Defining the expanding mechanisms of phage-mediated activation of bacterial immunity

Due to recent discovery efforts, over 100 immune systems encoded by bacteria that antagonize bacteriophage (phage) replication have been uncovered. These systems employ direct and indirect mechanisms to detect phage infection and activate bacterial immunity. The most well-studied mechanisms are direct detection and activation by phage-associated molecular patterns (PhAMPs), such as phage DNA and RNA sequences, and expressed phage proteins that directly activate abortive infection systems. Phage effectors may also inhibit host processes and, therefore, indirectly activate immunity. Here, we discuss our current understanding of these protein PhAMPs and effectors expressed during various stages of the phage life cycle that activate immunity. Immune activators are predominantly identified from genetic approaches that isolate phage mutants that escape a bacterial immune system, coupled with biochemical validation. Although the mechanism of phage-mediated activation remains uncertain for most systems, it has become clear that each stage of the phage life cycle has the potential to induce a bacterial immune response.