Mg²⁺ signalling defines the group A streptococcal CsrRS (CovRS) regulon

CsrRS (or CovRS) is a two-component system implicated in the control of multiple virulence determinants in the important human pathogen, group A Streptococcus (GAS). Earlier studies suggested that extracellular Mg²⁺ signalled through the presumed sensor histidine kinase, CsrS. We now confirm those findings, as complementation of a csrS mutant restored Mg²⁺-dependent gene regulation. Moreover, we present strong evidence that Mg²⁺ signals through CsrS to regulate an extensive and previously undefined repertoire of GAS genes. The effect of Mg²⁺ on regulation of global gene expression was evaluated using genomic microarrays in an M-type 3 strain of GAS and in an isogenic csrS mutant. Unexpectedly, of the 72 genes identified in the Mg²⁺-stimulated CsrRS regulon, 42 were absent from the CsrR regulon (the latter being defined by comparison of wild-type and CsrR mutant transcriptomes at low Mg²⁺). We observed CsrS-dependent regulation of 72 of the 73 genes whose expression changed in response to elevated extracellular Mg²⁺ in wild-type bacteria, a result that identifies CsrS as the principal, if not exclusive, sensor for extracellular Mg²⁺ in GAS. To our knowledge, this study is the first to characterize global gene regulation by a GAS two-component system in response to a specific environmental stimulus.