Cation Homeostasis: Coordinate Regulation of Polyamine and Magnesium Levels in Salmonella

Polyamines are organic cations that are important in all domains of life. Here, we show that in Salmonella, polyamine levels and Mg21 levels are coordinately regulated and that this regulation is critical for viability under both low and high concentrations of polyamines. Upon Mg21 starvation, polyamine synthesis is induced, as is the production of the high-affinity Mg21 transporters MgtA and MgtB. Either polyamine synthesis or Mg21 transport is required to maintain viability. Mutants lacking the polyamine exporter PaeA, the expression of which is induced by PhoPQ in response to low Mg21, lose viability in the stationary phase. This lethality is suppressed by blocking either polyamine synthesis or Mg21 transport, suggesting that once Mg21 levels are reestablished, the excess polyamines must be excreted. Thus, it is the relative levels of both Mg21 and polyamines that are regulated to maintain viability. Indeed, sensitivity to high concentrations of polyamines is proportional to the Mg21 levels in the medium. These results are recapitulated during infection. Polyamine synthesis mutants are attenuated in a mouse model of systemic infection, as are strains lacking the MgtB Mg21 transporter. The loss of MgtB in the synthesis mutant background confers a synthetic phenotype, confirming that Mg21 and polyamines are required for the same process(es). Mutants lacking PaeA are also attenuated, but deleting paeA has no phenotype in a polyamine synthesis mutant background. These data support the idea that the cell coordinately controls both the polyamine and Mg21 concentrations to maintain overall cation homeostasis, which is critical for survival in the macrophage phagosome.