PROTEIN SIC, A NOVEL EXTRACELLULAR PROTEIN OF STREPTOCOCCUS-PYOGENES INTERFERING WITH COMPLEMENT FUNCTION

The human pathogen Streptococcus pyogenes possesses a chromosomal regi on, the mga regulon, that contains co-regulated genes important to the virulence of these bacteria. A novel gene located in the mga regulon of a S. pyogenes strain of serotype M1 was cloned and sequenced. It tr anslates into a protein of 305 amino acid residues, including a signal sequence of 32 amino acids and a central region consisting of three t andem repeats, The sequence represents a navel structure with no signi ficant homology to any previously published sequence. The protein was purified from the streptococcal culture media where it is present in s ubstantial amounts. Affinity chromatography of human plasma on Sepharo se coupled with the protein specifically adsorbed two plasma proteins which were identified as clusterin and histidine-rich glycoprotein (HR G). The interactions between the streptococcal protein and the plasma proteins were further characterized using purified clusterin and HRG. Inhibition experiments indicated that they have affinity for overlappi ng or closely located sites in the streptococcal protein. Both cluster in and HRG are regulators of the membrane attack complex (C5b-C9) of c omplement. When the streptococcal protein was added to serum, compleme nt-mediated lysis of sensitized sheep erythrocytes and guinea pig eryt hrocytes was inhibited. In addition, the streptococcal protein was inc orporated into C5b-C9 in serum, indicating the location of its action. The name, protein SIC, streptococcal inhibitor of complement mediated lysis, is therefore suggested for this novel protein, The occurrence of protein SIC and its gene was investigated in a collection of S. pyo genes strains comprising 55 different M serotypes. Only M1 and M57 str ains were positive in this screening, indicating that protein SIC coul d be a virulence determinant. Thus, during recent years, the M1 seroty pe has been connected with a world-wide in crease of severe and toxic S. pyogenes infections.