The Rgg2/Rgg3 quorum sensing system of Group A Streptococcus (GAS) controls expression of 12 genes in response to short hydrophobic peptide (SHP) pheromones. This system is among the most highly up-regulated genes following the inoculation of GAS in an intact-skin model of infection. Because the system is regulated by both positive (Rgg2) and negative (Rgg3) means, we have generated mutants that lock the system in either ‘QS-ON’ (Drgg3) or ‘QS-OFF’ (Drgg2) states that mimic gene expression levels seen when GAS is provided a synthetic SHP (producing QS-ON) or a reversed-sequence peptide (rev-SHP, bacteria remain in QS-OFF state). We find that infection of cultured macrophages with QS-ON GAS, but not QS-OFF GAS, inhibit inflammatory responses induced by Pathogen-Associated Molecular Patterns and Toll-like receptor agonists. It is our objective to identify the mechanisms preventing macrophage activation, asking what aspects of gene expression are disrupted in the macrophage and how do the bacteria induce this effect. The conventional NFkB signal transduction pathway connecting TLRs to transcription factor nuclear translocation is functional in both QS-ON and QS-OFF infection conditions, indicating that the block in gene expression must occur in the nucleus. Phosphoproteomic analysis supports this conclusion and suggests epigenetic regulators and a possible differential activity of the c-Rel subunit may account for suppressed gene expression. The QS-induced 10-gene qim operon is required for immune suppression and its expression is associated with the presence of a ribitol-N-acetylglucosamine modification on the cell wall. We hypothesize this modification elicits the suppressive effects on macrophages, possibly through immunosuppressive receptors or regulatory networks that have been identified by a CRISPR mutagenesis screen. Finally, we have observed that invasive M1 and M89 strains produce an uncharacterized pigment whose color development occurs only upon exposure to oxygen. We are seeking the molecular structure of this pigment, pursuing the benefit it provides the bacteria, and why activation of the Rgg2/Rgg3 QS system blocks its biosynthesis.