Virus-host interactions and microbial ecology

病毒-宿​​主相互作用和微生物生态学

• 批准号: 9070973
• 负责人: Rasika M Harshey
• 金额: $ 61.9万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-06 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9070973
• 关键词: Animals; Antibiotics; Area; Bacteria; Bacterial Genome; Bacterial Infections; Bacteriophage mu; Behavior; Biological Assay; Biological Phenomena; Birds; Boxing; DNA Integration; DNA Repair; DNA Sequence; Development; Drug Design; Ecology; Elements; Escherichia coli; Event; Fishes; Flagella; Genetic Transcription; Goals; HIV; HIV Integrase Inhibitors; Health; Human; Investigation; Knowledge; Life; Marketing; Memory; Microbial Biofilms; Microbiology; Modeling; Motor; Pathogenesis; Pathway interactions; Play; Polysaccharides; Positioning Attribute; Process; Property; Proteins; Research; Role; Sensory; Signal Transduction; Signaling Molecule; Site; Surface; Swimming; System; Time; Virulence; Walking; Work; base; cell motility; improved; in vivo; insight; microbial; public health relevance; repaired; response; sedentary; sensor; virus host interaction

 DESCRIPTION (provided by applicant): Virus-host interactions and microbial ecology. This proposal encompasses two very different microbial systems. While directed at understanding fundamental biological phenomena, both systems are also acutely relevant to microbial virulence and to human health. These are: (1) Repair of DNA transposition events and bacterial genome organization, using transposable phage Mu as our model, and (2) Sensory prowess of the flagella motor and survival strategies of bacteria within a group, using swarming as our model. (1) Transposable phage Mu has played a central role in elucidating the transposition mechanism of all mobile elements. When the mechanism of HIV DNA integration was discovered to be similar to that of Mu, high-throughput integration assays modeled after Mu, led to the development and marketing of the HIV integrase inhibitor Raltegravir. We are currently focused on the last step of transposition, which involves post-strand transfer repair of gaps still remaining in the target, a process that is still a black box. The in vivo repair assays we have developed have recently revealed an essential role of the E. coli replisome in repair. The work has implications for the replisome-transpososome interface as a new target for drug design. In addition, our recent insights into properties of the target-site selection protein MuB, combined with the advances in DNA sequencing, open up new ground for exploiting Mu as a probe for the nucleoid organization of E. coli, whose details are still foggy. (2) In a large number of flagellatd bacteria, the flagellar motor perceives a `surface' signal that informs the bacterium of its environmental niche. In response, the bacteria can decide to grow more flagella to swarm over the surface, or secrete polysaccharides and live a sedentary life in surface-adherent biofilms. These responses play important roles in bacterial infection, surface colonization, persistence and pathogenesis. Results from different bacteria have now unequivocally implicated the motor in regulating not only transcription, but also post-transcriptional pathways. However, the sensing mechanism is still in the dark, likely because we don't completely understand motor function. The knowledge of swarming we have amassed thus far, as well as our more recent discovery of the signaling molecule c-di-GMP acting as a brake on the motor, has placed us in a position to understand how the flagellar motor might act as a surface sensor. Another curious aspect of swarming bacteria is their higher tolerance to antibiotics. Our recent finding that these bacteria move by an entirely different strategy called `Lévy walk', offers a new avenue of investigation into this behavior and its relevance to antibiotic tolerance. The Lévy-walk strategy is known to be used by large animals such as birds, fish and even humans in times of scarcity. The Lévy walk is thought to optimize search of sparsely distributed targets in the absence of memory. Interestingly, bacteria use a memory-based random walk strategy during swimming, but not during swarming.

 描述（由适用提供）：病毒宿主相互作用和微生物生态学。该建议包括两个截然不同的微生物系统。尽管针对理解基本生物学现象，但这两个系统也与微生物病毒和人类健康敏感。这些是：（1）使用可转座的噬菌体MU作为我们的模型来修复DNA换位事件和细菌基因组组织，以及（2）使用群体作为我们的模型，将鞭毛运动的感觉和细菌的生存策略的感觉。 （1）可转座噬菌体MU在阐明所有移动元件的换位机理方面发挥了核心作用。当发现HIV DNA整合的机制与MU相似时，以MU建立了建模的高通量整合测定，导致HIV整合抑制剂Raltegravir的开发和营销。我们目前专注于移位的最后一步，该步骤涉及链后转移差距的修复 留在目标中，一个仍然是黑匣子的过程。我们开发的体内维修刺客最近揭示了大肠杆菌复制体在修复中的重要作用。这项工作对复制体 - 转子体界面的影响是药物设计的新目标。此外，我们最近对目标位点选择蛋白MUB的性质的见解，再加上DNA测序的进步，为利用MU作为大肠杆菌核组织的探针开辟了新的基础，其细节仍然有雾。 （2）在大量的Flagllatd细菌中，Flagllar电动机感知了一个“表面”信号，该信号为细菌的环境生态位提供了信息。作为回应，细菌可以决定种植更多的旗杆，以蜂拥而至，或者秘密多糖并在表面粘附的生物膜中过着久坐的寿命。这些反应在细菌感染，表面定植，持久性和发病机理中起着重要作用。现在，不同细菌的结果已明确地实施了调节的电动机，不仅是转录，而且还实施了转录后途径。但是，感应机制仍然处于黑暗状态，可能是因为我们不完全了解运动功能。到目前为止，我们已经积累了蜂群的知识，以及我们最近发现的信号传导分子C-DI-GMP充当电动机上的制动器，使我们能够了解鞭毛电动机如何充当表面传感器。蜂群的另一个现代方面是它们对抗生素的耐受性更高。我们最近的发现，这些细菌通过称为“LévyWalk”的完全不同的策略移动，为这一行为及其与抗生素耐受性相关的新途径提供了新的投资途径。众所周知，莱维步行策略将被鸟类，鱼类甚至人类等大型动物使用。人们认为，在没有记忆的情况下，莱维步道可以优化对稀疏分布的目标的搜索。有趣的是，细菌在游泳过程中使用基于内存的随机步行策略，但在蜂群中不使用。