The Central Metabolism Regulator EIIAGlc Switches Salmonella from Growth Arrest to Acute Virulence through Activation of Virulence Factor Secretion

The ability of Salmonella to cause disease depends on metabolic activities and virulence factors. Here, we show that a key metabolic protein, EIIAGlc, is absolutely essential for acute infection, but not for Salmonella survival, in a mouse typhoid fever model. Surprisingly, phosphorylation-dependent EIIAGlc functions, including carbohydrate transport and activation of adenylate cyclase for global regulation, do not explain this virulence phenotype. Instead, biochemical studies, in vitro secretion and translocation assays, and in vivo genetic epistasis experiments suggest that EIIAGlc binds to the type three secretion system 2 (TTSS-2) involved in systemic virulence, stabilizes its cytoplasmic part including the crucial TTSS-2 ATPase, and activates virulence factor secretion. This unexpected role of EIIAGlc reveals a striking direct link between central Salmonella metabolism and a crucial virulence mechanism. [Display omitted] •EIIAGlc is crucial for Salmonella virulence•EIIAGlc virulence function is independent of its well-studied metabolic roles•EIIAGlc is required for virulence factor secretion through TTSS-2•A peculiar EIIAGlc interaction surface is required for TTSS-2 activation Salmonella causes diarrhea but also systemic diseases, including typhoid fever. Mazé et al. now show that Salmonella systemic virulence requires EIIAGlc. Surprisingly, this is independent of the well-characterized major roles of EIIAGlc in sugar transport and metabolic regulation. Instead, EIIAGlc activates virulence factor secretion into host cells by interacting with type three secretion system 2. These results establish a striking direct link between Salmonella metabolism and virulence and might offer opportunities for controlling Salmonella infection.