When the genetic material of a highly virulent bacteriophage penetrates a bacterium, the bacterial chromosome is disintegrated and the bacterium consequently becomes incapable of producing messengers and bacterial proteins. The DNA of the bacteriophage synthesizes its own messengers with the aid ofribonucleotides synthesized by its host and of the enzymes of its host. The messengers of the bacteriophage will establish themselves on the bacterialribosomes. With the aid of the activatedtransfer RNA and of the bacterial enzymes, the proteins of the bacteriophage are synthesized. Some of these proteins are enzymes necessary, for example, for the manufacture of specific constituents of the phages such as5-hydroxymethylcytosine. Others are enzymes necessary for the replication of the bacteriophage DNA. Still others are structural proteins of thevirion. One of the last to be formed is endolysine, which destroys the wall of the bacterium, provokes its rupture, and ensures the liberation of the virions. When we examine the kinetics of production of the various proteins, we find that each is formed in a given period of the evolutionary cycle. Everything takes place as if a system of sequential repression and derepression was acting.
BacterialCRISPR-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 byListeria monocytogenes prophages. More than half ofL. monocytogenes strains with cas9 contain at least one prophage-encoded inhibitor, suggesting widespread CRISPR-Cas9 inactivation. Two of these inhibitors also blocked the widely usedStreptococcus pyogenes Cas9 when assayed inEscherichia 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".Cell168 (1-2): 150–158.e10.ISSN00928674.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".Viruses10 (7): 351.ISSN1999-4915.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 resistantGram-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 microbiology8.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".Science363 (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.
