Evolutionary adaptation of an AraC-like regulatory protein in Citrobacter rodentium and Escherichia species
Tan, A; Petty, NK; Hocking, D; Bennett-Wood, V; Wakefield, M; Praszkier, J; Tauschek, M; Yang, J; Robins-Browne, R
The evolution of pathogenic bacteria is a multifaceted and complex process, which is strongly influenced by the horizontal acquisition of genetic elements and their subsequent expression in their new hosts. A well-studied example is the RegA regulon of the enteric pathogen Citrobacter rodentium. The RegA regulatory protein is a member of the AraC/XylS superfamily, which co-ordinates the expression of a gene repertoire that is necessary for full pathogenicity of this murine pathogen. Upon stimulation by an exogenous, gut-associated signal, namely, bicarbonate ions, RegA activates the expression of a series of genes including virulence factors, such as auto-transporters, fimbriae, a dispersin-like protein, and the grlRA operon on the locus of enterocyte effacement pathogenicity island. Interestingly, the genes encoding RegA homologues are distributed across the Escherichia genus, encompassing pathogenic and non-pathogenic subtypes. In this study, we carried out a series of bioinformatic, transcriptional and functional analyses of the RegA regulons of these bacteria. Our results demonstrated that regA has been horizontally transferred to Escherichia spp. and C. rodentium. Comparative studies of two RegA homologues, namely, those from C. rodentium and E. coli SMS-3-5, a multiresistant, environmental strain of E. coli, showed that these two regulators acted similarly in vitro, but differed in terms of their ability to activate virulence of C. rodentium in vivo, which evidently was due to their differential activation of grlRA. Our data indicate that RegA from C. rodentium has strain-specific adaptations that facilitate infection of its murine host. These findings shed new light on the development of virulence by C. rodentium, and on the evolution of virulence regulatory genes of bacterial pathogens in general.