Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan.
Human Biology Program, School of Integrative and Global Majors, University of Tsukuba, Tsukuba, Japan.
mBio. 2019 Aug 6;10(4):e00796-19. doi: 10.1128/mBio.00796-19.
is an important human pathogen whose success is largely attributed to its vast arsenal of virulence factors that facilitate its invasion into, and survival within, the human host. The expression of these virulence factors is controlled by the quorum sensing accessory gene regulator (Agr) system. However, a large proportion of clinical isolates are consistently found to have a mutationally inactivated Agr system. These mutants have a survival advantage in the host but are considered irreversible mutants. Here we show, for the first time, that a fraction of Agr-negative mutants can revert their Agr activity. By serially passaging Agr-negative strains and screening for phenotypic reversion of hemolysis and subsequent sequencing, we identified two mutational events responsible for reversion: a genetic duplication plus inversion event and a poly(A) tract alteration. Additionally, we demonstrate that one clinical Agr-negative methicillin-resistant (MRSA) isolate could reproducibly generate Agr-revertant colonies with a poly(A) tract genetic mechanism. We also show that these revertants activate their Agr system upon phagocytosis. We propose a model in which a minor fraction of Agr-negative strains are phase variants that can revert their Agr activity and may act as a cryptic insurance strategy against host-mediated stress. is responsible for a broad range of infections. This pathogen has a vast arsenal of virulence factors at its disposal, but avirulent strains are frequently isolated as the cause of clinical infections. These isolates have a mutated locus and have been believed to have no evolutionary future. Here we show that a fraction of Agr-negative strains can repair their mutated locus with mechanisms resembling phase variation. The revertants sustain an Agr OFF state as long as they exist as a minority but can activate their Agr system upon phagocytosis. These revertant cells might function as a cryptic insurance strategy to survive immune-mediated host stress that arises during infection.
金黄色葡萄球菌是一种重要的人类病原体，其成功在很大程度上归因于其大量的毒力因子，这些因子有助于其入侵和在人类宿主中存活。这些毒力因子的表达受群体感应辅助基因调节（Agr）系统控制。然而，大量临床分离株被发现具有突变失活的 Agr 系统。这些突变体在宿主中有生存优势，但被认为是不可逆突变体。在这里，我们首次表明，一部分 Agr 阴性突变体可以恢复其 Agr 活性。通过连续传代 Agr 阴性菌株并筛选溶血表型的回复和随后的测序，我们确定了两个负责回复的突变事件：基因重复加倒位事件和多（A）区改变。此外，我们证明，一个临床 Agr 阴性耐甲氧西林金黄色葡萄球菌（MRSA）分离株可以通过多（A）区遗传机制重复产生 Agr 回复菌落。我们还表明，这些回复体在吞噬作用下激活其 Agr 系统。我们提出了一个模型，其中一小部分 Agr 阴性菌株是相位变体，可以恢复其 Agr 活性，并可能作为一种针对宿主介导应激的隐性保险策略。金黄色葡萄球菌是一种广泛感染的病原体。这种病原体拥有大量的毒力因子，但经常分离出无毒性的菌株作为临床感染的原因。这些分离株的 基因座发生了突变，并且被认为没有进化的未来。在这里，我们表明一小部分 Agr 阴性菌株可以通过类似于相位变异的机制修复其突变的 基因座。只要 Agr 阴性菌株作为少数存在，回复体就会维持 Agr OFF 状态，但在吞噬作用下可以激活其 Agr 系统。这些回复细胞可能作为一种隐性保险策略，以在感染过程中免疫介导的宿主应激中存活。
