霍乱弧菌和肠道微生物信号交流促进其抗逆和定殖的分子机理

Up to date, Vibrio cholera are still endemic in many parts of the world, especially the developing countries in Asia and South America. Gut microbes efficiently protect host through prohibiting the colonization and proliferation of V. cholerae in intestine. Meanwhile, V. cholerae can sense and response the changes of surrounding environment via the pathway termed “Quorum sensing”, and reprogramme their behaviors for better fitness. That may explain why V. cholerae can successfully infect antibiotic-treated adult mouse and human in Cholera area. Together with ours and others reports, we demonstrated that V. cholerae repress their virulence expression by sensing the self-produced autoinducers CAI-1 and AI-2. So, we hypothesize that V. cholerae perform their host colonization and stress resistance through sensing exogenous quorum sensing signals. In our preliminary data, we showed that V. cholerae don’t product AHLs but sense them instead, and V. cholerae resistance to hydroperoxide was induced by AHLs addition. Moreover, we observed the increased V. cholerae population in adult mice by AHLs-pretreatment and AHLs oral ingestion. We will further investigate the molecular mechanism how V. cholerae sense the exogenous quorum sensing signals and how this novel quorum sensing system endows V. cholerae's traits of fighting the colonization resistance of gut microbes. Our studies will shed lights on discovering the long time secret of V. cholerae colonization in human.

霍乱弧菌至今仍然危害着人类生命健康，以发展中国家为甚。肠道微生物菌群能够有效抵御霍乱弧菌在肠道内的定殖和繁衍，但同时霍乱弧菌能够通过群体感应系统感应到环境中的信号分子，从而调整自身的行为，迅速适应外界环境变化，这是霍乱弧菌在抗生素处理的成鼠模型以及霍乱区域人体中造成感染的原因。我们和他人的研究结果都表明，霍乱弧菌自身产生的群体感应信号CAI-1和AI-2实际上是抑制霍乱弧菌体内定殖的。因此推测霍乱弧菌可能通过感应外源信号因子来实现宿主体内的抗逆和定殖。我们在前期实验中发现，霍乱弧菌不产高丝氨内酯类物质(AHLs),却能感应这些信号，增强对过氧化氢的抗性。同时，体内添加AHLs能增加霍乱弧菌在成鼠肠道内的数量。在此基础上，我们将进一步研究霍乱弧菌应答外源群体感应信号分子的机制，以及这种调控途径对霍乱弧菌克服肠道微生物定殖抗性的影响。我们的研究成果将有助于揭示霍乱弧菌在人体肠道定殖的秘密。

霍乱弧菌感染人体需要克服肠道环境内的微生物形成的定殖抗性的挑战。霍乱弧菌能够通过群体感应系统感应环境中的信号分子，调整自身的行为，适应肠道环境。本研究收集、分离、培养了肠道内的78株细菌，构成了肠道细菌的资源库。通过收集78株菌的代谢物，检测肠道微生物对霍乱弧菌定殖相关的生长、ROS、QS、生物膜的影响。进一步精确的研究霍乱弧菌抗ROS的新机制，结果显示内源性H2S参与霍乱弧菌抗氧化胁迫，H2S可以通过以下方式减轻氧化应激：刺激抗氧化剂的表达，促进H2O2的解毒能力。这种对ROS的细胞保护作用在缺铁的宿主肠道中起作用。浮游状态过渡到静止的表面附着是霍乱弧菌生物膜形成的第一步，这个由着陆过程介导。结合基于半胱氨酸替换的标记方法和单细胞追踪技术，我们阐述了霍乱弧菌在粘弹性条件下着陆的动态变化机制，揭示了真实的粘液环境中霍乱弧菌着陆的情况，为更好地控制霍乱弧菌感染提供参考。