Proinflammatory virulence mechanisms of GAS and their targets. The GAS protease SpeB is directly proinflammatory by activating pro-IL-1β, other host substrates, and inactivating anti-inflammatory GAS effectors. SpeB cleavage of other proinflammatory cytokines, and proinflammatory virulence factors such as superantigens (SAgn), streptolysin O (SLO), and M protein can lead to their inactivation and have anti-inflammatory contributions. Superantigens forcibly bind T lymphocytes and APCs, leading to excessive T cell activation. Activated T cells kill other immune cells and release a “cytokine storm” of IFN-γ, TNF, and IL-6, hallmark of STSS. The pore-forming toxins SLO and streptolysin S (SLS) form large pores in host cells that can lead to the passive release DAMPs, and other cytosolic or organelle-associated proinflammatory compounds, or be detected by the inflammasome to further activate inflammatory cell death by pyroptosis. Proinflammatory effects of SLO can include aiding translocation of the virulence factors Nga. M protein proteolytically released from the GAS surface can similarly form complexes that induce pyroptosis in macrophages or hyper-degranulation by neutrophils. Like other microbes, GAS has numerous TLR agonists that activate proinflammatory regulatory programs [reviewed in (LaRock and Nizet, 2015)]. Created with BioRender.com.