Virus-host interactions and microbial ecology

病毒-宿​​主相互作用和微生物生态学

• 批准号: 9924555
• 负责人: Rasika M Harshey
• 金额: $ 53.52万
• 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/9924555
• 关键词: Acute; Animals; Area; Bacteria; Bacterial Genome; Bacterial Infections; Bacteriophage mu; Behavior; Biological Assay; Biological Phenomena; Birds; DNA Integration; DNA Repair; DNA sequencing; 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; antibiotic tolerance; base; cell motility; improved; in vivo; insight; microbial; new therapeutic target; 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.

 性状（由申请方提供）：病毒-宿主相互作用和微生物生态学。这个提议包含两个非常不同的微生物系统。虽然这两个系统的目的是了解基本的生物现象，但它们也与微生物的毒力和人类健康密切相关。这些是：（1）DNA转座事件和细菌基因组组织的修复，使用转座噬菌体Mu作为我们的模型，以及（2）鞭毛运动的感觉能力和细菌在群体中的生存策略，使用群集作为我们的模型。(1)转座噬菌体Mu在阐明所有移动的元件的转座机制中发挥了核心作用。当发现HIV DNA整合的机制与Mu相似时，以Mu为模型的高通量整合测定导致了HIV整合酶抑制剂雷特格韦的开发和销售。我们目前专注于转座的最后一步，这涉及到链转移后的缺口修复， 仍然存在于目标中，一个仍然是黑盒的过程。我们开发的体内修复试验最近揭示了E。大肠杆菌复制体的修复。这项工作对复制体-转座体界面作为药物设计的新靶点具有重要意义。此外，我们最近对靶点选择蛋白MuB性质的了解，结合DNA测序的进展，为利用Mu作为大肠杆菌类核组织的探针开辟了新的天地。大肠杆菌，其细节仍然模糊。(2)在大量的鞭毛细菌中，鞭毛马达感知“表面”信号，告知细菌其环境生态位。作为回应，细菌可以决定长出更多的鞭毛来聚集在表面上，或者分泌多糖并在表面粘附的生物膜中生活。这些反应在细菌感染、表面定殖、持久性和致病性中起重要作用。来自不同细菌的结果现在已经明确地暗示马达不仅调节转录，而且调节转录后途径。然而，感知机制仍然处于黑暗中，可能是因为我们不完全了解运动功能。到目前为止，我们已经积累了关于群集的知识，以及我们最近发现的信号分子c-di-GMP作为马达的制动器，使我们能够理解鞭毛马达如何作为表面传感器。群集细菌的另一个奇怪的方面是它们对抗生素的耐受性更高。我们最近发现，这些细菌通过一种完全不同的策略移动，称为“Lévy walk”，这为研究这种行为及其与抗生素耐受性的相关性提供了新的途径。Lévy-walk策略被认为是鸟类、鱼类甚至人类等大型动物在稀缺时期使用的策略。Lévy walk被认为可以在没有内存的情况下优化稀疏分布目标的搜索。有趣的是，细菌在游泳过程中使用基于记忆的随机行走策略，而不是在群集过程中。