Pathogenesis of Group A Streptococcal Infections
Madeleine W. Cunningham



Group A streptococci are model extracellular gram-positive pathogens responsible for pharyngitis, impetigo, rheumatic fever, and acute glomerulonephritis. A resurgence of invasive streptococcal diseases and rheumatic fever has appeared in outbreaks over the past 10 years, with a predominant M1 serotype as well as others identified with the outbreaks. emm (M protein) gene sequencing has changed serotyping, and new virulence genes and new virulence regulatory networks have been defined. The emm gene superfamily has expanded to include antiphagocytic molecules and immunoglobulin-binding proteins with common structural features. At least nine superantigens have been characterized, all of which may contribute to toxic streptococcal syndrome. An emerging theme is the dichotomy between skin and throat strains in their epidemiology and genetic makeup. Eleven adhesins have been reported, and surface plasmin-binding proteins have been defined. The strong resistance of the group A streptococcus to phagocytosis is related to factor H and fibrinogen binding by M protein and to disarming complement component C5a by the C5a peptidase. Molecular mimicry appears to play a role in autoimmune mechanisms involved in rheumatic fever, while nephritis strain-associated proteins may lead to immune-mediated acute glomerulonephritis. Vaccine strategies have focused on recombinant M protein and C5a peptidase vaccines, and mucosal vaccine delivery systems are under investigation.
INTRODUCTION.......................................................................................................................................................471
RESURGENCE OF SEVERE GROUP A STREPTOCOCCAL INFECTIONS AND SEQUELAE.................471
FEATURES OF GROUP A STREPTOCOCCAL SUPPURATIVE INFECTIONS............................................471
Pharyngitis and Scarlet Fever...............................................................................................................................472
Pyoderma and Streptococcal Skin Infections .....................................................................................................472
Invasive Streptococcal Disease: Streptococcal Toxic Shock Syndrome, Necrotizing Fasciitis, and
Septicemia........................................................................................................................................................472
Introduction.........................................................................................................................................................472
Pyrogenic exotoxins and superantigens in invasive disease .........................................................................472
Pyrogenic exotoxin B ..........................................................................................................................................472
M protein serotypes............................................................................................................................................473
Animal models of invasive soft-tissue infection..............................................................................................473
Treatment.............................................................................................................................................................473
IDENTIFICATION OF THE ORGANISM: OLD AND NEW TECHNIQUES..................................................473
Description and Clinical Microbiology................................................................................................................473
Throat culture .....................................................................................................................................................473
Lancefield group .................................................................................................................................................473
M protein and T typing: development of a molecular biology approach....................................................474
Serological Diagnosis of Streptococcal Infection: Anti-Streptolysin O, Anti-DNase B, and Other
Diagnostic Antibodies.....................................................................................................................................474
PATHOGENESIS: INTERACTION BETWEEN HOST AND PATHOGEN......................................................475
Adherence and Colonization .................................................................................................................................475
Multiple adhesins ...............................................................................................................................................475
Intracellular Invasion.............................................................................................................................................476
Host Response to Infection: Opsonization and Phagocytosis...........................................................................477
Extracellular Surface Molecules and Virulence Factors...................................................................................478
Hyaluronic acid capsule.....................................................................................................................................478
M protein .............................................................................................................................................................479
emm-like genes and the emm gene superfamily..............................................................................................480
Plasminogen-binding proteins: glyceraldehyde-3-phosphate dehydrogenase, enolase,
and streptokinase............................................................................................................................................482
Streptococcal pyrogenic exotoxins and the novel mitogen SMEZ: role as superantigens........................483
Streptococcal proteinase (streptococcal exotoxin B) .....................................................................................484
C5a peptidase ......................................................................................................................................................485
Streptococcal inhibitor of complement-mediated lysis ..................................................................................485
Analysis of the Group A Streptococcal Genome ................................................................................................486
Global Regulators of Virulence Genes.................................................................................................................486
Determinants of Protective Immunity..................................................................................................................487
Protective opsonic and mucosal antibody against M protein.......................................................................487
Other streptococcal surface components potentially involved in protection against infection ...............488
T-cell immunity to infection with group A streptococci ................................................................................488
NONSUPPURATIVE SEQUELAE ...........................................................................................................................489
Acute Poststreptococcal Glomerulonephritis ......................................................................................................489
Introduction.........................................................................................................................................................489
Diagnosis..............................................................................................................................................................489
Potential mechanisms of pathogenesis ............................................................................................................489
Circulating immune complexes.........................................................................................................................489
Molecular mimicry..............................................................................................................................................490
Streptococcal antigens and nephritis strain-associated proteins.................................................................490
Animal models of poststreptococcal acute glomerulonephritis ....................................................................490
Rheumatic Fever .....................................................................................................................................................491
Introduction.........................................................................................................................................................491
Association of group A streptococci with rheumatic fever............................................................................491
Clinical features of rheumatic fever.................................................................................................................491
Host susceptibility...............................................................................................................................................492
Autoimmunity and Molecular Mimicry in Rheumatic Fever ...........................................................................493
Autoantibodies cross-reactive with streptococcal antigens ...........................................................................493
Molecular mimicry and M protein...................................................................................................................495
Potential pathogenic mechanisms of cross-reactive antibodies in rheumatic fever ..................................495
Autoreactive T cells in rheumatic fever...........................................................................................................495
Animal models of carditis..................................................................................................................................496
Streptococcal Reactive Arthritis ...........................................................................................................................498
Tics and Other Brain Disorders...........................................................................................................................498
VACCINATION AND PREVENTION......................................................................................................................498
Antibiotic Therapy and Prophylaxis ....................................................................................................................498
Vaccine Strategies ...................................................................................................................................................499
M proteins ...........................................................................................................................................................499
C5a peptidase ......................................................................................................................................................500
Other vaccine candidates...................................................................................................................................500
ACKNOWLEDGMENTS ...........................................................................................................................................500
REFERENCES ............................................................................................................................................................500

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