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

霍乱弧菌病毒卫星和噬菌体拮抗协同进化的分子机制

• 批准号: 10401451
• 负责人: Kimberley Diane Seed
• 金额: $ 63.69万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10401451
• 关键词: Address; Automobile Driving; Back; Bacterial Antibiotic Resistance; Bacteriophages; Bangladesh; Biochemical; Biological Assay; Biological Models; Cause of Death; Cholera; Collection; Conflict (Psychology); Dangerousness; Depressed mood; Disease; Dysentery; Elements; Epidemic; Evolution; Extinction (Psychology); Genetic; Genetic Recombination; Genome; Genomic Instability; Genomics; Genotype; Geography; Goals; Human; In Vitro; Incidence; Infection; Infection Control; Integrase; Intestines; Island; Knowledge; Laboratories; Left; Life; Link; Measures; Mediating; Mobile Genetic Elements; Molecular; Monitor; Natural Disasters; Organism; Parasites; Patients; Pattern; Population; Positioning Attribute; Predatory Behavior; Predisposition; Production; Public Health; Replication Origin; Resources; Role; Shapes; Source; Study models; System; Testing; Therapeutic; Therapeutic community technique; Time; Variant; Vibrio cholerae; Viral; Virus; Work; antagonist; arms race; diarrheal disease; driving force; human disease; in vivo; insight; microbial; novel; nuclease; pandemic disease; pathogen; pathogenic bacteria; prophylactic; socioeconomic development; stool sample; transmission process

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.

由霍乱弧菌等传染性腹泻病原引起的疾病和死亡是对人类的主要威胁。 公共卫生和全球社会经济发展的重大障碍。自然灾害和 一些萧条地区的持续冲突有可能加剧本已上升的霍乱发病率 全球。作为记录流行毒株基因组变化的几项优雅研究的焦点 上个世纪，霍乱弧菌已成为病原体进化的深入研究模型。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 病毒与其宿主生物之间的竞争是所有细胞生命进化的关键驱动力。的确 霍乱弧菌必须防御水库和水体中普遍存在的捕食性噬菌体的威胁 人类疾病期间的肠道。我们的实验室表明霍乱弧菌已经进化到可以使用 PLE 防御主要的掠食性噬菌体 ICP1。 PLE 是寄生移动遗传元件 完全废除 ICP1 生产，同时利用噬菌体资源进一步传播。所以， PLE 既可以被视为霍乱弧菌的防御系统，也可以被视为利用 ICP1 进行感染的噬菌体卫星。 他们自己的动员。霍乱弧菌 PLE 的一个重要特征是以前流行的 PLE 消失了 当新的变体出现时，这表明每个变体都是随着时间的推移由未知因素选择的。 然而，我们不明白为什么会发生这样的变化，以及新的变体如何主导早期的变体 流行的变体。我们假设 V 中与 ICP1 和其他可移动遗传元件的拮抗作用。 霍乱推动了 PLE 的连续进化。我们还假设 PLE 中的相互适应 为了应对这些攻击，导致了变异灭绝和替换的标志性模式。到 剖析 PLE 连续进化的机制，我们将追求以下具体目标：1）我们将 确定 ICP1 拮抗作用如何选择具有替代复制模块的 PLE 变体。 2）我们会 定义 PLE 2 动员如何使其容易受到 ICP1 拮抗作用的影响。 3）我们将确定如何 干扰防御岛会对抗 ICP1 和 PLE 活性。 4）我们将调查PLE-PLE竞争并 重组作为 PLE 进化驱动力的潜力。拟议的研究将深入了解如何 随着时间的推移，选择流行性霍乱弧菌将有助于追踪流行性菌株的传播。 这些知识将进一步增强我们对噬菌体介导的微生物扰动的理解 健康和患病国家的人口，并提高我们操纵这些社区的能力 治疗或预防益处。