Virulence gene regulation inside and outside

Much knowledge about microbial gene regulation and virulence is derived fro m genetic and biochemical studies done outside of hosts. The aim of this re view is to correlate observations made in vitro and in vivo with two differ ent bacterial pathogens in which the nature of regulated gene expression le ading to virulence is quite different. The first is Vibrio cholerae, in whi ch the concerted action of a complicated regulatory cascade involving sever al transcription activators lead ultimately to expression of cholera toxin and the toxin-coregulated pilus. The regulatory cascade is active in vivo a nd is also required for maintenance of V. cholerae in the intestinal tract during experimental infection. Nevertheless, specific signals predicted to be generated in vivo, such as bile and a temperature of 37 degrees C, have a severe down-modulating effect on activation of toxin and pilus expression . Another unusual aspect of gene regulation in this system is the role play ed by inner membrane proteins that activate transcription. Although the top ology of these proteins suggests an appealing model for signal transduction leading to virulence gene expression, experimental evidence suggests that such a model may be simplistic. In Streptococcus pyogenes, capsule producti on is critical for virulence in an animal model of necrotizing skin infecti on. Yet capsule is apparently produced to high levels only from mutation in a two-component regulatory system, CsrR and CrsS. Thus it seems that in V. cholerae a complex regulatory pathway has evolved to control virulence by induction of gene expression in vivo, whereas in S. pyogenes at least one m ode of pathogenicity is potentiated by the absence of regulation.