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

Streptococcal inhibitor of complement (SIC) was first described in 1996 as a putative inhibitor of the membrane attack complex of complement (MAC). SI C is a 31 000 MW protein secreted in large quantities by the virulent Strep tococcus pyogenes strains M1 and M57, and is encoded by a gene which is ext remely 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 purified 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 p rior to C5b67 complexes binding to cell membranes, presumably by blocking t he transiently expressed membrane insertion site on C7. The ability of SIC and clusterin (another putative fluid phase complement inhibitor) to inhibi t complement lysis was compared, and found to be equally efficient. In para llel, 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 weakl y to individual complement components. The implications of these data for v irulence of SIC-positive streptococci are discussed, in light of the fact t hat Gram-positive organisms are already protected against complement lysis by the presence of their peptidoglycan cell walls. We speculate that MAC in hibition may not be the sole function of SIC.