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Understanding how bacteriophages affect wound ecologies and developing new tools to harness bacteria-phage interactions

了解噬菌体如何影响伤口生态并开发新工具来利用细菌-噬菌体相互作用

基本信息

批准号：
10204665
负责人：
Irene Ann Chen
金额：
$ 99.35万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
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：
2016-09-30 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10204665
关键词：
Understanding how bacteriophages affect wound

项目摘要

The alarming rise of resistance to antibiotics among bacterial pathogens is a major challenge to the effective treatment of infections. A possible orthogonal strategy for countering bacterial pathogens is to make use of bacteriophages (phages), viruses that infect bacteria and are thus natural predators of bacteria. Little is known about the phages that live with the human microbiome, as they have been called the 'dark matter' of microbial ecology. However, phages are known to control bacterial populations in the marine environment and are suspected of curbing seasonal epidemics of cholera. An open question is whether phages affect bacterial populations in individual infections. The first goal of this proposal is to investigate the natural role of phages in the microbiome of wounds, using three systems: chronic wounds, abscesses, and superficial surgical wounds. The microbiome, including the phages, will be characterized to look for correlations between healing status, phage amount, and specific phage species. Phages that are found to correlate with healing are interesting targets for further study and engineering. An important related aspect of any potential phage-based therapy is to understand the consequences of phage application on the entire microbial ecology. Therefore, the second goal of this project is to develop an experimental model of a microbial ecosystem, and to perturb this ecosystem using phages specific for a particular bacterial species. The response of the ecosystem will reveal the underlying ecological interactions in the microbial community. This analysis will be used to develop a model of phage-bacteria systems. Finally, the safe application of a specific phage would, in principle, require considerable study of the biology of that phage to prevent unwanted interactions, such as gene transduction. Alternatively, hybrid phages may be developed to incorporate desirable genes from relatively uncharacterized phages (e.g., a coat protein targeted a particular bacterial pathogen) into a scaffold phage whose biology is well-known and whose safety has been previously described. Therefore, the third goal of this project is to develop a systematic approach to designing and engineering hybrid phages with known, controllable properties, based on incorporation of coat proteins from the phage metagenome into the model phage M13. The work proposed here will help delineate the potential of phage-based alternatives to antibiotics.

细菌病原体对抗生素抗药性的惊人上升是一个主要原因对有效治疗感染的挑战。一种可能的正交策略对抗细菌病原体是利用噬菌体，病毒感染细菌，因此是细菌的天敌。人们对此知之甚少与人类微生物群生活在一起的噬菌体，因为它们被称为“暗物质” 微生物生态学的研究。然而，众所周知，噬菌体可以控制细菌在并被怀疑可遏制霍乱的季节性流行。一个悬而未决的问题是，噬菌体是否会影响个体感染中的细菌种群。这项提议的第一个目标是研究噬菌体在伤口的微生物组，使用三种系统：慢性伤口，脓肿，和浅表的外科伤口。微生物群，包括噬菌体，将被描述寻找愈合状态、噬菌体数量和特定噬菌体之间的相关性物种。被发现与愈合相关的噬菌体是进一步的学习和工程。任何潜在的基于噬菌体的重要相关方面治疗是了解噬菌体应用对整个微生物的影响生态学。因此，这个项目的第二个目标是开发一个实验模型来扰乱这一生态系统，并使用一种特定于特定的细菌种类。生态系统的反应将揭示潜在的微生物群落中的生态相互作用。这一分析将用于开发噬菌体-细菌系统的模型。最后，一种特定噬菌体的安全应用原则上需要对该噬菌体的生物学进行大量研究，以防止有害的相互作用，如基因转导。或者，杂交噬菌体可以是被开发成整合来自相对未表征的噬菌体的所需基因(例如，针对特定细菌病原体的外壳蛋白)进入支架噬菌体，其生物学是众所周知的，其安全性之前已经被描述过了。因此，该项目的第三个目标是开发一种系统的方法来设计和基于掺入的具有已知、可控特性的工程杂交噬菌体将外壳蛋白从噬菌体Metagenome转移到模型噬菌体M13。这项工作将有助于描述基于噬菌体的替代方案的潜力抗生素。