A single bacterial defence system in *Streptomyces* lets phage replicate during the first infection, then marks their DNA so that any subsequent infection by the same phage is blocked. This matters because bacteria and the viruses that attack them—phages—are locked in an evolutionary arms race, and the defence systems bacteria evolve have given us transformative tools like CRISPR-Cas. The Phage Growth Limitation (Pgl) system is unusual: it sacrifices some cells to release modified phage, protecting the rest of the colony. But no one knows what molecular trigger sets it off, how it distinguishes tagged from untagged phage, or how it ultimately stops replication. This project will identify that trigger and the mechanism of action. If successful, the work will fill fundamental gaps in our understanding of bacterial immunity and virus–host co-evolution. It could also help control phage outbreaks in industrial antibiotic fermentations, where infections threaten production capacity. This is primarily curiosity-driven fundamental science, but past discoveries from similar systems—restriction enzymes, CRISPR—show how such knowledge can yield unexpected biotechnological tools.
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Context Since their discovery, (bacterio)phages and the systems bacteria use to defend against them have contributed significantly to our understanding of basic molecular biology and provided numerous resources for molecular biology and biotechnology such as CRIPSR-Cas and Restriction-Modification (R-M) systems. Identification of novel phage defence systems is currently an area of great interest. One system recently discovered is the BacteRiophage Exclusion (BREX) defence system, which is widespread amongst bacteria and similar to the Phage Growth Limitation (Pgl) system identified in the multicellular bacterium Streptomyces in the 1980s.The Pgl system is unique among phage defence systems (including other BREX-like systems), in that it does not prevent phage replication and host lysis during the initial infection: appearing instead to ‘tag’ the DNA of phage produced during the initial infection. If these ‘tagged’ phage subsequently infect a Pgl+ host they are recognised and replication is blocked, but these ‘tagged’ phages can go on to cause productive infections in hosts lacking a Pgl system. We have recently been working on the evolution of this unusual system – revealing the costs of the Pgl system, how the benefits are distributed among surviving cells, whether the system can act as a biological weapon, and why the system is subject to phase variation. We have also recently discovered the Pgl system is located in a wider bacteriophage ‘defence island’ comprised of multiple phage defence systems. Challenge Our recent work has focussed on the evolutionary aspects of Pgl and the cost/benefits of sacrificing cellular compartments to release modified phage. Yet, we still do not know the phage-specific molecular trigger of the Pgl system that enables the defence system to act. Furthermore, we do not know how the Streptomyces Pgl system senses and responds to phage infections and how it distinguishes between ‘untagged’ and ‘tagged’ phage. Other gaps in our knowledge include how phage replication is blocked - it has been shown in some BREX-like systems that nucleic acids are targeted by the system but without cleavage. These are fundamental gaps in our knowledge of Pgl and of BREX-systems more widely. Aims and objectives Our aim is to understand how the Pgl system senses phage infection, how the response to infection unfolds, and how phage replication is ultimately blocked. To do this we will identify the phage-specific trigger of the Pgl system in Streptomyces and determine how the activity of the system is modulated. We will test mechanisms that allow the Pgl system to distinguish between ‘tagged’ and ‘untagged’ phage and will determine the currently unknown mechanism that inhibits phage replication. Finally, we will explore the interplay between the Pgl system and the novel phage defence genes we have recently identified that are co-located with Pgl. Potential applications The characterisation and understanding of bacterial defence systems is vital to our understanding of bacteria-phage co-evolution and the evolution of immunity mechanisms. Moreover, understanding these systems has the potential to provide both new methods for controlling phage infections in biotechnological, agricultural and healthcare settings and providing new molecular biology tools. Relevance to BBSRC priorities The project’s aims align closely with the BBSRC strategic priorities such as Understanding the Rules of Life, along with relevance to industrial biotechnology as bacteriophage infections in industrial antibiotic fermentations represent a significant threat to antibiotic production capability.
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