The Streptococcus pyogenes Rgg2/Rgg3 quorum sensing system causes global suppression of macrophage inflammatory programs via an intranuclear mechanism

Streptococcus pyogenes or Group A Streptococcus (GAS), a significant human pathogen, employs quorum sensing (QS) systems to coordinate its behavior and genetic regulation to enhance survival. Our previous research established that one such QS system, the Rgg2/3 system, can suppress macrophage NFκB activity and production of pro-inflammatory cytokines. Yet, the scope of suppression and the mechanism by which it occurs remain unknown. In this study, transcriptomic and phosphoproteomic approaches were used to address these unanswered questions. It was found that QS-ON GAS broadly suppressed most inflammatory transcriptional pathways, including those of NFκB, type I and type II interferon responses, and intracellular stress responses. Yet, we found that no alternative transcriptional programs were activated after QS-ON GAS Infection. Additionally, phosphoproteomics showed no disruption in typical inflammatory pathways such as those related to NFκB and MAPK activation, which was confirmed by western blotting and translocation assays. Instead, the proteomic data highlighted a potential role for epigenetic mechanisms of inflammatory regulation. A role for epigenetic regulation in QS-mediated immunomodulation was validated using pharmacological inhibitors of histone and chromatin modifiers. These findings expand our understanding of QS-mediated suppression and of GAS virulence strategies that appear to employ atypical methods of restricting inflammation. Uncovering this mechanism will offer invaluable insight into GAS itself, as well as into understudied immunological pathways.IMPORTANCEStreptococcus pyogenes is a ubiquitous pathogen that causes over 600 million infections every year and 500,000 to 1 million fatalities. While in developed countries, it is generally known to cause mild conditions such as pharyngitis, it can also manifest as severe infections, such as necrotizing fasciitis and septic arthritis, and lead to post-infectious sequelae including rheumatic heart disease and glomerulonephritis. Elucidating new mechanisms of virulence in this organism, including how it evades and suppresses immune responses, is critical in understanding its pathogenicity and epidemiology, as well as identifying novel treatment avenues in this era of multidrug-resistant bacteria. In this study, we characterize the broad spectrum by which GAS modulates the host innate immune response and begin to uncover host pathways that the bacteria can use or inhibit for its survival.

epigenetics; group A Streptococcus; immune evasion; innate immunity; macrophages; quorum sensing.