Bacteria defend against phage infection through a variety of antiphage defence systems¹. Many defence systems were recently shown to deplete cellular nicotinamide adenine dinucleotide (NAD⁺) in response to infection, by cleaving NAD⁺ into ADP-ribose (ADPR) and nicotinamide^2,3,4,5,6,7. It was demonstrated that NAD⁺ depletion during infection deprives the phage of this essential molecule and impedes phage replication. Here we show that a substantial fraction of phages possess enzymatic pathways allowing reconstitution of NAD⁺ from its degradation products in infected cells. We describe NAD⁺ reconstitution pathway 1 (NARP1), a two-step pathway in which one enzyme phosphorylates ADPR to generate ADPR pyrophosphate (ADPR-PP), and the second enzyme conjugates ADPR-PP and nicotinamide to generate NAD⁺. Phages encoding NARP1 can overcome a diverse set of defence systems, including Thoeris, DSR1, DSR2, SIR2–HerA and SEFIR, all of which deplete NAD⁺ as part of their defensive mechanism. Phylogenetic analyses show that NARP1 is primarily encoded on phage genomes, suggesting a phage-specific function in countering bacterial defences. A second pathway, NARP2, allows phages to overcome bacterial defences by building NAD⁺ using metabolites different from ADPR-PP. Our findings reveal a unique immune evasion strategy in which viruses rebuild molecules depleted by defence systems, thus overcoming host immunity.

细菌通过各种抗噬菌体防御系统来防御噬菌体感染¹。最近显示，许多防御系统通过将 NAD⁺ 裂解成 ADP-核糖 （ADPR） 和烟酰胺^2,3,4,5,6,7 来消耗细胞烟酰胺腺嘌呤二核苷酸 （NAD⁺） 以响应感染。研究表明，感染过程中 NAD ⁺ 的耗竭剥夺了噬菌体的这种必需分子并阻碍了噬菌体复制。在这里，我们表明很大一部分噬菌体具有酶促途径，允许从感染细胞中的降解产物中重建 NAD⁺。我们描述了 NAD ⁺ 重建途径 1 （NARP1），这是一个两步途径，其中一种酶磷酸化 ADPR 以产生 ADPR 焦磷酸盐 （ADPR-PP），第二种酶结合 ADPR-PP 和烟酰胺以产生 NAD ⁺ 。编码 NARP1 的噬菌体可以克服多种防御系统，包括 Thoeris、DSR1、DSR2、SIR2-HerA 和 SEFIR，所有这些系统都会消耗 NAD⁺ 作为其防御机制的一部分。系统发育分析表明，NARP1 主要编码在噬菌体基因组上，表明噬菌体在对抗细菌防御方面具有特异性功能。第二种途径 NARP2 允许噬菌体通过使用与 ADPR-PP 不同的代谢物构建 NAD⁺ 来克服细菌防御。我们的研究结果揭示了一种独特的免疫逃避策略，其中病毒重建被防御系统耗尽的分子，从而克服宿主免疫。