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Protein SIC, a novel extracellular protein of Streptococcus pyogenes interfering with complement function
P Akesson1, A G Sjöholm, L Björck
1Department of Cell and Molecular Biology, Lund University, Sweden.
Abstract:
The human pathogen Streptococcus pyogenes possesses a chromosomal region, 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 translates into a protein of 305 amino acid residues, including a signal sequence of 32 amino acids and a central region consisting of three tandem repeats. The sequence represents a novel structure with no significant homology to any previously published sequence. The protein was purified from the streptococcal culture media where it is present in substantial amounts. Affinity chromatography of human plasma on Sepharose coupled with the protein specifically absorbed two plasma proteins which were identified as clusterin and histidine-rich glycoprotein (HRG). 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 overlapping or closely located sites in the streptococcal protein. Both clusterin and HRG are regulators of the membrane attack complex (C5b-C9) of complement. When the streptococcal protein was added to serum, complement-mediated lysis of sensitized sheep erythrocytes and guinea pig erythrocytes was inhibited. In addition, the streptococcal protein was incorporated 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. pyogenes strains comprising 55 different M serotypes. Only M1 and M57 strains were positive in this screening, indicating that protein SIC could be a virulence determinant. Thus, during recent years, the M1 serotype has been connected with a world-wide increase of severe and toxic S. pyogenes infections.
Insights
A novel Streptococcus pyogenes protein, SIC, inhibits complement-mediated lysis by binding clusterin and HRG. This protein is found in M1 and M57 serotypes, potentially explaining the rise in severe infections.
Area of Science:
- Microbiology
- Immunology
- Molecular Biology
Background:
- Streptococcus pyogenes virulence is regulated by the mga regulon.
- M1 serotype strains are increasingly associated with severe infections.
Purpose of the Study:
- To identify and characterize novel virulence factors in Streptococcus pyogenes.
- To investigate the role of a newly discovered protein in complement evasion.
Main Methods:
- Gene cloning and sequencing of a novel S. pyogenes protein.
- Protein purification and characterization.
- Interaction studies with human plasma proteins (clusterin, HRG) and complement components.
Main Results:
- A novel protein, designated SIC (streptococcal inhibitor of complement-mediated lysis), was identified.
- SIC binds to human clusterin and histidine-rich glycoprotein (HRG).
- SIC inhibits complement-mediated lysis and is incorporated into the C5b-C9 complex.
- SIC is present in M1 and M57 S. pyogenes serotypes.
Conclusions:
- Protein SIC is a novel virulence factor that inhibits complement-mediated lysis.
- SIC's presence in M1 strains may contribute to the increased severity of infections.
- Further research into SIC could lead to new therapeutic strategies against S. pyogenes.