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Virus-host interactions and microbial ecology

病毒-宿主相互作用和微生物生态学

基本信息

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
项目类别：
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

项目摘要

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.