HYPERVARIABILITY GENERATED BY NATURAL-SELECTION IN AN EXTRACELLULAR COMPLEMENT-INHIBITING PROTEIN OF SEROTYPE M1 STRAINS OF GROUP-A STREPTOCOCCUS

In many countries, M1 strains of the human pathogenic bacterium group A Streptococcus are the most common serotype recovered from patients w ith invasive disease episodes. Strains of this serotype express an ext racellular protein that inhibits complement [streptococcal inhibitor o f complement (Sic)] and is therefore believed to be a virulence factor . Comparative sequence analysis of the 915-bp sic gene in 165 M1 organ isms recovered from diverse localities and infection types identified 62 alleles. Inasmuch as multilocus enzyme electrophoresis and pulsed-f ield gel electrophoresis previously showed that most M1 organisms repr esent a distinct streptococcal clone, the extent of sic gene polymorph ism was unexpected. The level of polymorphism greatly exceeds that rec orded for all other genes examined in serotype M1 strains. All inserti ons and deletions are in frame, and virtually all nucleotide substitut ions alter the amino acid sequence of the Sic protein. These molecular features indicate that structural change in Sic is mediated by natura l selection, Study of 70 strains recovered from two temporally distinc t epidemics of streptococcal infections in the former East Germany fou nd little sharing of Sic variants among strains recovered in the diffe rent time periods. Taken together, the data indicate that sic is a uni quely variable gene and provide insight into a potential molecular mec hanism contributing to fluctuations in streptococcal disease frequency and severity.