Bacterial defense against phage predation involves diverse defense systems acting individually and concurrently, yet their interactions remain poorly understood. We investigated >100 defense systems in 42,925 bacterial genomes and identified numerous instances of their non-random co-occurrence and negative association. For several pairs of defense systems significantly co-occurring in Escherichia coli strains, we demonstrate synergistic anti-phage activity. Notably, Zorya II synergizes with Druantia III and ietAS defense systems, while tmn exhibits synergy with co-occurring systems Gabija, Septu I, and PrrC. For Gabija, tmn co-opts the sensory switch ATPase domain, enhancing anti-phage activity. Some defense system pairs that are negatively associated in E. coli show synergy and significantly co-occur in other taxa, demonstrating that bacterial immune repertoires are largely shaped by selection for resistance against host-specific phages rather than negative epistasis. Collectively, these findings demonstrate compatibility and synergy between defense systems, allowing bacteria to adopt flexible strategies for phage defense.

细菌针对噬菌体捕食的防御涉及单独和同时发挥作用的多种防御系统，但它们的相互作用仍然知之甚少。我们研究了 42,925 个细菌基因组中的超过 100 个防御系统，并发现了许多它们非随机共现和负相关的实例。对于在大肠杆菌菌株中显着共存的几对防御系统，我们证明了协同抗噬菌体活性。值得注意的是，Zorya II 与 Druantia III 和 ietAS 防御系统具有协同作用，而 tmn 与同时出现的系统 Gabija、Septu I 和 PrrC 具有协同作用。对于 Gabija，tmn 结合了感觉开关 ATP 酶结构域，增强了抗噬菌体活性。一些在大肠杆菌中呈负相关的防御系统对显示出协同作用，并且在其他分类群中显着共现，这表明细菌免疫库很大程度上是通过对宿主特异性噬菌体的抗性选择而不是负上位性来形成的。总的来说，这些发现证明了防御系统之间的兼容性和协同作用，使细菌能够采取灵活的噬菌体防御策略。