Mechanisms of phagocytosis resistance in Streptococcus pyogenes

A distinguishing feature of Streptococcus pyogenes (GAS) is their ability to resist phagocytosis in whole human blood in the absence of type-specific antibodies, a property that is dependent on the expression of the surface associated M proteins. A common characteristic of M proteins is their interaction with a variety of host proteins including the complement regulatory protein factor H (FH) and fibrinogen that plays a key role in coagulation. Here, we report that GAS also interact with Factor H-like protein-1 (FHL-1), an alternative splice product of FH comprising the first seven short consensus repeats (SCRs) of the FH molecule. Furthermore, we have localised the binding site for the M protein in SCR 7 of FH and FHL-1. Although FH and FHL-1 are very similar, GAS, at a low bacteria to plasma ratio reminiscent of the physiological situation, selectively absorbed FHL-1 but not FH from plasma. Further analysis demonstrated a major binding site for FH/FHL-1 in the A- repeat region of the streptococcal M protein. Unexpectedly, deletion of this region in the M5 protein did not influence the ability of streptococci expressing this protein to resist phagocytosis in human blood. While the interaction with FH/FHL-1 is restricted to a certain subset of GAS strains, the binding of fibrinogen is common to all GAS strains. We mapped the fibrinogen-binding regions in the M1 and M5 proteins to the so-called B-repeats of these proteins. Furthermore, we could demonstrate that these regions contribute to streptococcal survival in human blood thereby suggesting that fibrinogen plays an important role for resistance against phagocytosis Traditionally, resistance against phagocytosis is correlated to the expression of the M proteins. However, we found, that the antiphagocytic property of M proteins is restricted by the genetic background of the strain expressing the particular M protein suggesting that phagocytosis resistance may require cooperation between M proteins and other strain-specific components