Rgg2/Rgg3 Quorum Sensing Mediated Immune Modulation and Cell Wall Modifications in Streptococcus pyogenes

Streptococcus pyogenes (Group A Streptococcus, GAS) is a human-restricted pathogen with a range of clinical manifestations and worldwide prevalence. GAS utilizes bacterial communication mechanisms known as quorum sensing (QS) to respond to coordinate population level responses and regulate various virulence mechanisms. The Rgg2/Rgg3 QS system in GAS modifies the bacterial cell surface resulting in increased lysozyme resistance, biofilm formation, and expression of the spy49_0450-0460 QS regulon, responsible for modulation of the host innate immune response in macrophages. We found that the spy49_0450-0460 operon is responsible for increased virulence during in vivo bacterial colonization of the skin, resulting in a more severe infection. The operon encodes 10 genes which have homology to enzymes involved in bacterial cell surface associated carbohydrate and teichoic acid biosynthesis pathways. This operon was found to be responsible for modifications to S. pyogenes’ cell surface, with increased O-acetylation of peptidoglycan, changes to surface associated carbohydrates, and the addition of a novel N-acetylglucosmine (GlcNAc) linked ribitol phosphate (GlcNAc-RboP) wall teichoic acid-like structure to the bacterial cell wall. Alterations to charged modifications on structures on the bacterial cell surface altered the ability of QS-active GAS to suppress the innate immune response in macrophages and suggests that electrostatic interactions are important for this QS-dependent phenotype. The results of this study suggest that unique structures on the surface of S. pyogenes during QS-active infection could be employed as a useful target for therapeutics and demonstrate a novel surface modifications in GAS.