Bacterial pathogens rely on chemical signaling and environmental cues to regulate disease-causing behavior in complex microenvironments. The human pathogen Streptococcus mutans employs a particularly complex signaling and sensing scheme to regulate genetic competence and other virulence behaviors in the oral biofilms it inhabits. Individual S. mutans cells make the decision to enter the competent state by integrating chemical and physical cues received from their microenvironment along with endogenously produced peptide signals. Studies at the single-cell level, using microfluidics to control the extracellular environment, provide physical insight into how the cells process these inputs to generate complex and often heterogeneous outputs. Fine changes in environmental stimuli can dramatically alter the behavior of the competence circuit. Small shifts in pH can switch the quorum sensing response on or off, while peptide-rich media appear to switch the output from a unimodal to a bimodal behavior. Therefore, depending on environmental cues, the quorum sensing circuitry can either synchronize virulence across the population, or initiate and amplify heterogeneity in that behavior. Much of this complex behavior can be understood within the framework of a quorum sensing system that can operate both as an intercellular signaling mechanism and intracellularly as a noisy bimodal switch.
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