Molecular mechanisms driving the antagonistic coevolution of viral satellites and bacteriophages in Vibrio cholerae

霍乱弧菌等传染性腹泻病原体引起的疾病和死亡是对 公共卫生和世界范围内社会经济发展的重大障碍。自然灾害和 一些贫困地区持续不断的冲突可能会加剧本已上升的霍乱发病率 全球范围内。作为几项优雅研究的重点，这些研究记录了过去几年流行毒株的基因组变化 上个世纪，霍乱弧菌已经成为研究病原体进化的一个很好的模型。尽管如此， 历史和当前变化背后的机制和驱动力尚不清楚。手臂 病毒和它们的宿主生物之间的竞争是所有细胞生命进化的关键驱动力。确实如此 霍乱弧菌必须防御在水上水库和 在人类疾病过程中的肠道。我们的实验室已经证明霍乱弧菌已经进化到使用PLE 以抵御主要的捕食性噬菌体ICP1。PLE是寄生的可移动遗传元件 完全取消ICP1的生产，同时利用噬菌体资源进一步传播。因此， PLE既可被视为霍乱弧菌的防御系统，也可被视为利用ICP1为霍乱弧菌服务的噬菌体卫星。 他们自己的动员。霍乱弧菌的一个重要特征是以前流行的PLE消失了 在全球范围内，当新的变种出现时，这表明随着时间的推移，每个变种都是由未知因素选择的。 然而，我们不明白为什么会发生这样的变化，以及新的变种是如何在早期占据主导地位的 流行的变种。我们推测，与ICP1和其他可移动遗传元件的拮抗作用可能与V。 霍乱弧菌推动了PLE的不断进化。我们还假设PLE中的互惠适应 为了反击这些攻击，导致了变种灭绝和替换的标志性模式。至 剖析PLE的连续进化机制，我们将追求以下具体目标：1)我们将 确定ICP1拮抗如何为具有替代复制模块的PLE变体选择。2)我们会 确定PLE 2动员如何使其对ICP1拮抗敏感。3)我们将确定 干扰防御岛拮抗ICP1和PLE活性。4)我们将调查PLE-PLE竞争和 重组作为PLE进化的驱动力的潜力。拟议的研究将提供关于如何 流行性霍乱弧菌是经过一段时间选择的，将有助于跟踪流行菌株的传播。 这一知识将进一步加强我们对噬菌体介导的微生物扰动的理解 在健康和患病状态下的人口，并提高我们操纵这些社区的能力 治疗或预防方面的好处。

Illness and death caused by infectious diarrheal disease agents, like Vibrio cholerae, are major threats to public health and significant barriers to socioeconomic development worldwide. Natural disasters and continuing conflict in some depressed regions threaten to exacerbate the already rising incidence of cholera globally. As the focus of several elegant studies documenting genomic changes in epidemic strains over the last century, V. cholerae has become a well-studied model for pathogen evolution. Despite this, the mechanisms and driving forces underlying historical and current changes are not yet understood. The arms race between viruses and their host organisms is a key driving force in the evolution of all cellular life. Indeed V. cholerae must defend against the ubiquitous threat of predatory phages in aquatic reservoirs and in the intestinal tract during disease in humans. Our laboratory has shown that V. cholerae has evolved to use PLEs to defend against the predominant predatory phage ICP1. PLEs are parasitic mobile genetic elements that completely abolish ICP1 production while exploiting phage resources to further their own spread. Therefore, PLEs can be viewed both as defense systems for V. cholerae, and as phage satellites that exploit ICP1 for their own mobilization. A significant hallmark of V. cholerae PLEs is that previously prevalent PLEs disappear globally when new variants emerge, indicating that each variant is selected by unknown factors over time. However, we do not understand why such changes occur, and how new variants come to dominate over earlier prevalent variants. We hypothesize that antagonism with ICP1 and other mobile genetic elements in V. cholerae has driven the successive evolution of PLEs. We also hypothesize that reciprocal adaptations in PLE to counter those attacks have contributed to the hallmark pattern of variant extinction and replacement. To dissect the mechanisms of successive evolution of PLEs we will pursue the following specific aims: 1) We will determine how ICP1 antagonism selected for PLE variants with alternative replication modules. 2) We will define how PLE 2 mobilization renders it susceptible to ICP1 antagonism. 3) We will determine how an interfering defense island antagonizes ICP1 and PLE activity. 4) We will investigate PLE-PLE competition and the potential for recombination as a driver of PLE evolution. The proposed studies will provide insight into how epidemic V. cholerae is selected for over time and will aid in tracking the dissemination of epidemic strains. This knowledge will further enhance our understanding of phage-mediated perturbations to microbial populations in healthy and diseased states, and advance our ability to manipulate these communities for therapeutic or prophylactic benefit.