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.

由传染性霍乱病原体（如霍乱弧菌）引起的疾病和死亡是对人类健康的主要威胁。 公共卫生和社会经济发展的重大障碍。自然灾害和 在一些萧条地区持续不断的冲突有可能使本已上升的霍乱发病率进一步恶化 在全球作为几个优雅的研究的重点，记录了流行菌株在20世纪70年代的基因组变化。 上个世纪，霍乱弧菌已成为病原体进化研究良好模型。尽管如此， 对历史和当前变化的机制和驱动力尚不了解。武器 病毒与其宿主有机体之间的竞争是所有细胞生命进化的关键驱动力。确实 诉霍乱必须抵御水生水库和湖泊中普遍存在的捕食性鱼类的威胁。 在人类疾病期间的肠道。我们的实验室已经表明，霍乱弧菌已经进化到使用PLEs 来抵御主要的捕食性噬菌体ICP 1。PLEs是寄生的移动的遗传元件， 完全消除ICP 1生产，同时利用噬菌体资源以进一步自身传播。因此，我们认为， PLEs既可以被看作是霍乱弧菌的防御系统，也可以被看作是利用ICP 1的噬菌体卫星， 自己的动员。霍乱弧菌PLEs的一个重要特征是以前流行的PLEs消失 当新的变体出现时，这表明每个变体随着时间的推移被未知因素选择。 然而，我们不明白为什么会发生这样的变化，以及新的变体是如何在早期占主导地位的 流行的变体。我们推测，在V. 霍乱导致了PLEs的连续进化。我们还假设，在PLE互惠适应 对抗这些攻击的手段促成了变异灭绝和替换的标志性模式。到 通过剖析PLEs连续演化的机制，我们将追求以下具体目标：1）我们将 确定ICP 1拮抗作用如何选择具有替代复制模块的PLE变体。2)我们将 定义PLE 2动员如何使其对ICP 1拮抗作用敏感。3)我们将决定如何 干扰防御岛拮抗ICP 1和PLE活性。4)我们将研究PLE-PLE竞争， 重组作为PLE进化驱动力的潜力。拟议的研究将提供洞察如何 随着时间的推移，流行性霍乱弧菌被选择，并将有助于跟踪流行菌株的传播。 这些知识将进一步增强我们对噬菌体介导的微生物干扰的理解。 健康和疾病状态的人群，并提高我们操纵这些社区的能力， 治疗或预防益处。