Clin Microbiol Rev. 2000 Jul; 13(3): 470–511.

ABSTRACT
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.

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Streptococcal diseases have been recognized in recorded history for over two thousand years and remain today as a serious cause of worldwide health problems. Early research revealed that the streptococci were not only among the first organisms thought to be the cause of contagious diseases, but their presence initiated the introduction of cleanliness and the use of sterile procedures into hospital settings. More recent research on streptococci demonstrated that the hereditary material was DNA, paving the way to present day molecular and genomic studies. This book is focused on one of the streptococci, Streptococcus pyogenes (the group A Streptococcus), the bacteria responsible for diseases, such as scarlet fever, pharyngitis, impetigo, cellulitis, necrotizing fasciitis and toxic shock syndrome, as well as the sequelae of rheumatic fever and acute poststreptococcal glomerulonephritis. The goal of the 30 chapters in this volume is to present an up to date and comprehensive review of research on this organism, including its basic biology, epidemiology, genetics and pathways that facilitate group A streptococcal infections. Our intention is that this information will provide an important resource for the general public, students, researchers, and clinicians in future work towards an understanding of the mechanism of Streptococcus pyogenes disease, in hopes that it will lead to better methods of disease control.

Contents
Preface
History of Streptococcal Research
Joseph Ferretti and Werner Köhler.
Created: February 10, 2016.
M Protein and Other Surface Proteins on Streptococci
Vincent A. Fischetti.
Created: February 10, 2016.
Streptococcus pyogenes Pili
Immaculada Margarit y Ros.
Created: February 10, 2016; Last Update: March 25, 2016.
Cell Wall and Surface Molecules: Capsule
Michael R. Wessels.
Created: February 10, 2016; Last Update: March 25, 2016.
The spatial regulation of protein sorting in Streptococcus pyogenes
Assaf Raz.
Created: February 10, 2016; Last Update: March 25, 2016.
Molecular Basis of Serotyping and the Underlying Genetic Organization of Streptococcus pyogenes
Debra E. Bessen.
Created: February 10, 2016; Last Update: March 25, 2016.
Streptococcus pyogenes Metabolism
Vijay Pancholi and Michael Caparon.
Created: February 10, 2016.
Streptococcus pyogenes Genomics
Fumito Maruyama, Takayasu Watanabe, and Ichiro Nakagawa.
Created: February 10, 2016.
The Bacteriophages of Streptococcus pyogenes
W. Michael McShan and Scott V. Nguyen.
Created: February 10, 2016; Last Update: March 25, 2016.
The CRISPR-Cas system of Streptococcus pyogenes: function and applications
Luciano A. Marraffini.
Created: April 7, 2016.
The Streptococcal Proteome
Eduardo A. Callegari and Michael S. Chaussee.
Created: February 10, 2016.
Virulence-Related Transcriptional Regulators of Streptococcus pyogenes
Luis A. Vega, Horst Malke, and Kevin S. McIver.
Created: February 10, 2016; Last Update: March 25, 2016.
Secreted Extracellular Virulence Factors
Wayne Hynes and Melanie Sloan.
Created: February 10, 2016; Last Update: March 25, 2016.
Streptococcal Superantigens: Biological properties and potential role in disease
Thomas Proft and John D. Fraser.
Created: February 10, 2016.
Streptococcus pyogenes Biofilm
Christie Young, Robert C. Holder, Lily Dubois, and Sean D. Reid.
Created: February 10, 2016.
Group A Streptococcal Adherence
Patricia A. Ryan and Barbara Juncosa.
Created: February 10, 2016; Last Update: March 25, 2016.
Adhesion and invasion of Streptococcus pyogenes into host cells and clinical relevance of intracellular streptococci
Manfred Rohde and P. Patrick Cleary.
Created: February 10, 2016.
The Streptococcus pyogenes Carrier State
Judith Martin.
Created: July 25, 2016.
Epidemiology of Streptococcus pyogenes
Androulla Efstratiou and Theresa Lamagni.
Created: February 10, 2016; Last Update: April 3, 2017.
Animal Models of Streptococcus pyogenes Infection
Michael E. Watson, Jr., Melody N. Neely, and Michael G. Caparon.
Created: February 10, 2016.
Global Disease Burden of Group A Streptococcus
Amy Sims Sanyahumbi, Samantha Colquhoun, Rosemary Wyber, and Jonathan R. Carapetis.
Created: February 10, 2016.
Pharyngitis and Scarlet Fever
Michael R. Wessels.
Created: February 10, 2016; Last Update: March 25, 2016.
Impetigo, Erysipelas and Cellulitis
Dennis L. Stevens and Amy E. Bryant.
Created: February 10, 2016.
Severe Group A Streptococcal Infections
Dennis L. Stevens and Amy E. Bryant.
Created: February 10, 2016.
Acute Rheumatic Fever and Rheumatic Heart Disease
Dianne Sika-Paotonu, Andrea Beaton, Aparna Raghu, Andrew Steer, and Jonathan Carapetis.
Created: March 10, 2017; Last Update: April 3, 2017.
Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS)
Graziella Orefici, Francesco Cardona, Carol J. Cox, and Madeleine W. Cunningham.
Created: February 10, 2016.
Post-Streptococcal Glomerulonephritis
Bernardo Rodriguez-Iturbe and Mark Haas.
Created: February 10, 2016.
Post-Streptococcal Autoimmune Sequelae: Rheumatic Fever and Beyond
Madeleine W. Cunningham.
Created: February 10, 2016.
Laboratory Diagnosis of Streptococcus pyogenes (group A streptococci)
Barbara Spellerberg and Claudia Brandt.
Created: February 10, 2016.
Mechanisms of Antibiotic Resistance
Vincent Cattoir.
Created: February 10, 2016.
Current Approaches to Group A Streptococcal Vaccine Development
James B. Dale, Michael R. Batzloff, P. Patrick Cleary, Harry S. Courtney, Michael F. Good, Guido Grandi, Scott Halperin, Immaculada Y. Margarit, Shelly McNeil, Manisha Pandey, Pierre R. Smeesters, and Andrew C. Steer.

