Macrophage Immunosuppression by Quorum-Induced Streptococcus pyogenes

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Abstract Macrophage Immunosuppression by Quorum-Induced Streptococcus pyogenes The human-restricted pathosymbiont Streptococcus pyogenes (Group A Streptococcus, GAS) uses the Rgg2/Rgg3 QS system to modify the bacterial surface, allowing coordination of biofilm formation and lysozyme resistance. Preliminary findings demonstrate that innate immune cell responses to GAS are substantially altered by the QS status of the bacteria. Published and preliminary data show that macrophage activation, stimulated by multiple agonists and assessed by cytokine production and NFB activity, was substantially suppressed upon interaction with QS-ON GAS but not QS-OFF bacteria. Neither macrophage viability nor bacterial adherence were seen as different between QS activity states, yet TNF, IL-6, INF levels and an NFB reporter were drastically lower when QS was ON. Suppression required contact between viable bacteria and macrophages. A QS-regulated biosynthetic gene cluster (BGC) in the GAS genome, encoding several putative enzymes, was also required for macrophage modulation. Newly acquired transcriptomic analysis (RNA-Seq) of macrophages infected with QS-ON and QS-OFF GAS indicate clear divergence in gene expression patterns between infection types. QS-OFF infections induce macrophage characteristics with signatures of classic activation (M1-like), whereas QS-ON infections produced genetic signatures consistent with alternatively activated (M2-like) macrophages, where metabolic pathways of oxidative phosphorylation and fatty acid beta-oxidation are induced. We propose a model that upon contact with macrophages, QS-ON GAS produce a BGC-derived factor capable of suppressing inflammatory responses. The suppressive capability of QS-ON GAS is abolished after treatment with a specific QS inhibitor. These observations suggest that interfering with the ability of bacteria to collaborate via QS can serve as a strategy to counteract microbial efforts to manipulate host defenses. This application seeks to accomplish three primary objectives: 1) identify the QS-regulated factor generated by the BGC and the biosynthetic intermediates; 2) identify the macrophage target and mechanism of NFB inhibition; and 3) evaluate the physiological impact on immune cell activity and the advantage provided to GAS in vivo and in human explant tissue models.