Quorum Sensing Controls Biofilm Formation in Vibrio cholerae through Modulation of Cyclic Di-GMP Levels and Repression of vpsT

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Abstract
Two chemical signaling systems, quorum sensing (QS) and 3′,5′-cyclic diguanylic acid (c-di-GMP), reciprocally control biofilm formation in Vibrio cholerae . QS is the process by which bacteria communicate via the secretion and detection of autoinducers, and in V. cholerae , QS represses biofilm formation. c-di-GMP is an intracellular second messenger that contains information regarding local environmental conditions, and in V. cholerae , c-di-GMP activates biofilm formation. Here we show that HapR, a major regulator of QS, represses biofilm formation in V. cholerae through two distinct mechanisms. HapR controls the transcription of 14 genes encoding a group of proteins that synthesize and degrade c-di-GMP. The net effect of this transcriptional program is a reduction in cellular c-di-GMP levels at high cell density and, consequently, a decrease in biofilm formation. Increasing the c-di-GMP concentration at high cell density to the level present in the low-cell-density QS state restores biofilm formation, showing that c-di-GMP is epistatic to QS in the control of biofilm formation in V. cholerae . In addition, HapR binds to and directly represses the expression of the biofilm transcriptional activator, vpsT . Together, our results suggest that V. cholerae integrates information about the vicinal bacterial community contained in extracellular QS autoinducers with the intracellular environmental information encoded in c-di-GMP to control biofilm formation.