Kidney Int. 2007 Jun;71(11):1094-104. link

Abstract
Considerable insight has been gained into the etiopathogenesis of poststreptococcal glomerulonephritis since the landmark theoretical construct of Clemens von Pirquet postulated that disease-causing immune complexes were responsible for the nephritis that followed scarlet fever. Over the years, molecular mimicry between streptococcal products and renal components, autoimmune reactivity and several streptococcal antigens have been extensively studied. Recent investigations assign a critical role to both in situ formation and deposition of circulating immune complexes that would trigger a variety of effector mechanisms. Glomerular plasmin-binding activity of streptococcal glyceraldehyde-3-phosphate-dehydrogenase may play a role in nephritogenicity and streptococcal pyrogenic exotoxin B and its zymogen precursor may be the long-sought nephritogenic antigen.

J Am Soc Nephrol. 2004 Jul;15(7):1785-93.

Abstract
The role of nephritis-associated antigen as a virulence factor for acute poststreptococcal glomerulonephritis (APSGN) remains to be fully clarified. Nephritis-associated plasmin receptor (NAPlr) was previously isolated from group A streptococcus (GAS) and shown to bind plasmin(ogen). The nucleotide sequence of the naplr gene from GAS isolates obtained from patients with APSGN was determined. The sequence of the putative open reading frame (1011 bp) showed 99.8% identity among isolated strains. Homology screen revealed an exact match with streptococcal glyceraldehyde-3-phosphate dehydrogenase (GAPDH). NAPlr exhibited GAPDH activity in zymography, and it activated the complement pathway in vitro. In APSGN kidney biopsy specimens, NAPlr was observed mainly in the early stage of the disease (1 to 14 d after onset) but was not colocalized with either C3 or IgG as assessed by double immunofluorescence staining. Sera of patients with APSGN, patients with GAS infection without renal involvement, nonrenal pediatric patients, and healthy adults as controls were assayed for anti-NAPlr antibody titers. Anti-NAPlr antibodies were present most frequently in APSGN sera, and antibody titers were also significantly higher than in patients with GAS infection alone or in other control patients. Moreover, antibody titers remained elevated during the entire 10-yr follow-up period.

J Biomed Biotechnol. 2012;2012:417675. doi: 10.1155/2012/417675. Epub 2012 Oct 14.

Takashi Oda,1 Nobuyuki Yoshizawa,2 Kazuo Yamakami,3 Yutaka Sakurai,3 Hanako Takechi,1
Kojiro Yamamoto,1 Naoki Oshima,1 and Hiroo Kumagai1
1Department of Nephrology, National Defense Medical College, 3-2 Namiki, Tokorozawa-shi, Saitama 359-8513, Japan
2Hemodialysis Unit, Himawari Clinic, Tokyo 196-0015, Japan
3Department of Preventive Medicine and Public Health, National Defense Medical College, Saiatama 359-8513, Japan

