Cyclo-(L-Phe-L-Pro), A Quorum-Sensing Signal Of Vibrio Vulnificus, Induces Expression Of Hydroperoxidase Through A Toxr-Leuo-Hu-Rpos Signaling Pathway To Confer Resistance Against Oxidative Stress

Vibrio vulnificus, an opportunistic human pathogen, produces cyclo (L-Phe-L-Pro) (cFP), which serves as a signaling molecule controlling the ToxR-dependent expression of innate bacterial genes, and also as a virulence factor eliciting pathogenic effects on human cells by enhancing intracellular reactive oxygen species levels. We found that cFP facilitated the protection of V. vulnificus against hydrogen peroxide. At a concentration of 1 mM, cFP enhanced the level of the transcriptional regulator RpoS which, in turn, induced expression of katG, encoding hydroperoxidase I, an enzyme that detoxifies H2O2 to overcome the oxidative stress. We found that cFP upregulated the transcription of the histone-like proteins vHU alpha and vHU beta through the cFP-dependent regulator LeuO. LeuO binds directly to upstream regions of vhuA and vhuB to enhance transcription. vHU alpha and vHU beta then enhance the level of RpoS post-transcriptionally by stabilizing the mRNA. This cFP-mediated ToxR-LeuO-vHU alpha beta-RpoS pathway also upregulates genes known to be members of the RpoS regulon, suggesting that cFP acts as a cue for the signaling pathway responsible for both the RpoS and the LeuO regulons. Taken together, this study shows that cFP plays an important role as a virulence factor as well as a signal for the protection of the cognate pathogen.