Streptococcal Protein H Forms Soluble Complement-activating Complexes with IgG, but Inhibits Complement Activation by IgG-coated Targets

Abstract

Protein H, a surface protein of Streptococcus pyogenes interacting with the constant Fc region of IgG, is known to be released from the streptococcal surface by a cysteine proteinase produced by the bacteria. Poststreptococcal glomerulonephritis and rheumatic fever are conditions in which immune complexes and autoimmune mechanisms have been suggested to play pathogenetic roles. The present study demonstrates that addition of protein H to human serum produces complement activation with dose-dependent cleavage of C3. The activation was IgG-dependent and the result of complexes formed between IgG and protein H. These complexes were size heterogeneous with molecular masses of 400 kDa to 1.4 MDa. Using complement-depleted serum reconstituted with complement proteins, the activation by protein H was found to be dependent of the classical, but independent of the alternative pathway of complement. In contrast to results of experiments based on soluble protein H⅐IgG complexes, complement activation was inhibited by protein H when IgG was immobilized on a surface. The interaction between C1q and immunoglobulins represents the first step in the activation of the classical pathway, and protein H efficiently inhibited the binding of C1q to IgG immobilized on polyacrylamide beads. Protein H reduced C3 deposition on the IgG-coated beads and inhibited immune hemolysis of IgG-sensitized erythrocytes. Finally, significantly less C3 was deposited on the surface of protein H-expressing wild-type streptococci than on the surface of isogenic mutant bacteria devoid of protein H. The results demonstrate that protein H⅐IgG complexes released from the streptococcal surface can produce complement breakdown at the sites of infection, whereas complement activation on bacterial surfaces is inhibited. This should have important implications for host-parasite relationships. In addition, soluble protein H⅐IgG complexes might contribute to immunological complications of streptococcal infections.

Antigen-43-mediated autoaggregation impairs motility in Escherichia coli

“…This confers an ability to resist various host defences, e.g. complement attack and phagocytosis (Berge et al, 1997;Ochiai et al, 1993), which supports the notion that bacterial autoaggregation is an important virulence mechanism. Formation of aggregates usually takes place through autoaggregation of cells.…”

Mouse skin passage of Streptococcus pyogenes results in increased streptokinase expression and activity

“…This type of discrepancy between message level and protein expression has been reported previously for other S. pyogenes gene products (Raeder et al, 2000). For example, surface M protein and other cell-surface and secreted proteins can be expressed and then post-translationally degraded by the secreted cysteine protease SpeB (Berge et al, 1997;Lei et al, 2000;Pinkney et al, 1995;Raeder et al, 1998).…”

A Common Theme in Interaction of Bacterial Immunoglobulin-binding Proteins with Immunoglobulins Illustrated in the Equine System

“…However, protein A has been shown to be capable of inhibiting C1q binding to surface-immobilized IgG, thereby preventing complement activation (42). Similarly, the binding of protein H from S. pyogenes to surface-immobilized IgG can inhibit C1q binding and partially block complement-mediated lysis (42). In the current study, binding of FgBP to surface-immobilized eqIgG4 and eqIgG7 was clearly able to disrupt the binding of C1q and prevent subsequent activation of the classical complement pathway.…”

“…The majority of available evidence appears to argue against the ability of such proteins to inhibit the binding of IgG to Fc␥R on phagocytic cells (41). However, protein A has been shown to be capable of inhibiting C1q binding to surface-immobilized IgG, thereby preventing complement activation (42). Similarly, the binding of protein H from S. pyogenes to surface-immobilized IgG can inhibit C1q binding and partially block complement-mediated lysis (42).…”