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

基本信息

批准号：
10624961
负责人：
Kimberley Diane Seed
金额：
$ 62.67万
依托单位：
UNIVERSITY OF CALIFORNIA BERKELEY
依托单位国家：
美国
项目类别：
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/10624961
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 Genetic Genetic Recombination Genome Genomic Instability Genomics Genotype Geography Goals Human In Vitro Incidence Infection Infection Control Integrase Intestines Island Knowledge Laboratories Left Life Life Cycle Stages 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

项目摘要

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.

感染性腹泻病毒剂（如弧菌霍乱）引起的疾病和死亡是对公共卫生和全球社会经济发展的重大障碍。自然灾害和在某些沮丧的地区继续进行冲突，可能会加剧霍乱已经上升的发生率全球。作为一些优雅研究的重点，记录了流行病的基因组变化上个世纪，V。Cholerae已成为病原体进化的良好模型。尽管如此，尚不了解历史和当前变化的机制和驱动力。手臂病毒与其宿主生物之间的竞赛是所有细胞生命的进化中的关键驱动力。的确 V.霍乱必须防御水库中的无处不在掠食性噬菌体威胁人类疾病期间的肠道。我们的实验室表明，V。Cholerae已经进化为使用PLES 防御主要的掠夺性噬菌体ICP1。 PLE是寄生的移动遗传元素完全废除了ICP1的生产，同时利用噬菌体资源来进一步扩大自己的差异。所以，可以将PLE视为V.霍乱的防御系统，又是将ICP1的噬菌体卫星视为他们自己的动员。 V.霍乱的一个重要标志是先前普遍存在的Ples消失当新变体出现时，在全球范围内表明，随着时间的推移，每个变体都是由未知因素选择的。但是，我们不明白为什么会发生这种变化，以及新变体如何统治早期普遍的变体。我们假设V. V. ICP1和其他移动遗传元件的对抗。霍乱驱动了PLE的连续演变。我们还假设PLE中的相互适应为了应对这些攻击，已导致变异灭绝和替换的标志模式。到剖析我们将追求以下特定目的的连续演变的机制：1）我们将确定如何选择具有替代复制模块的PLE变体的ICP1拮抗作用。 2）我们会的定义PLE 2动员如何使其容易受到ICP1拮抗作用。 3）我们将确定如何干扰国防岛使ICP1和PLE活动对抗。 4）我们将调查PLE-PE-PLE竞争和作为PLE进化驱动力的重组的潜力。拟议的研究将提供有关如何随着时间的流逝，流行病霍乱弧菌被选中，并将有助于跟踪流行病的传播。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在健康和患病国家中的人口，并提高我们操纵这些社区的能力治疗或预防性益处。