Quorum sensing in Pseudomonas aeruginosa

描述（由申请人提供）：该项目的PI E. P. Greenberg博士从事群体感应研究超过25年。他的长期目标是研究细菌社会活动的分子机制，并了解合作行为存在的原因、时间、地点和方式。本课题拟继续开展铜绿假单胞菌群体感应的研究。该项目的前期工作已经证实，铜绿假单胞菌采用两种群体感应信号以复杂的方式控制一组基因的表达。虽然铜绿假单胞菌作为一种物种表现出大量的多样性，但主要是在从人类感染中分离出的单一菌株PAO1的背景下研究的。除了已知的两种群体感应信号和受体回路外，格林伯格博士还指出，其中一种信号，即3-氧- c12 -同丝氨酸内酯，还有一种所谓的孤儿受体。这个信号有两个受体。对于一个信号拥有两个受体的价值，有一些基本的生物学问题。此外，这种机会致病菌的毒力需要完整的群体感应系统，孤儿受体似乎可以抑制毒力。拟议的研究源于该项目最近的工作，并代表了关于铜绿假单胞菌群体感应的生物学意义的下一个逻辑集。我们将研究除PAO1以外的铜绿假单胞菌菌株，以确定该物种中普遍受群体感应调节的基因，并深入了解环境如何影响调节的组成。我们将测试两个假设，每个假设都解决了为什么铜绿假单胞菌可能拥有两个受体来接收相同的信号。这项研究与公共卫生的相关性是铜绿假单胞菌可引起难以解决和往往无法治愈的人类感染。虽然群体感应不太可能进化为激活人类感染的功能，但在各种动物感染模型中，群体感应是铜绿假单胞菌完全毒力所必需的。也许是因为群体感应参与毒力，铜绿假单胞菌的细胞间交流和合作行为是我们对细菌社会行为的认识的前沿。这里提出的工作将有助于深入了解细菌交流和合作行为的选择优势。公共卫生相关性：本研究项目对铜绿假单胞菌群体感应机制有了深入的了解，铜绿假单胞菌是一种导致毁灭性人类感染的机会性病原体。由于群体感应控制铜绿假单胞菌的毒力，它已成为治疗发展的目标。提出的研究旨在增加我们对铜绿假单胞菌群体感应系统的元素的理解，以及这种细菌如何使用群体感应来控制其社会活动。这些发现将为如何在感染过程中有效地靶向群体感应提供指导。

DESCRIPTION (provided by applicant): The PI for this project, Dr. E. P. Greenberg has worked on quorum sensing for over 25 years. His long-term goals are to investigate the molecular mechanisms of social activity in bacteria, and to learn about why, when, where and how cooperative behavior exists. This proposal is to continue studies on quorum sensing in Pseudomonas aeruginosa. Prior work on this project has established that P. aeruginosa employs two quorum-sensing signals to govern expression of a battery of genes in a complex fashion. Although it is clear that P. aeruginosa shows substantial diversity as a species quorum sensing has been studied primarily in the context of the single strain PAO1, which was isolated from a human infection. In addition to the two known quorum-sensing signal and receptor circuits, Dr. Greenberg has shown there is a so-called orphan receptor for one of the signals, 3-oxo-C12-homoserine lactone. There are two receptors for this single signal. There are fundamental biological questions about the value of possessing two receptors for a single signal. In addition, the complete quorum-sensing systems are required for virulence of this opportunistic pathogen and the orphan receptor appears to suppress virulence. The proposed research derives from recent work on this project and represents a next logical set of about the biological significance of P. aeruginosa quorum sensing. We will study P. aeruginosa strains other than PAO1 to identify genes universally regulated by quorum sensing in this species and to gain insights about how environment might influence the makeup of the regulon. We will test two hypotheses that each address why P. aeruginosa might possess two receptors for the same signal. The relevance of this research to public health is that P. aeruginosa can cause difficult to resolve and often incurable human infections. Although it is unlikely that quorum sensing evolved to activate functions for human infections it is nevertheless true that quorum sensing is required for full P. aeruginosa virulence in a variety of animal infection models. Perhaps because of the quorum sensing involvement in virulence, cell-cell communication and cooperative behavior in P. aeruginosa are at the forefront of our knowledge of bacterial social behavior. The work proposed here will lend insight into the selective advantage of bacterial communication and cooperative behavior. PUBLIC HEALTH RELEVANCE: This research program has developed a mechanistic understanding of quorum sensing in Pseudomonas aeruginosa, an opportunistic pathogen that causes devastating human infections. Because quorum sensing controls virulence of P. aeruginosa it has become a target for therapeutic development. The proposed research aims to increase our understanding of the elements of the P. aeruginosa quorum sensing system and how this bacterium uses quorum sensing to control its social activities. The findings will provide guidance about how to effectively target quorum sensing in the course of an infection.