Tissue tropism among group A streptococci - importance of bacteria associated proteolytic activity

Group A streptococcus (GAS) is one of the most common of bacterial pathogens infecting humans, frequently causing throat and skin infection. Some GAS strains have surface-expressed virulence factors called M proteins that bind human plasminogen with high affinity. Plasminogen is a central component of the human fibrinolytic system, and is bound by an M protein termed PAM through defined binding motifs called a-repeats. We show that PAM and secreted streptokinase that activates plasminogen to active plasmin are the key factors for the generation of surface-bound plasmin activity. An epidemiological correlation between the plasminogen-binding PAM-like phenotype and strains with a genotype associated with skin infection was found. Both streptokinase and PAM were tested for their role in virulence in a mouse model mimicking human impetigo and bacteria deleted for expression of these factors showed reduced capacity for in vivo reproduction and induction of pathological changes. The group of strains that were prone to cause skin infection was also found to produce larger amounts of a secreted cysteine protease, SpeB, as compared to strains that are associated mainly with throat infection. Using the mouse model for impetigo we were able to demonstrate that SpeB is important for virulence. In summary, our studies indicate that bacteria-generated proteolytic activity may affect the tissue tropic characteristics of GAS infection of the skin or the throat.