Streptococcus pyogenes, also known as group A streptococcus (GAS), causes a wide variety of acute infections, ranging from localized purulent infections to severe, even fatal, invasive disease. Systemic spread is usually caused by bacterial penetration of the epithelial barrier of the pharynx or damaged skin and, if not well controlled, can lead to blood and soft tissue invasion. Superficial colonization and invasive infection of GAS depend on secreted GAS virulence factors, of which cysteine protease exotoxin (SpeB) is the key. SpeB is initially an inactive zymogen that is proteolytically converted to a mature catalytically active enzyme. SpeB contributes to epidermal localization and systemic spread, but the underlying mechanisms are unknown.