Modulation of expression of the ToxR regulon in Vibrio cholerae by a member of the two-component family of response regulators

The ToxRS system in Vibrio cholerae plays a central role in the modulation of virulence gene expression in response to environmental stimuli. An integ ration of multiple signalling inputs mediated by ToxR, -S, and -T controls virulence gene expression leading to cholera toxin (CT) production. Recentl y, we identified a new virulence locus, varA (virulence associated regulato r), in classical V. cholerae O1 that positively controls transcription of t cpA, the major subunit of the toxin-coregulated pilus (TCP) and the product ion of CT, two key factors in cholera pathogenesis. The varA locus is a hom olog of gacA (originally described for the soil organism Pseudomonas fluore scens), which encodes a conserved global regulator belonging to the family of two-component signal transducing molecules. GacA homologs in a number of diverse gram-negative pathogenic bacterial species have been implicated in controlling the production of diverse virulence factors. varA mutants show ed reduced levels of tcpA message and TcpA protein, lacked visible signs of autoagglutination (a phenotype associated with functional TCP), produced d ecreased levels of CT, and were attenuated in colonizing infant mice. Trans cription of varA appears to be independent of ToxR, and overexpression of t he regulators tcpPH and toxT from plasmids in the varA mutant restored wild -type levels of CT production and the ability to autoagglutinate. varA repr esents an additional modulating factor in the coordinate expression of viru lence factors in V. cholerae.