms.
Lucy L. Furfaro, Matthew S. Payne, and Barbara J. Chang: (2018). "Bacteriophage therapy: clinical trials and regulatory hurdles". Frontiers in cellular and infection microbiology 8. DOI:10.3389/fcimb.2018.00376.We have identified previously unsuspected, directly pathogenic roles for bacteriophage (phage) virions in bacterial infections. In particular, we report that internalization of phage by human and murine immune cells triggers maladaptive viral pattern recognition receptors and suppressed bacterial clearance from infected wounds.
J.M. Sweere, J.D. Van Belleghem, H. Ishak, M.S. Bach, M. Popescu, V. Sunkari, G. Kaber, R. Manasherob, G.A. Suh, X. Cao. and C.R. de Vries: (2019). "Bacteriophage trigger antiviral immunity and prevent clearance of bacterial infection". Science 363 (6434). DOI:10.1126/science.aat9691.Despite the fact that phages were recognized early to be extremely abundant in the biosphere, existing in all environments where bacteria occur, only very little research was targeted to understand their ecological roles (Summers, 2012). Even today, studies about the role of bacterial viruses in most complex ecosystems are uncommon and the impact of bacterial viruses on cohabitating microorganisms is little appreciated (Rohwer et al., 2009). While knowledge of environmental bacteriophages has increased in the last 10 years (Miller, 2001; Muniesa et al., 2013), there is still much to learn about their roles in even the most widely-studied environments such as the rhizosphere, phyllosphere, and human gut. It will be through such work that we might more wisely use phages in medical and technological applications.
Robert Czajkowski, Steven Earl Lindow, and Robert Wilson Jackson: "Editorial: Environmental Bacteriophages: From Biological Control Applications to Directed Bacterial Evolution". Environmental Bacteriophages: From Biological Control Applications to Directed Bacterial Evolution. Frontiers Media SA. 20 November 2019. pp. 5–8. ISBN 978-2-88963-181-0. doi:10.3389/fmicb.2019.01830
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