Perspectives in Biology and Medicine

CHANGING STREPTOCOCCI AND PROSPECTS FOR THE GLOBAL ERADICATION OF RHEUMATIC FEVER GENE H. STOLLERMAN* Introduction If we have learned anything about the association of infectious agents with a given disease during the first half of this century, during its second halfwe should have learned to appreciate the innate capacity ofa microbial pathogen for variation. Such variation can produce strains with striking differences in their pathogenic potential over a period of time. The secular changes of one such species, Streptococcus pyogenes, or group A streptococci (GrAS) , offer insights to the study of the etiology and pathogenesis of rheumatic fever that have absorbed me in their clinical investigation for the better part of this century [I]. I shall argue in this review that it is timely for us to consider the development of a vaccine against rheumatogenic strains of GrAS as a high priority for human health. Although the demonstration of the effectiveness oflongacting penicillin injections for the prevention ofrheumatic fever was a seminal part of my early investigative contributions, antibiotic prophylaxis may be but a temporary stopgap against an organism that still remains endemic, and episodically epidemic, in the greater part of the world's population. We should have learned, too, in this century ofaccelerated travel, that transmission ofinfectious strains oforganisms isjet-propelled, and that isolationist policies are medically as well as politically ineffectual, if not dangerous. Establishing GrAS as the Etiological Agent ofRheumatic Fever THE CLASSIFICATION OF HEMOLYTIC STREPTOCOCCI Many investigators contributed to the identification of the GrAS as the causative agent of rheumatic fever, beginning in 1903 with Schotmuller's differentiation of hemolytic from nonhemolytic streptococci on blood agar and Schick's recognition of rheumatic fever and acute glomerulonephritis *10 Willow Springs Lane, #21, Hanover, NH 03755.© 1996 by The University of Chicago. All rights reserved. 0031-5982/97/3904-0980$01.00 Perspectives in Biology and Medicine, 40, 2 ¦ Winter 1997 165 as post-scarlatinal sequels [2, 3] . During the next 25 years, hemolytic streptococci were confirmed as the cause of scarlet fever by the Dicks' studies of erythrogenic toxin and by Dochez's painstaking immunologic identification of GrAS as a member of a single major serologic group [4, 5]. In the late 1920s the stage was thus set for Griffith in England and Lancefield in the United States to serotype a great variety of strains of the organism [6, T]. Griffith's typing system was based on a slide agglutination method, which classified the organisms by their serologically heterogeneous surface antigens. Lancefield, however, classified the hemolytic streptococci into major serogroups on the basis of their cell wall carbohydrate antigens. Strains containing the group A carbohydrate also contained the heterogeneous surface proteins that were responsible for Griffith's slide agglutination system of classification. These Lancefield sorted into two kinds of proteins, T and M. The latter were readily removable by their sensitivity to proteolysis, leaving the stable T proteins intact. The M proteins, far less stable, were easily lost by dissociation when freshly isolated strains were subcultured on artificial media. Lancefield showed that it was the M proteins that were primarily responsible for a strain's resistance to phagocytosis, and thus for its virulence in mice and humans. Protection by anti-M antibodies was exquisitely type specific, explaining the basis for immunity to S. pyogenes. Solid immunity is acquired to but a single M serotype of GrAS at a time, which accounts for the frequency of recurrent episodes of GrAS pharyngitis [7] . Rebecca Lancefield's studies of M protein laid the groundwork for future vaccine development. The usefulness of the Griffith slide agglutination typing system, however, is that strains no longer virulent still can be identified with typing antisera by their stable T-antigens, even when they have lost their M protein and the striking hyaluronate capsules that are a feature of M-rich, virulent strains and that are responsible for the formation of "mucoid" colonies on blood agar plates [8]. LINKING GrAS TO RHEUMATIC FEVER AND THE PREVENTION OF SECONDARY AND PRIMARY ATTACKS By the early 1930s, the development by E. W. Todd ofthe antistreptolysin O titer as a marker ofantecedent streptococcal sore throat reinforced Alvin Coburn's seminal efforts to establish rheumatic fever as a sequel...