美国麻省理工学院Michael T. Laub等研究人员合作发现病毒外壳蛋白对细菌先天免疫系统的直接激活。2022年11月16日，《自然》杂志在线发表了这项成果。

研究人员确定并研究了CapRel^SJ46的抗噬菌体功能，它是一个融合的毒素-抗毒素系统，可以保护大肠杆菌对抗各种噬菌体。利用遗传、生化和结构分析，研究人员证明CapRel^SJ46的C端结构域调节有毒的N端区域，既作为抗毒素又作为噬菌体感染传感器。在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端结构域结合来解除自体抑制，使毒素结构域能够焦磷酸化tRNA，从而阻止翻译，限制病毒感染。

总之，这些研究结果揭示了细菌免疫系统直接感知噬菌体的一个保守的分子机制，并提出一个类似病原体相关分子模式（PAMP）的感知模型用于毒素-抗毒素介导的细菌先天免疫。研究人员提供的证据表明，CapRel及其噬菌体编码的触发器参与了“红皇后冲突”，并揭示了噬菌体和细菌之间激烈的共同演化斗争的一个新战线。鉴于一些真核病毒的外壳蛋白已知可刺激哺乳动物宿主的先天免疫信号，这些结果揭示了免疫的一个深层次的保守面。

据介绍，细菌已经演化出多种免疫机制来保护自己免受噬菌体的不断侵袭。与真核生物先天免疫系统通过PAMP感知外来入侵者的方式相似，许多应对噬菌体感染的细菌免疫系统需要噬菌体特异性触发器才能被激活。然而，这种触发器的身份和感应机制在很大程度上仍然未知。

附：英文原文

Title: Direct activation of a bacterial innate immune system by a viral capsid protein

Author: Zhang, Tong, Tamman, Hedvig, Coppieters t Wallant, Kyo, Kurata, Tatsuaki, LeRoux, Michele, Srikant, Sriram, Brodiazhenko, Tetiana, Cepauskas, Albinas, Talavera, Ariel, Martens, Chloe, Atkinson, Gemma C., Hauryliuk, Vasili, Garcia-Pino, Abel, Laub, Michael T.

Issue&Volume: 2022-11-16

Abstract: Bacteria have evolved diverse immunity mechanisms to protect themselves against the constant onslaught of bacteriophages1,2,3. 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 CapRelSJ46, 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 CapRelSJ46 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 CapRelSJ46 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 hosts6,7,8,9,10, our results reveal a deeply conserved facet of immunity.

DOI: 10.1038/s41586-022-05444-z

Source: https://www.nature.com/articles/s41586-022-05444-z