ROLE OF THE HYPERVARIABLE REGION IN STREPTOCOCCAL-M-PROTEINS - BINDING OF A HUMAN-COMPLEMENT INHIBITOR

Antigenic variation allows pathogenic microorganisms to evade the immu ne system of the infected host, The variable structure must play an im portant role in pathogenesis, but its function is in most cases unknow n, Here, we identify a function for the surface-exposed hypervariable region of streptococcal M5 protein, a virulence factor that inhibits p hagocytosis. The hypervariable region of M5 was found to bind the huma n complement inhibitor FHL-1 (factor If-like protein 1), a 42-kDa plas ma protein, Plasma absorption experiments with M5-expressing bacteria showed that the interaction with FHL-1 occurs also under physiologic c onditions, Studies of another extensively characterized M protein, M6, indicated that this protein also has a binding site for FHL-1 in the hypervariable region, The complement-inhibitory function of FHL-1 was retained after binding to streptococci, suggesting that bound FHL-1 pr otects bacteria against complement attack, All available data now indi cate that FHL-1, or another human complement inhibitor, binds to the h ypervariable region of M proteins. These findings provide insights int o the forces that drive antigenic variation and may explain why the hy pervariable region of M protein is essential for phagocytosis resistan ce, Moreover, these data add to a growing body of evidence that human complement inhibitors are major targets for pathogenic microorganisms.