Streptococcal inhibitor of complement (SIC) inhibits the membrane attack complex by preventing uptake of C567 onto cell membranes

Abstract

SUMMARYStreptococcal inhibitor of complement (SIC) was ®rst described in 1996 as a putative inhibitor of the membrane attack complex of complement (MAC). SIC is a 31 000 MW protein secreted in large quantities by the virulent Streptococcus pyogenes strains M1 and M57, and is encoded by a gene which is extremely variable. In order to study further the interactions of SIC with the MAC, we have made a recombinant form of SIC (rSIC) in Escherichia coli and puri®ed native M1 SIC which was used to raise a polyclonal antibody. SIC prevented reactive lysis of guinea pig erythrocytes by the MAC at a stage prior to C5b67 complexes binding to cell membranes, presumably by blocking the transiently expressed membrane insertion site on C7. The ability of SIC and clusterin (another putative¯uid phase complement inhibitor) to inhibit complement lysis was compared, and found to be equally ef®cient. In parallel, by enzyme-linked immunosorbent assay both SIC and rSIC bound strongly to C5b67 and C5b678 complexes and to a lesser extent C5b-9, but only weakly to individual complement components. The implications of these data for virulence of SIC-positive streptococci are discussed, in light of the fact that Gram-positive organisms are already protected against complement lysis by the presence of their peptidoglycan cell walls. We speculate that MAC inhibition may not be the sole function of SIC.

Serum-Resistant Strains of Borrelia burgdorferi Evade Complement-Mediated Killing by Expressing a CD59-Like Complement Inhibitory Molecule

“…An alternative explanation for the reduced deposition of MAC, besides the relative inefficiency of the C5 convertase, is that an inhibitor may prevent the assembly of the complex on the bacterial surface. The near normal amount of C7 bound to the C-resistant strain tends to exclude that the uptake of C5b-7 is impaired by the action of an inhibitor released from the spirochetes, as it has recently been shown for virulent strains of Streptococcus pyogenes (45) or as a result of the inhibitory effect of S protein and clusterin acting in the fluid phase (40). were allowed to react with DOC extract from Borrelia (100 g/ml) and the bound proteins were revealed by their reaction with goat IgG anti-CD59 followed by alkaline phosphatase-labeled secondary Abs.…”

Streptococcus pneumoniae Phosphoglycerate Kinase Is a Novel Complement Inhibitor Affecting the Membrane Attack Complex Formation

“…Although the MAC formation directly kills the Gram-negative bacteria either by lysis or disturbance of metabolic processes, the role of MAC deposition-mediated lysis or attenuation of the Gram-positive organisms is perceived to be ineffective. Nevertheless, to date two MAC inhibitors have been identified in Gram-positive bacteria that include streptococcal inhibitor of complement (SIC) from Group A streptococci and staphylococcal superantigen-like protein 7 (SSL7) from S. aureus (20,21,38). In addition, several other MAC inhibitors are known that include the recently identified terminal pathway inhibitor CspA and the CD59-like protein from Gram-negative bacteria Borrelia burgdorferi, schistosome C inhibitory protein type 1 (SCIP-1) from Schistosoma mansoni, paramyosin from S. mansoni and Trichinella spiralis, and the galactose-specific adhesin from Entamoeba histolytica (39 -43).…”

SIC, a Secreted Protein of Streptococcus pyogenesThat Inactivates Antibacterial Peptides

“…SIC stands for streptococcal inhibitor of complement, as the protein incorporates into the membrane attack complex of complement and inhibits complement-mediated lysis of sensitized erythrocytes (7). This inhibition of membrane attack complex was recently shown to be the result of SIC preventing uptake of C567 onto cell membranes (9). A remarkable property of SIC was reported by Stockbauer et al (10).…”