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.

细菌病原体中对抗生素的耐药性令人震惊挑战有效治疗感染。可能的正交策略对抗细菌病原体是为了利用噬菌体（噬菌体），病毒感染细菌，因此是细菌的天然捕食者。关于与人类微生物组一起生活的噬菌体，被称为“暗物质” 微生物生态学。但是，已知噬菌体可以控制细菌种群海洋环境，涉嫌遏制霍乱的季节性流行病。一个空旷的问题是噬菌体是否影响各个感染中的细菌种群。该提议的第一个目标是调查噬菌体在伤口的微生物组，使用三个系统：慢性伤口，脓肿和浅表手术伤口。微生物组（包括噬菌体）将被表征寻找治愈状态，噬菌体数量和特定噬菌体之间的相关性物种。发现与康复相关的噬菌体是有趣的目标进一步的学习和工程。任何潜在基于噬菌体的重要方面治疗是要了解噬菌体应用对整个微生物的后果生态。因此，该项目的第二个目标是开发实验模型微生物生态系统，并使用特定于A的噬菌体扰动该生态系统特定的细菌物种。生态系统的响应将揭示基础微生物群落中的生态互动。该分析将用于开发噬菌体 - 细菌系统的模型。最后，安全应用特定的噬菌体原则上，是否需要对噬菌体的生物学进行大量研究以防止不需要的相互作用，例如基因转导。或者，混合噬菌体可能是开发是为了合并来自相对未表征的噬菌体所需的基因（例如，外套蛋白针对特定细菌病原体）进入脚手架噬菌体生物学是众所周知的，并且先前已经描述了其安全性。因此，该项目的第三个目标是开发一种系统的设计方法和基于Incompation 从噬菌体元基因组到模型噬菌体M13的外套蛋白的蛋白质。工作这里提出的将有助于描述基于噬菌体的替代方案的潜力抗生素。