Diffusible Signal Factors Act through AraC-Type Transcriptional Regulators as Chemical Cues To Repress Virulence of Enteric Pathogens.

Successful colonization by enteric pathogens is contingent upon effective interactions with the host and the resident microbiota. These pathogens thus respond to and integrate myriad signals to control virulence. Long-chain fatty acids repress the virulence of the important enteric pathogens and by repressing AraC-type transcriptional regulators in pathogenicity islands. While several fatty acids are known to be repressive, we show here that -2-unsaturated fatty acids, a rare chemical class used as diffusible signal factors (DSFs), are highly potent inhibitors of virulence functions. We found that DSFs repressed virulence gene expression of enteric pathogens by interacting with transcriptional regulators of the AraC family. In serovar Typhimurium, DSFs repress the activity of HilD, an AraC-type activator essential to the induction of epithelial cell invasion, by both preventing its interaction with target DNA and inducing its rapid degradation by Lon protease. -2-Hexadecenoic acid (c2-HDA), a DSF produced by , was the most potent among those tested, repressing the HilD-dependent transcriptional regulator and the type III secretion effector >200- and 68-fold, respectively. Further, c2-HDA attenuated the transcription of the ToxT-dependent cholera toxin synthesis genes of c2-HDA significantly repressed invasion gene expression by in the murine colitis model, indicating that the HilD-dependent signaling pathway functions within the complex milieu of the animal intestine. These data argue that enteric pathogens respond to DSFs as interspecies signals to identify appropriate niches in the gut for virulence activation, which could be exploited to control the virulence of enteric pathogens.