Mutation in the negative regulators such as covR/covS and rgg has been shown to be correlated with invasive group A streptococcal infections. Our previous study showed that the expression of rgg is upregulated in the emm1-type covR mutant but is repressed in its covS mutant. The current study further showed that the transcription of rgg was similarly regulated by the CovR/CovS in the emm49-type NZ131 strain, indicating that the interaction between these two important regulatory systems could be similar among different emm-type strains. The kinase and phosphatase activity of the sensor protein CovS was further inactivated to elucidate whether the transcription of rgg is regulated by different levels of the phosphorylated CovR. Results showed that inactivation of the kinase activity of CovS results in the repression of rgg expression; however, inactivation of the phosphatase activity of CovS upregulates the rgg transcription compared to the wild-type strain, indicating that the nonphosphorylated CovR represses the transcription of rgg more effectively than the phosphorylated CovR. The regulatory activity of Rgg is repressed when binding to the LacD.1. Compared to the wild-type strain, the expression of lacD.1 was upregulated in the covS and covR isogenic mutants. These results indicate that CovR/S regulates the transcription of rgg and lacD.1; furthermore, the different levels of phosphorylated CovR acts differently to regulate the transcription of rgg. Results from this study may provide hints to explain why mutations in the covS and covR contribute differently to GAS pathogenesis.