The Salmonella virulence protein MgtC promotes phosphate uptake inside macrophages

The MgtC virulence protein from the intracellular pathogen Salmonella enterica is required for its intramacrophage survival and virulence in mice and this requirement of MgtC is conserved in several intracellular pathogens including Mycobacterium tuberculosis. Despite its critical role in survival within macrophages, only a few molecular targets of the MgtC protein have been identified. Here, we report that MgtC targets PhoR histidine kinase and activates phosphate transport independently of the available phosphate concentration. A single amino acid substitution in PhoR prevents its binding to MgtC, thus abrogating MgtC-mediated phosphate transport. Surprisingly, the removal of MgtC’s effect on the ability to transport phosphate renders Salmonella hypervirulent and decreases a non-replicating population inside macrophages, indicating that MgtC-mediated phosphate transport is required for normal Salmonella pathogenesis. This provides an example of a virulence protein directly activating a pathogen’s phosphate transport inside host.