Fig. 5. Proposed mechanistic model outlining inter-relationships between SLO mediated cytotoxicity towards epithelial cells and SSA superantigen potency.

(1) During initial bacterial colonization, GAS secretes the DNase Spd1 to escape neutrophil clearance, allowing GAS to establish infection. (2) As infection progresses, SLO binds to host cell membranes and then oligomerizes to form large pores which induces the release of lactate dehydrogenase (LDH) and GSH from perforated host cells as well as cation influx^{71, 72}. Glutathione exists at a much higher concentration in the intracellular compartment (GSH_i) than the extracellular space (GSH_e) (~1000-fold) causing a significant difference in redox potential across the plasma membrane of eukaryotic cells. This gradient makes the extracellular and intracellular areas, respectively, oxidative and reductive. GSH efflux from perforated cells serves as a stimulus for SSA release, reduces SSA dimers and activates SSA monomers. (3) Thiol-activated SSA, in conjunction with other superantigens like SpeC, then cross-links major histocompatibility complex II molecules on antigen-presenting cells (APCs) and the variable region of the β-chain of T-cell receptor (TCR) to induce an overwhelming T-cell response with uncontrolled cytokine release.