Role of the Mga regulon in the resistance of M type 4 Streptococcus pyogenes to phagocytosis

M type 4 Streptococcus pyogenes is a frequent cause of infections, yet little is known concerning its anti-phagocytic factors. We investigated the role of the Mga regulon on growth in blood by inactivating individual genes within this regulon. Ablation of mrp4, emm4, or sof4 reduced streptococcal growth in human blood. Inactivation of enn4 had little impact on streptococcal growth in blood. Thus, expression of mrp, emm, and sof were required for optimal resistance to phagocytosis of M type 4 S. pyogenes. M proteins from class II serotypes contribute to resistance to phagocytosis by binding C4BP, a regulator of complement activation. Our data indicate that there is an additional pathway for resistance in these streptococci that is mediated by the binding of fibrinogen. Fibrinogen was required for growth of M type 4 S. pyogenes in blood and Mrp4 was the major fibrinogen-binding protein on these bacteria. Fibrinogen–Mrp interactions prevented activation of the classical pathway, thereby contributing to the ability of these streptococci to evade phagocytosis.