Infectious Diseases and Immunity Graduate Group, School of Public Health, University of California, Berkeley, California, USA.
Department of Plant and Microbial Biology, University of California, Berkeley, California, USA.
mBio. 2024 Oct 16;15(10):e0011124. doi: 10.1128/mbio.00111-24. Epub 2024 Sep 17.
Bacteria and their viral predators (phages) are constantly evolving to subvert one another. Many bacterial immune systems that inhibit phages are encoded on mobile genetic elements that can be horizontally transmitted to diverse bacteria. Despite the pervasive appearance of immune systems in bacteria, it is not often known if these immune systems function against phages that the host encounters in nature. Additionally, there are limited examples demonstrating how these phages counter-adapt to such immune systems. Here, we identify clinical isolates of the global pathogen harboring a novel genetic element encoding the bacterial immune system DarTG and reveal the immune system's impact on the co-circulating lytic phage ICP1. We show that DarTG inhibits ICP1 genome replication, thus preventing ICP1 plaquing. We further characterize the conflict between DarTG-mediated defense and ICP1 by identifying an ICP1-encoded protein that counters DarTG and allows ICP1 progeny production. Finally, we identify this protein, AdfB, as a functional antitoxin that abrogates the toxin DarT likely through direct interactions. Following the detection of the DarTG system in clinical isolates, we observed a rise in ICP1 isolates with the functional antitoxin. These data highlight the use of surveillance of and its lytic phages to understand the co-evolutionary arms race between bacteria and their phages in nature.IMPORTANCEThe global bacterial pathogen causes an estimated 1 to 4 million cases of cholera each year. Thus, studying the factors that influence its persistence as a pathogen is of great importance. One such influence is the lytic phage ICP1, as once infected by ICP1, is destroyed. To date, we have observed that the phage ICP1 shapes evolution through the flux of anti-phage bacterial immune systems. Here, we probe clinical isolates for novel anti-phage immune systems that can inhibit ICP1 and discover the toxin-antitoxin system DarTG as a potent inhibitor. Our results underscore the importance of and ICP1 surveillance to elaborate novel means by which can persist in both the human host and aquatic reservoir in the face of ICP1.
细菌及其病毒捕食者（噬菌体）不断进化以相互颠覆。许多抑制噬菌体的细菌免疫系统是由可水平传播到不同细菌的移动遗传元件编码的。尽管细菌中普遍存在免疫系统，但并不总是知道这些免疫系统是否对宿主在自然界中遇到的噬菌体起作用。此外，能够展示这些噬菌体如何对抗这种免疫系统的例子有限。在这里，我们鉴定了携带编码细菌免疫系统 DarTG 的新型遗传元件的全球病原体 的临床分离株，并揭示了该免疫系统对共同循环的裂解噬菌体 ICP1 的影响。我们表明，DarTG 抑制 ICP1 基因组复制，从而阻止 ICP1 空斑形成。我们进一步通过鉴定一种对抗 DarTG 的 ICP1 编码蛋白来表征 DarTG 介导的防御和 ICP1 之间的冲突，该蛋白允许 ICP1 后代的产生。最后，我们确定该蛋白 AdfB 是一种功能性抗毒素，通过直接相互作用消除了毒素 DarT。在临床 分离株中检测到 DarTG 系统后，我们观察到具有功能性抗毒素的 ICP1 分离株数量增加。这些数据强调了利用 和其裂解噬菌体的监测来了解细菌及其噬菌体在自然界中的共同进化军备竞赛。
全球细菌病原体 每年估计导致 100 万至 400 万例霍乱。因此，研究影响其作为病原体持续存在的因素非常重要。其中一个影响因素是裂解噬菌体 ICP1，因为一旦感染 ICP1， 就会被破坏。迄今为止，我们已经观察到噬菌体 ICP1 通过抗噬菌体细菌免疫系统的通量来塑造 的进化。在这里，我们探测临床 分离株中的新型抗噬菌体免疫系统，以抑制 ICP1，并发现毒素-抗毒素系统 DarTG 作为一种有效的抑制剂。我们的研究结果强调了 和 ICP1 监测的重要性，以详细阐述 在面对 ICP1 时在人类宿主和水生库中持续存在的新方法。
