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  • Review Article
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Molecular insight into invasive group A streptococcal disease

Nature Reviews Microbiology volume 9, pages 724–736 (2011)Cite this article

Subjects

Key Points

  • Streptococcus pyogenes, also called group A Streptococcus (GAS), is a Gram-positive bacterial pathogen that naturally infects only humans and is the aetiological agent of several potentially fatal syndromes, including 'flesh-eating disease' (necrotizing fasciitis).

  • The worldwide resurgence of severe invasive GAS infections over the past 30 years is correlated with the global dissemination of the GAS serotype M1T1 clone.

  • Recent work demonstrates that the capacity of GAS serotype M1T1 to cause invasive disease is increased by selection for mutations within the covRS two-component regulator operon. This genetic alteration dramatically changes the transcriptome, resulting in the downregulation of a broad-spectrum cysteine protease, streptococcal pyrogenic exotoxin B (SpeB), and the upregulation of several virulence factors, including the nuclease extracellular streptodornase D (Sda1).

  • Elevated Sda1 nuclease activity enhances the resistance of GAS serotype M1T1 to neutrophil-mediated killing, through the degradation of DNA-based neutrophil extracellular traps, and the absence of SpeB protease activity permits the accumulation of plasmin activity on the GAS cell surface, triggering tissue destruction and systemic spread.

  • GAS uses a repertoire of virulence factors to thwart the host innate immune response, and several of these factors are critical for invasive disease. The switch from non-invasive to hyperinvasive GAS is triggered by particular genetic events, and our increased understanding of this switch has led to a model for the initiation of invasive GAS disease in humans.

  • An understanding of the mechanism by which GAS causes serious invasive infections may augment the development of new-generation therapeutics and provide better health outcomes in the fight against this globally important human pathogen.

Abstract

Streptococcus pyogenes is also known as group A Streptococcus (GAS) and is an important human pathogen that causes considerable morbidity and mortality worldwide. The GAS serotype M1T1 clone is the most frequently isolated serotype from life-threatening invasive (at a sterile site) infections, such as streptococcal toxic shock-like syndrome and necrotizing fasciitis. Here, we describe the virulence factors and newly discovered molecular events that mediate the in vivo changes from non-invasive GAS serotype M1T1 to the invasive phenotype, and review the invasive-disease trigger for non-M1 GAS. Understanding the molecular basis and mechanism of initiation for streptococcal invasive disease may expedite the discovery of novel therapeutic targets for the treatment and control of severe invasive GAS diseases.

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Figure 1: The repertoire of virulence factors expressed by group A Streptococcus serotype M1T1 cells that disable neutrophils.
Figure 2: Proposed model for the initiation and progression of infections with severe invasive group A Streptococcus serotype M1T1.

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Acknowledgements

The authors thank the Australian National Health and Medicine Research Council and the US National Institutes of Health for their funding support.

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Authors and Affiliations

  1. Department of Pediatrics and Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, 92093-0687, California, USA

    Jason N. Cole & Victor Nizet

  2. School of Chemistry and Molecular Biosciences and the Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, 4072, QLD, Australia

    Jason N. Cole, Timothy C. Barnett & Mark J. Walker

  3. Rady Children's Hospital, 3020 Children's Way, San Diego, 92123, California, USA

    Victor Nizet

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Switching mutations observed in covRS in GAS from human isolates and murine models of invasive infections (PDF 399 kb)

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Glossary

Rheumatic fever

An inflammatory disease caused by cross-reactive antibodies that are induced after a streptococcal infection.

Acute glomerulonephritis

Inflammation of the glomeruli of the kidney that follows streptococcal infection and is caused by a build-up of immune complexes.

Necrotizing fasciitis

Commonly known as flesh-eating disease; an infection of the skin, causing destruction of underlying tissues and muscle.

Cathelicidin

A mammalian cationic antimicrobial polypeptide with an important role in host innate immunity and prevention of bacterial infections.

Membrane attack complex

An assemblage of complement proteins that forms pores across cell membranes, resulting in cell death.

α-defensins

A family of mammalian cationic antimicrobial peptides that are secreted by leukocytes and inhibit the activity of serine proteases.

Lysozyme

A mammalian muramidase that catalyses the hydrolysis of bacterial cell walls.

Subcutaneous-chamber infection model

A disease model system that uses micropore teflon diffusion chambers which are subcutaneously implanted into mice to enable the post-infection recovery of bacteria and immune infiltrate.

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Cole, J., Barnett, T., Nizet, V. et al. Molecular insight into invasive group A streptococcal disease. Nat Rev Microbiol 9, 724–736 (2011). https://doi.org/10.1038/nrmicro2648

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