It is well known that glomerulonephritis can occur after streptococcal infection, which is classically referred to as acute poststreptococcal glomerulonephritis (APSGN). The pathogenic mechanism of APSGN has been described by so-called immune complex theory, which involves glomerular deposition of nephritogenic streptococcal antigen and subsequent formation of immune complexes in situ and/or the deposition of circulating antigen-antibody complexes. However, the exact entity of the causative antigen has remained a matter of debate. We isolated a nephritogenic antigen for APSGN from the cytoplasmic fractions of group A streptococcus (GAS) depending on the affinity for IgG of APSGN patients. The amino acid and the nucleotide sequences of the isolated protein revealed to be highly identical to those of reported plasmin(ogen) receptor of GAS. Thus, we termed this antigen nephritis-associated plasmin receptor (NAPlr). Immunofluorescence staining of the renal biopsy tissues with anti-NAPlr antibody revealed glomerular NAPlr deposition in essentially all patients with early-phase APSGN. Furthermore, glomerular plasmin activity was detected by in situ zymography in the distribution almost identical to NAPlr deposition in renal biopsy tissues of APSGN patients. These data suggest that NAPlr has a direct, nonimmunologic function as a plasmin receptor and may contribute to the pathogenesis of APSGN by maintaining plasmin activity.

Autoimmun Rev. 2015 Aug;14(8):710-25. doi: 10.1016/j.autrev.2015.04.005. Epub 2015 Apr 17.

Abstract
There is a pressing need to reduce the high global disease burden of rheumatic heart disease (RHD) and its harbinger, acute rheumatic fever (ARF). ARF is a classical example of an autoimmune syndrome and is of particular immunological interest because it follows a known antecedent infection with group A streptococcus (GAS). However, the poorly understood immunopathology of these post-infectious diseases means that, compared to much progress in other immune-mediated diseases, we still lack useful biomarkers, new therapies or an effective vaccine in ARF and RHD. Here, we summarise recent literature on the complex interaction between GAS and the human host that culminates in ARF and the subsequent development of RHD. We contrast ARF with other post-infectious streptococcal immune syndromes – post-streptococcal glomerulonephritis (PSGN) and the still controversial paediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS), in order to highlight the potential significance of variations in the host immune response to GAS. We discuss a model for the pathogenesis of ARF and RHD in terms of current immunological concepts and the potential for application of in depth “omics” technologies to these ancient scourges.

Curr Opin Neurol. 2003 Jun;16(3):359-65.

Abstract
PURPOSE OF REVIEW:
Autoimmune disease has long been intertwined with investigations of infectious causes. Antibodies that are formed against an infectious agent can, through the process of molecular mimicry, also recognize healthy cells. When this occurs, the immune system erroneously destroys the healthy cells causing autoimmune disease in addition to appropriately destroying the offending infectious agent and attenuating the infectious process. The first infectious agent shown to cause a post-infectious autoimmune disorder in the central nervous system was Streptococcus pyogenes in Sydenham’s chorea. The present review summarizes the most recent published findings of central nervous system diseases that have evidence of a post-streptococcal autoimmune etiology.

RECENT FINDINGS:
Sydenham’s chorea and other central nervous system illnesses that are hypothesized to have a post-streptococcal autoimmune etiology appear to arise from targeted dysfunction of the basal ganglia. PANDAS (pediatric autoimmune disorders associated with streptococcal infections) is the acronym applied to a subgroup of children with obsessive-compulsive disorder or tic disorders occurring in association with streptococcal infections. In addition, there are recent reports of dystonia, chorea encephalopathy, and dystonic choreoathetosis occurring as sequelae of streptococcal infection. Investigators have begun to isolate and describe antistreptococcal-antineuronal antibodies as well as possible genetic markers in patients who are susceptible to these illnesses.

SUMMARY:
Clinical and research findings in both immunology and neuropsychiatry have established the existence of post-streptococcal neuropsychiatric disorders and are beginning to shed light on possible pathobiologic processes.

Clin Microbiol Rev. 2000 July; 13(3): 470–511.

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

Post streptococcal syndromes may manifest in multiple organs including the musculoskeletal, central nervous, urinary, integumentary, and circulatory systems. The commonly described post streptococcal syndromes include acute rheumatic fever, post streptococcal glomerulonephritis, post streptococcal arthritis, and pediatric autoimmune neuropsychiatric disorders. Classically, these complications occur more often in children. While much is written in the pediatric literature regarding these syndromes, a compilation of information is difficult to find. This article summarizes some of the frequently described post streptococcal syndromes and associations.
– See more at: http://www.ispub.com/journal/the-internet-journal-of-rheumatology/volume-6-number-2/post-streptococcal-syndromes-a-rheumatologist-perspective.html#sthash.xpSsFgEo.dpuf

Clinical Infectious Diseases 2002; 35:113–25

This statement is an update of the practice guideline published in 1997 and takes into account relevant research published since that time. A major substantive change is the acceptance of negative results of rapid antigen detection testing (RADT) for exclusion of acute streptococcal pharyngitis, without the previously mandated confirmation with a negative culture result.

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