Department of Molecular Biology and Microbiology, Graduate School of Biomedical Sciences, Tufts University School of Medicine, Boston, Massachusetts, USA.
mBio. 2024 Nov 13;15(11):e0245724. doi: 10.1128/mbio.02457-24. Epub 2024 Oct 8.
Bacteria and their predatory viruses (bacteriophages or phages) are in a perpetual molecular arms race. This has led to the evolution of numerous phage defensive systems in bacteria that are still being discovered, as well as numerous ways of interference or circumvention on the part of phages. Here, we identify a unique molecular battle between the classical biotype of and virulent phages ICP1, ICP2, and ICP3. We show that classical biotype strains resist almost all isolates of these phages due to a 25-kb genomic island harboring several putative anti-phage systems. We observed that one of these systems, Nezha, encoding SIR2like and helicase proteins, inhibited the replication of all three phages. Bacterial SIR2-like enzymes degrade the essential metabolic coenzyme nicotinamide adenine dinucleotide (NAD), thereby preventing replication of the invading phage. In support of this mechanism, we identified one phage isolate, ICP1_2001, which circumvents Nezha by encoding two putative NAD regeneration enzymes. By restoring the NAD pool, we hypothesize that this system antagonizes Nezha without directly interacting with its proteins and should be able to antagonize other anti-phage systems that deplete NAD.IMPORTANCEBacteria and phages are in a perpetual molecular arms race, with bacteria evolving an extensive arsenal of anti-phage systems and phages evolving mechanisms to overcome these systems. This study identifies a previously uncharacterized facet of the arms race between and its phages. We identify an NAD-depleting anti-phage defensive system called Nezha, potent against three virulent phages. Remarkably, one phage encodes proteins that regenerate NAD to counter the effects of Nezha. Without Nezha, the NAD regeneration genes are detrimental to the phage. Our study provides new insight into the co-evolutionary dynamics between bacteria and phages and informs the microbial ecology and phage therapy fields.
细菌及其捕食性病毒（噬菌体或 phage）处于持续的分子军备竞赛中。这导致了细菌中许多噬菌体防御系统的进化，这些系统仍在不断被发现，同时噬菌体也进化出了许多干扰或规避这些系统的方法。在这里，我们鉴定了经典生物型 和毒性噬菌体 ICP1、ICP2 和 ICP3 之间的独特分子战斗。我们表明，由于含有几个假定的抗噬菌体系统的 25kb 基因组岛，经典生物型菌株几乎可以抵抗所有这些噬菌体的分离株。我们观察到，这些系统之一，Nezha，编码 SIR2 样和解旋酶蛋白，抑制了所有三种噬菌体的复制。细菌 SIR2 样酶降解必需的代谢辅酶烟酰胺腺嘌呤二核苷酸（NAD），从而阻止入侵噬菌体的复制。支持这一机制，我们鉴定了一个噬菌体分离株，ICP1_2001，它通过编码两个假定的 NAD 再生酶来规避 Nezha。通过恢复 NAD 池，我们假设该系统通过不直接与其蛋白质相互作用来拮抗 Nezha，并且应该能够拮抗其他消耗 NAD 的抗噬菌体系统。
重要性：细菌和噬菌体处于持续的分子军备竞赛中，细菌进化出了广泛的抗噬菌体系统，噬菌体进化出了克服这些系统的机制。这项研究确定了 及其噬菌体之间军备竞赛的一个以前未被描述的方面。我们鉴定了一种称为 Nezha 的消耗 NAD 的抗噬菌体防御系统，对三种毒性噬菌体有效。值得注意的是，一种噬菌体编码了可以再生 NAD 的蛋白来对抗 Nezha。没有 Nezha，NAD 再生基因对噬菌体有害。我们的研究为细菌和噬菌体之间的协同进化动态提供了新的见解，并为微生物生态学和噬菌体治疗领域提供了信息。
