Asymmetric regulation of quorum-sensing receptors drives autoinducer-specific gene expression programs in Vibrio cholerae

Quorum sensing (QS) is a mechanism of chemical communication that bacteria use to monitor cell-population density and coordinate group behaviors. QS relies on the production, detection, and group-wide response to extracellular signal molecules called autoinducers. Vibrio cholerae employs parallel QS circuits that converge into a shared signaling pathway. At high cell density, the CqsS and LuxPQ QS receptors detect the intra-genus and inter-species autoinducers CAI-1 and AI-2, respectively, to repress virulence factor production and biofilm formation. We show that positive feedback, mediated by the QS pathway, increases CqsS but not LuxQ levels during the transition into QS-mode, which amplifies the CAI-1 input into the pathway relative to the AI-2 input. Asymmetric feedback on CqsS enables responses exclusively to the CAI-1 autoinducer. Because CqsS exhibits the dominant QS signaling role in V. cholerae, agonism of CqsS with synthetic compounds could be used to control pathogenicity and host dispersal. We identify nine compounds that share no structural similarity to CAI-1, yet potently agonize CqsS via inhibition of CqsS autokinase activity.群体感应（Quorum sensing, QS）是细菌用以监测细胞种群密度、协调群体行为的化学通信机制。QS依赖于对一类被称为自诱导物（autoinducers）的胞外信号分子的产生、检测以及群体层面的响应。霍乱弧菌（Vibrio cholerae）拥有多条并行的QS信号通路，这些通路最终汇聚于一条共享的信号转导途径。在高细胞密度环境下，CqsS与LuxPQ这两种QS受体可分别感知种内自诱导物CAI-1与种间自诱导物AI-2，进而抑制毒力因子的合成与生物膜形成。本研究证实，由QS通路介导的正反馈会在细胞进入QS模式的过程中提升CqsS的蛋白水平（而非LuxQ），相较于AI-2信号输入，这一效应会放大通路对CAI-1信号的响应强度。对CqsS的不对称反馈使得霍乱弧菌仅能响应CAI-1自诱导物。由于CqsS在霍乱弧菌中发挥主导性的QS信号传导功能，利用合成化合物激动CqsS或可用于调控病原菌的致病性与宿主扩散能力。本研究筛选得到9种与CAI-1无结构相似性的化合物，这些化合物可通过抑制CqsS的自身激酶活性强效激动CqsS。