Extensive allelic variation in GAS structural genes

393 Group A Streptococcus (GAS) is a Gram-positive bacterium that is responsible for a wide range of human infections, including pharyngitis and tonsillitis, skin infections (impetigo, erysipelas, and cellulitis), sepsis, osteomyelitis, a toxic-shock syndrome, and necrotizing fasciitis (1). The organism is also responsible for nonsuppurative sequelae such as acute rheumatic fever and acute glomerulonephritis. Globally, GAS causes extensive human morbidity and mortality (1). In the US, approximately 10,000 cases of severe invasive GAS disease occur each year. Direct costs associated with pharyngitis in the US have been estimated to be $1 billion annually. Although antibiotic treatment has largely eliminated rheumatic fever and subsequent rheumatic heart disease in North America and Western Europe, these crippling forms of heart disease are still very common in the developing world and in certain indigenous populations in developed countries. The resurgence of GAS as a cause of serious human infections in the US, Europe, and elsewhere in the 1980s and into the 1990s has been thoroughly documented and has heightened public awareness about this organism (1). Disease resurgence, coupled with the lack of a licensed GAS vaccine and ongoing concern about acquisition of penicillin resistance, has stimulated renewed interest in the molecular pathogenesis of GAS disease. The return of GAS as a cause of serious infections was a strong reminder that biomedical science knows relatively little about the evolutionary and other forces that drive temporal variation in bacterial disease frequency and severity. GAS’s revival has also taught the importance of understanding the molecular basis of pathogen variation, not merely as a means to discriminate between clinically relevant strains, but to provide data relevant to pathogenesis, host adaptation, and the origin of new pathogenic forms. In this Perspective, we highlight certain aspects of the genetic variation present in GAS, and we stress the biomedical relevance of this diversity. Extensive allelic variation in GAS structural genes Until 1989, most information pertaining to variation in GAS was based on serologic differences in M protein, an antiphagocytic surface molecule that is a critical virulence factor in many GAS (2). Although approximately 80 M types were recognized, and knowledge of variation in this protein was quite useful for certain kinds of epidemiological studies, serologic classification alone failed to reveal the special characteristics of GAS that were associated with certain infection types, such as streptococcal toxic shock syndrome (STSS). The convention of classifying isolates on the basis of one surface antigen was not satisfactory for the study of genomic relationships because serologic methods do not reflect the complexity of the genetic structure of