Molecular analysis of Streptococcus pyogenes and its interactions with the human host

Sammanfattning: Streptococcus pyogenes causes infections only in humans, from trivial tonsillitis to life-threatening conditions. One of its most important virulence factors is the M-like protein family conferring resistance to phagocytosis to the bacterium. The M-like proteins are surface exposed rod-like molecules attached to the cell wall. Each strain of S. pyogenes expresses unique M-like proteins that bind to many divers human molecules. An M53 strain was shown to express a plasminogen binding M-like protein called PAM, interacting with a lysine binding site in the kringle domains of plasminogen. Plasminogen bound to the surface of bacteria or artificial surfaces coated with PAM could be activated by t-PA and streptokinase. M1 protein and protein H are two IgG-binding proteins of the M protein family expressed by the AP1 strain of the M1 serotype. Protein H reduces the deposition of opsonizing complement protein C3 compared to an isogenic mutant strain lacking protein H. The C3 deposition on the mutant requires IgG in the serum and an intact classical pathway of complement activation. Further, protein H inhibits C3 deposition and assembly of the membrane attack complex induced by IgG-coated targets. Protein H and C1q are mutually exclusive for binding to IgG which might be the explanation for the inhibition of the complement activation. An IgG-binding fragment of protein H could be cleaved off by the streptococcal cysteine proteinase, SCP, another virulence factor of S. pyogenes. In solution, the released fragment forms oligomeric complexes with IgG. The molecular mass is between 400 kDa and 1.5 MDa. The complexes bind C1q and induce complement activation via the classical pathway. SCP also releases a 110 kDa enzymatically active fragment of the C5a peptidase as well as two defined fibrinogen binding fragments of M1 protein. The genes encoding the M-like proteins and the C5a peptidase are located together on the streptococcal chromosome, in a pathogenicity island called the mga regulon. In strains of the M1, 12, and 55 serotypes these genes are separated by a DNA segment harbouring an insertional sequence, IS1562. The same or similar IS exist in most strains of S. pyogenes but at other locations on the chromosome.