Immunity to Group A Streptococcal M Proteins: Forging a Single-Edged Sword

Pharyngitis due to group A streptococcus (Streptococcus pyogenes [GAS]) remains one of the most common infections occurring in childhood. Infections due to Streptococcus pyogenes, including skin and soft tissue infections, are believed to account for 110 million cases each year in the United States [1]. Although the number of cases of serious postinfection se-quelae—mainly acute rheumatic fever and glomerulonephritis—has decreased markedly in industrialized countries during the past 60 years, these complications remain major causes of morbidity in the developing world, and periodic outbreaks still occur in the United States. The devastating invasive manifestations of GAS disease include necrotizing fasciitis, streptococcal toxic shock syndrome (STSS), bacteremia, and pneumonia. In 2002, the Centers for Disease Control and Prevention estimated that there were 9000 cases of invasive GAS disease and 1200 GAS-associated deaths in the United States. A pathogen with so diverse an array of disease manifestations would be expected to possess many mechanisms for causing disease, and indeed, numerous virulence factors have been described [2]. Pyrogenic exotoxins account for the syndrome of scarlet fever and play a role in STSS. A hyaluronic acid capsule, present in varying amounts on the surface of virtually all strains of GAS, is essential for both col-onization and virulence [3]. Numerous secreted products—including streptolysin, streptokinase, and DNAse—are linked to the ability of GAS to cross tissue planes and cause serious disease. However, Re-becca Lancefield, with uncanny insight, recognized the central role of the M pro-tein—found on the surface of GAS—in both virulence and immunity [4]. Lance-field realized that type-specific immunity was imparted by the M protein and that highly virulent isolates produced large quantities of this protein. M protein is a filamentous molecule that is expressed on the GAS surface as a coiled-coil dimer. The carboxy-terminus, anchored in the cell wall, contains conserved epitopes, whereas the more distal amino terminus displays the characteristic type-specificity. Well over 100 immuno-logically distinct M proteins are now recognized , with prevalent strains varying over time and geography [5]. In the naive host, the M proteins act to prevent phag-ocytic cells from killing GAS by binding to plasma proteins that inhibit activation of the complement cascade. Type-specific immunity, developed by contact or infection with GAS with a given M protein, overcomes this deficit and renders the strains susceptible to killing. Individuals with immunity to M proteins are protected from infection with GAS of the same M protein type. Why, then, have M …