病原菌群体感应监管(policing quorum sensing)的生理生态机理及分子调控机制

Quorum sensing, the cell-to-cell communication by exchanging auto-inducers and secreting public goods, is the key for pathogenesis to most of pathogenic bacteria. Public goods can be used by any community member and their secretion encourages the emergence of social cheaters who cannot produce public goods. With the increasing of cheaters, there would be no sufficient public goods for cooperation and the quorum sensing would be interrupted, which will be the most important breakthrough in controlling infection of pathogenic bacteria. However, it is shown in our recent study that there is a policing system in Pseudomonas aeruginosa, where cooperators produce costly toxins to sanction or punish cheaters and maintain quorum sensing. The existence of policing quorum sensing is the core bottleneck for the development of new strategies on control of pathogenic bacterial infection. Therefore, in this project, with aim to clarify the regulation and mechanism of policing quorum sensing, we will employ Pseudomonas aeruginosa as model bacterium to investigate the effects from environmental factors, auto-inducers and public goods on the relationship between toxins and cheaters; analyze the roles of different toxins on cheaters inhibition and various antioxidants on cooperators protection; construct the molecular regulation network which mainly focus on toxins and antioxidants secretion genes. The results of this project will not only enrich the theories of quorum sensing and evolution of biological cooperation, but also supply the theoretical basis for designing and developing new strategies on the control of pathogenic bacteria. It is of scientific significance and importance for future application.

细胞间交流信号分子、分泌公共物质形成的群体感应是病原菌致病的关键。不分泌公共物质的欺骗子大量增长会导致公共物质短缺、破坏群体感应，是病原菌控制新策略研究的重要突破口。然而前期研究发现，合作者可进行群体感应监管，即在分泌公共物质的同时，通过调控毒素分泌，抑制欺骗子增长，维持群感稳定。群感监管机制已然成了以欺骗子为切入点进行病原菌控制新策略研发的核心瓶颈。本申请项目拟以铜绿假单胞菌为模式菌，通过环境条件、信号分子、公共物质对毒素-欺骗子关系影响分析，阐明群感监管的作用规律；通过抑制欺骗子增长的毒素物质确定以及合作者用于解毒的抗氧化系统解析，探明群感监管的生理生态机理；通过以毒素及解毒的抗氧化物相关基因为核心的基因调控模型建立，探究群感监管的分子调控机制。本研究成果不但可以丰富群体感应、生物合作进化等相关理论，也可为病原菌感染控制新策略研发奠定理论基础，具有重要的科学意义和潜在的应用前景。

细胞间交流信号分子、分泌公共物质形成的群体感应是病原菌致病的关键。不分泌公共物质的欺骗子大量增长会导致公共物质短缺、破坏群体感应，是病原菌控制新策略研究的重要突破口。然而前期研究发现，合作者可进行群体感应监管，即在分泌公共物质的同时，通过调控毒素分泌，抑制欺骗子增长，维持群感稳定。群感监管机制已然成了以欺骗子为切入点进行病原菌控制新策略研发的核心瓶颈。本项目以铜绿假单胞菌为模式菌，通过环境条件、信号分子、公共物质对毒素-欺骗子关系影响分析，发现铵可以影响群体感应监管，但是吸附类污染物如石墨烯、内分泌干扰物如壬基酚等新兴污染物则对群体感应监管基本不产生影响，即群体感应监管是一种相对保守的微生物种群稳定策略；通过长期进化实验、短期竞争试验、物质回补验证，确定毒素物质氰化氢是群体感应监管的主要物质，虽然毒素物质绿脓素在监管中亦有显著增长，但其具体的机制仍有待进一步探究；在群体感应监管过程中，合作者对应的抗氧化酶SOD、CAT、GSH未发生改变，但其通过诱导氰化氢末端不敏感酶Cio用于合作者的自我保护，且这种保护通过甘氨酸代谢权衡、gcvP1及gcvP2表达进行调控，cioAB的表达亦同时受合作者分泌的毒素物质以及欺骗子产生的ROS所诱导，是一种缜密的双重调控机制。该研究不仅阐明了群体感应监管的作用规律，亦探明了群体感应监管的生理生态机理以及分子调控机制，研究成果不但丰富了群体感应、生物合作进化等相关理论，更为病原菌感染控制新策略研发奠定了理论基础，具有重要的科学意义和潜在的应用前景。