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sity of differing M types is proposed. The vast majority of GAS infection is benign. Nonetheless, many divergent M types possess limited capacity to cause invasive infection. M1T1 GAS readily switch to a covRS mutant form that is neutrophil resistant and frequently associated with systemic infection. Whilst non-M1 GAS are shown in this study to less frequently accumulate covRS mutations in vivo, such mutants are isolated from invasive infections and exhibit neutrophil resistance and enhanced virulence. The reduced capacity of non-M1 GAS to switch to the hypervirulent covRS mutant form provides an explanation for the comparatively less frequent isolation of non-M1 serotypes from invasive human infections. Key Words Animal models ؒ Bacteriology ؒ Immunity ؒ Innate ؒ Neutrophils ؒ Streptococcus ؒ Virulence factors ؒ Invasive infection Abstract Group A Streptococcus (GAS) causes rare but life-threatening syndromes of necrotizing fasciitis and toxic shock-like syndrome in humans. The GAS serotype M1T1 clone has globally disseminated, and mutations in the control of virulence regulatory sensor kinase (covRS) operon correlate with severe invasive disease. Here, a cohort of non-M1 GAS was screened to determine whether mutation in covRS triggers systemic dissemination in divergent M serotypes. A GAS disease model defining parameters governing invasive propen

Pathogenesis of group A streptococcal infections

Group A Streptococcus (GAS; Streptococcus pyogenes) is a human pathogen which causes significant morbidity and mortality globally. GAS typically infects the throat and skin of the host, causing mild infections such as pharyngitis and impetigo, in addition to life threatening conditions including necrotizing fasciitis, streptococcal toxic shock syndrome (STSS), and bacteremia. Repeated infection with GAS may result in the non-suppurative sequelae, acute rheumatic fever, and acute glomerulonephritis. GAS remains sensitive to the antibiotic penicillin which can be administered as a means to treat infection or as prophylaxis. However, issues with patient compliance and a growing concern over the possible emergence of resistant GAS strains may limit the usefulness of antibiotics in the future. A vaccine capable of preventing GAS infection may be the only effective way to control and eliminate GAS infection and disease. [Discovery Medicine 13(72):329-342, may 2012

Streptococcal collagen-like protein A and general stress protein 24 are immunomodulating virulence factors of group A Streptococcus

In Western countries, invasive infections caused by M1T1 serotype group A Streptococcus (GAS) are epidemiologically linked to mutations in the control of virulence regulatory 2-component operon (covRS). In indigenous communities and developing countries, severe GAS disease is associated with genetically diverse non-M1T1 GAS serotypes. Hypervirulent M1T1 covRS mutant strains arise through selection by human polymorphonuclear cells for increased expression of GAS virulence factors such as the DNase Sda1, which promotes neutrophil resistance. The GAS bacteremia isolate NS88.2 (emm 98.1) is a covS mutant that exhibits a hypervirulent phenotype and neutrophil resistance yet lacks the phage-encoded Sda1. Here, we have employed a comprehensive systems biology (genomic, transcriptomic, and proteomic) approach to identify NS88.2 virulence determinants that enhance neutrophil resistance in the non-M1T1 GAS genetic background. Using this approach, we have identified streptococcal collagen-like protein A and general stress protein 24 proteins as NS88.2 determinants that contribute to survival in whole blood and neutrophil resistance in non-M1T1 GAS. This study has revealed new factors that contribute to GAS pathogenicity that may play important roles in resisting innate immune defenses and the development of human invasive infectionsTsatsaronis, J. A., Hollands, A., Cole, J. N., Maamary, P. G., Gillen, C. M., Ben Zakour, N. L., Kotb, M., Nizet, V., Beatson, S. A. Walker, M. J., Sanderson-Smith, M. L. Streptococcal collagen-like protein A and general stress protein 24 are immunomodulating virulence factors of group A Streptococcus

Parameters Governing Invasive Disease Propensity of Non-M1 Serotype Group A Streptococci

Group A Streptococcus (GAS) causes rare but life-threatening syndromes of necrotizing fasciitis and toxic shock-like syndrome in humans. The GAS serotype M1T1 clone has globally disseminated, and mutations in the control of virulence regulatory sensor kinase (covRS) operon correlate with severe invasive disease. Here, a cohort of non-M1 GAS was screened to determine whether mutation in covRS triggers systemic dissemination in divergent M serotypes. A GAS disease model defining parameters governing invasive propensity of differing M types is proposed. The vast majority of GAS infection is benign. Nonetheless, many divergent M types possess limited capacity to cause invasive infection. M1T1 GAS readily switch to a covRS mutant form that is neutrophil resistant and frequently associated with systemic infection. Whilst non-M1 GAS are shown in this study to less frequently accumulate covRS mutations in vivo, such mutants are isolated from invasive infections and exhibit neutrophil resistance and enhanced virulence. The reduced capacity of non-M1 GAS to switch to the hypervirulent covRS mutant form provides an explanation for the comparatively less frequent isolation of non-M1 serotypes from invasive human infections

Tracing the evolutionary history of the pandemic group A streptococcal M1T1 clone

The past 50 years has witnessed the emergence of new viral and bacterial pathogens with global effect on human health. The hyperinvasive group A Streptococcus (GAS) M1T1 clone, first detected in the mid-1980s in the United States, has since disseminated worldwide and remains a major cause of severe invasive human infections. Although much is understood regarding the capacity of this pathogen to cause disease, much less is known of the precise evolutionary events selecting for its emergence. We used high-throughput technologies to sequence a World Health Organization strain collection of serotype M1 GAS and reconstructed its phylogeny based on the analysis of core genome single-nucleotide polymorphisms. We demonstrate that acquisition of a 36-kb genome segment from serotype M12 GAS and the bacteriophage-encoded DNase Sda1 led to increased virulence of the M1T1 precursor and occurred relatively early in the molecular evolutionary history of this strain. The more recent acquisition of the phage-encoded superantigen SpeA is likely to have provided selection advantage for the global dissemination of the M1T1 clone. This study provides an exemplar for the evolution and emergence of virulent clones from microbial populations existing commensally or causing only superficial infection.-Maamary, P. G., Ben Zakour, N. L., Cole, J. N., Hollands, A., Aziz, R. K., Barnett, T. C., Cork, A. J., Henningham, A., Sanderson-Smith, M., McArthur, J. D., Venturini, C., Gillen, C. M., Kirk, J. K., Johnson, D. R., Taylor, W. L., Kaplan, E. L., Kotb, M., Nizet, V., Beatson, S. A., Walker, M. J. Tracing the evolutionary history of the pandemic group A streptococcal M1T1 clone. FASEB J. 26, 4675-4684 (2012). www.fasebj.or