How bacterial immune systems sense phage infection.

Bacteria have evolved diverse anti-phage defence systems to counter the constant threat of viral infection. Like all immune systems, these defences must accurately detect infection while avoiding inappropriate activation that could harm the uninfected host. Recent years have witnessed a rapid expansion in the discovery of bacterial immune mechanisms, yet fundamental questions remain about how these systems recognize phage invasion. What molecules or events are reliable indicators of infection? How do the sensory mechanisms underlying immunity ensure rapid and robust activation? And what evolutionary trade-offs do phages face when mutating to evade detection? In this Review, we examine the experimental approaches used to identify phage-based triggers and organize known triggers into three classes: phage nucleic acids, phage proteins and perturbations to host processes. For each class, we summarize current evidence and highlight emerging principles that connect diverse defence mechanisms. By focusing on sensing rather than downstream responses, we aim to provide a cohesive framework for understanding how bacteria discriminate self from non-self, a challenge universal to immune systems across all domains of life.