Bacteria have evolved diverse immunity mechanisms to protect themselves against the constant onslaught of bacteriophages^1,2,3. Similar to how eukaryotic innate immune systems sense foreign invaders through pathogen-associated molecular patterns⁴ (PAMPs), many bacterial immune systems that respond to bacteriophage infection require phage-specific triggers to be activated. However, the identities of such triggers and the sensing mechanisms remain largely unknown. Here we identify and investigate the anti-phage function of CapRel^SJ46, a fused toxin–antitoxin system that protects Escherichia coli against diverse phages. Using genetic, biochemical and structural analyses, we demonstrate that the C-terminal domain of CapRel^SJ46 regulates the toxic N-terminal region, serving as both antitoxin and phage infection sensor. Following infection by certain phages, newly synthesized major capsid protein binds directly to the C-terminal domain of CapRel^SJ46 to relieve autoinhibition, enabling the toxin domain to pyrophosphorylate tRNAs, which blocks translation to restrict viral infection. Collectively, our results reveal the molecular mechanism by which a bacterial immune system directly senses a conserved, essential component of phages, suggesting a PAMP-like sensing model for toxin–antitoxin-mediated innate immunity in bacteria. We provide evidence that CapRels and their phage-encoded triggers are engaged in a ‘Red Queen conflict’⁵, revealing a new front in the intense coevolutionary battle between phages and bacteria. Given that capsid proteins of some eukaryotic viruses are known to stimulate innate immune signalling in mammalian hosts^6,7,8,9,10, our results reveal a deeply conserved facet of immunity.

细菌已经进化出多种免疫机制来保护自己免受噬菌体的持续攻击^1,2,3 。与真核先天免疫系统通过病原体相关分子模式⁴ (PAMP) 感知外来入侵者的方式类似，许多对噬菌体感染做出反应的细菌免疫系统需要激活噬菌体特异性触发器。然而，此类触发器的身份和传感机制仍然很大程度上未知。在这里，我们鉴定并研究了 CapRel ^SJ46的抗噬菌体功能，这是一种融合的毒素-抗毒素系统，可保护大肠杆菌免受多种噬菌体的侵害。通过遗传、生化和结构分析，我们证明 CapRel ^SJ46的 C 端结构域调节有毒的 N 端区域，充当抗毒素和噬菌体感染传感器。被某些噬菌体感染后，新合成的主要衣壳蛋白直接与 CapRel ^SJ46的 C 端结构域结合以解除自身抑制，使毒素结构域能够焦磷酸化 tRNA，从而阻止翻译以限制病毒感染。总的来说，我们的结果揭示了细菌免疫系统直接感知噬菌体保守的必需成分的分子机制，提出了细菌中毒素-抗毒素介导的先天免疫的类似 PAMP 的感知模型。我们提供的证据表明 CapRels 及其噬菌体编码的触发器参与了一场“红皇后冲突” ⁵ ，揭示了噬菌体和细菌之间激烈的共同进化战斗的新战线。 鉴于已知某些真核病毒的衣壳蛋白会刺激哺乳动物宿主的先天免疫信号^6,7,8,9,10 ，我们的结果揭示了免疫的一个深度保守的方面。