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      M Protein and Hyaluronic Acid Capsule Are Essential for In Vivo Selection of covRS Mutations Characteristic of Invasive Serotype M1T1 Group A Streptococcus

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          The initiation of hyperinvasive disease in group A Streptococcus (GAS) serotype M1T1 occurs by mutation within the covRS two-component regulon (named covRS for control of virulence regulatory sensor kinase), which promotes resistance to neutrophil-mediated killing through the upregulation of bacteriophage-encoded Sda1 DNase. To determine whether other virulence factors contribute to this phase-switching phenomenon, we studied a panel of 10 isogenic GAS serotype M1T1 virulence gene knockout mutants. While loss of several individual virulence factors did not prevent GAS covRS switching in vivo, we found that M1 protein and hyaluronic acid capsule are indispensable for the switching phenotype, a phenomenon previously attributed uniquely to the Sda1 DNase. We demonstrate that like M1 protein and Sda1, capsule expression enhances survival of GAS serotype M1T1 within neutrophil extracellular traps. Furthermore, capsule shares with M1 protein a role in GAS resistance to human cathelicidin antimicrobial peptide LL-37. We conclude that a quorum of GAS serotype M1T1 virulence genes with cooperative roles in resistance to neutrophil extracellular killing is essential for the switch to a hyperinvasive phenotype in vivo.


          The pathogen group A Streptococcus (GAS) causes a wide range of human infections ranging from the superficial “strep throat” to potentially life-threatening conditions, such as necrotizing fasciitis, also known as “flesh-eating disease.” A marked increase in the number of cases of severe invasive GAS infection during the last 30 years has been traced to the emergence and spread of a single clone of the M1T1 serotype. Recent studies have shown that GAS serotype M1T1 bacteria undergo a genetic “switch” in vivo to a hypervirulent state that allows dissemination into the bloodstream. The present study was undertaken to identify specific GAS serotype M1T1 virulence factors required for this switch to hypervirulence. The surface-anchored GAS M1 protein and hyaluronic acid capsule are found to be essential for the switching phenotype, and a novel role for capsule in GAS resistance to host defense peptides and neutrophil extracellular killing is revealed.

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          Most cited references 46

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          Neutrophil extracellular traps kill bacteria.

          Neutrophils engulf and kill bacteria when their antimicrobial granules fuse with the phagosome. Here, we describe that, upon activation, neutrophils release granule proteins and chromatin that together form extracellular fibers that bind Gram-positive and -negative bacteria. These neutrophil extracellular traps (NETs) degrade virulence factors and kill bacteria. NETs are abundant in vivo in experimental dysentery and spontaneous human appendicitis, two examples of acute inflammation. NETs appear to be a form of innate response that binds microorganisms, prevents them from spreading, and ensures a high local concentration of antimicrobial agents to degrade virulence factors and kill bacteria.
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            The global burden of group A streptococcal diseases.

            The global burden of disease caused by group A streptococcus (GAS) is not known. We review recent population-based data to estimate the burden of GAS diseases and highlight deficiencies in the available data. We estimate that there are at least 517,000 deaths each year due to severe GAS diseases (eg, acute rheumatic fever, rheumatic heart disease, post-streptococcal glomerulonephritis, and invasive infections). The prevalence of severe GAS disease is at least 18.1 million cases, with 1.78 million new cases each year. The greatest burden is due to rheumatic heart disease, with a prevalence of at least 15.6 million cases, with 282,000 new cases and 233,000 deaths each year. The burden of invasive GAS diseases is unexpectedly high, with at least 663,000 new cases and 163,000 deaths each year. In addition, there are more than 111 million prevalent cases of GAS pyoderma, and over 616 million incident cases per year of GAS pharyngitis. Epidemiological data from developing countries for most diseases is poor. On a global scale, GAS is an important cause of morbidity and mortality. These data emphasise the need to reinforce current control strategies, develop new primary prevention strategies, and collect better data from developing countries.
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              Pathogenesis of group A streptococcal infections.

              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.

                Author and article information

                Department of Pediatrics, University of California San Diego, La Jolla, California, USA [a ];
                School of Chemistry and Molecular Biosciences, The University of Queensland, St. Lucia, Queensland, Australia [b ];
                Department of Medicine, University of California San Diego, La Jolla, California, USA [c ];
                Veterans Affairs San Diego Healthcare Center, San Diego, California, USA [d ];
                Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, California, USA [e ]; and
                Rady Children’s Hospital, San Diego, California, USA [f ]
                Author notes
                Address correspondence to Victor Nizet, vnizet@ .

                Invited Editor Anna Norrby-Teglund, Karolinska Institute Editor Donald Low, Mt. Sinai Hospital

                American Society of Microbiology (1752 N St., N.W., Washington, DC )
                31 August 2010
                Sep-Oct 2010
                : 1
                : 4
                Copyright © 2010 Cole et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported License, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Research Article

                Life sciences


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