Immunoglobulin-binding bacterial surface proteins; biomedical tools and virulence factors

Abstract: Many bacteria express immunoglobulin(Ig)-binding proteins that interact with Ig in a non-immune manner. Several of these Ig-binding bacterial proteins have been well characterized and are widely used as reagents for analysis and purification of Ig's. Protein G found on group C and G streptococci has affinity for constant regions of IgG heavy chains, whereas protein L found on Peptostreptococcus magnus binds to Ig light chains. A hybrid Ig-binding protein, protein LG, was generated by combining the Ig-binding parts from proteins G and L. Protein LG has the most complete Ig-binding properties of the Ig-binding proteins described so far, and it specifically absorbs the majority of Ig in plasma from humans and a wide variety of other mammals. Binding of Ig is also a common property of Streptococcus pyogenes, an important human pathogen. The different Ig Fc-binding proteins expressed by S. pyogenes have structural similarities with the M proteins. The M proteins are important virulence factors in S. pyogenes, due to their ability to confer resistance to phagocytosis to the bacterium. However, the role for the Ig-binding proteins in bacterial pathogenesis is unclear. Expression of the M protein is under control of the trans-acting regulator Mga. Insertional inactivation of mga in a S. pyogenes strain of the M1 serotype showed that protein H, an IgG Fc-binding M-like protein, was co-regulated with the M1 protein, protein SIC, an extracellular inhibitor of complement-dependent lysis, and the surface-associated C5a peptidase in this strain. The wild type strain was resistant to phagocytosis and adhered to human skin tissue sections, properties that were lost in the mutant. In addition, the mga mutant was affected in the expression of the cytotoxin streptolysin S and the activation of the streptococcal cysteine proteinase. When S. pyogenes express more than one M-like protein the biological functions of these proteins have been unclear. Isogenic mutants devoid of either surface-associated M1 protein or protein H revealed that the M1 protein specifically mediated the observed adherence and was nessecary for activation of the cysteine proteinase, whereas proteins M1 and H were both efficient in protecting S. pyogenes against phagocytosis. The anti-phagocytic property of the M proteins has been suggested to be due to inhibition of the alternative pathway of complement activation. Both the M1 protein and protein H bind factor H, an inhibitor of the alternative pathway. In addition, bacterial-associated protein H was shown to inhibit Ig-dependent activation of the classical pathway. Protein H was also shown to inhibit the binding of C1q, a component of the classical pathway, to IgG. These data implicate an important role for the Ig-binding for the protein H mediated inhibition of the classical pathway.