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  • Review Article
  • Published:

Streptolysin S-like virulence factors: the continuing sagA

Nature Reviews Microbiology volume 9, pages 670–681 (2011)Cite this article

Subjects

Key Points

  • The operon that is responsible for the production, processing and export of streptolysin S (SLS), the post-translationally modified cytolytic toxin that causes the β-haemolytic phenotype of group A Streptococcus (GAS; also known as Streptococcus pyogenes), has been identified and characterized.

  • Initial steps have been made towards the elucidation of the structure of SLS.

  • SLS contributes to virulence through soft-tissue damage, its impact on host phagocytes and its role in the translocation of GAS across the epithelial barrier. It also functions as a signalling molecule, and there is speculation that it has a role in iron acquisition.

  • It has become evident that SLS-like toxins are more widespread among streptococci than was previously appreciated; SLS-like toxins are produced by invasive human isolates of β-haemolytic group C and G streptococci, by the zoonotic fish pathogen Streptococcus iniae and by the horse pathogen Streptococcus equi.

  • The SLS-like peptide family has been further extended to beyond the genus Streptococcus following the identification, initially using in silico approaches, of related gene clusters in a number of notorious Gram-positive pathogens, including Listeria monocytogenes, Clostridium botulinum and Staphylococcus aureus.

  • SLS-like peptides belong to a recently defined large class of bioactive natural products known as thiazole/oxazole-modified microcins (TOMMs). TOMMs are characterized by a biosynthetic gene cluster that encodes a small precursor peptide and three adjacent synthetase proteins which serve to introduce thiazole, oxazole and methyloxazole heterocycles onto a ribosomally produced protoxin scaffold.

Abstract

Streptolysin S (SLS) is a potent cytolytic toxin and virulence factor that is produced by nearly all Streptococcus pyogenes strains. Despite a 100-year history of research on this toxin, it has only recently been established that SLS is just one of an extended family of post-translationally modified virulence factors (the SLS-like peptides) that are produced by some streptococci and other Gram-positive pathogens, such as Listeria monocytogenes and Clostridium botulinum. In this Review, we describe the identification, genetics, biochemistry and various functions of SLS. We also discuss the shared features of the virulence-associated SLS-like peptides, as well as their place within the rapidly expanding family of thiazole/oxazole-modified microcins (TOMMs).

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Figure 1: Overview of the production, processing and export of streptolysin S and microcin B17.
Figure 2: Post-translational modification of the streptolysin S precursor.
Figure 3: Summary of the functions of streptolysin S.
Figure 4: Amino acid sequence and operon structure of selected thiazole/oxazole-modified microcins (TOMMs).

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Acknowledgements

Related work in the authors' laboratories is supported by the Irish Government under the National Development Plan; by the Irish Research Council for Science Engineering; by Enterprise Ireland; and by Science Foundation Ireland (SFI), through the Alimentary Pharmabiotic Centre (APC) at University College Cork, Ireland, which is supported by the SFI-funded Centre for Science, Engineering and Technology (SFI-CSET) and provided P.D.C., C.H. and R.P.R. with SFI Principal Investigator funding. E.M.M. has received travel-related funding from SFI and the UK Society for General Microbiology. D.A.M. is supported by the Department of Chemistry and the Institute for Genomic Biology (University of Illinois at Urbana-Champaign, USA).

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Authors and Affiliations

  1. Department of Microbiology, University College Cork, Cork, Ireland

    Evelyn M. Molloy & Colin Hill

  2. Alimentary Pharmabiotic Centre, Cork, Ireland

    Paul D. Cotter, Colin Hill & R. Paul Ross

  3. Teagasc Food Research Centre, Moorepark, Fermoy, Cork, Ireland

    Paul D. Cotter & R. Paul Ross

  4. Departments of Chemistry and Microbiology, and the Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, 61801, Illinois, USA

    Douglas A. Mitchell

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  1. Evelyn M. Molloy
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  2. Paul D. Cotter
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  3. Colin Hill
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  4. Douglas A. Mitchell
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Glossary

Impetigo

An acute and highly contagious infection of the surface layers of the skin, characterized by blisters, pustules and yellowish crusts.

Pharyngitis

Inflammation of the pharynx that can be caused by group A, C and G streptococci; also known as strep throat.

Necrotizing fasciitis

A rare but severe type of soft-tissue infection that can be caused by group A Streptococcus and can destroy the muscles, skin and underlying tissue. It develops when the bacteria enter the body, usually through a minor cut or as a complication of surgery. The mortality rate is high, even with aggressive treatment and powerful antibiotics.

Streptococcal toxic shock syndrome

A rare but extremely severe infection that usually presents in people who have pre-existing skin infections with group A Streptococcus. It has a high mortality rate and is characterized by hypotension and shock. Other symptoms can include kidney impairment, abnormality in blood-clotting ability, acute respiratory distress syndrome, rash and local tissue destruction.

β-haemolysis

A phenotype of complete red blood cell lysis (which appears as yellowing and transparency around and under colonies grown on blood agar medium) that is routinely used as a diagnostic tool for the identification of group A Streptococcus. It is primarily dependent on streptolysin S, with streptolysin O making a minimal contribution.

Streptolysin O

(SLO). A thiol-activated, ∼57-kDa cytolysin that is produced by group A, C and G streptococci and is inhibited by small amounts of cholesterol. As a result of its oxygen-labile nature, SLO is most often responsible for haemolysis under the surface of blood agar, whereas the oxygen-stable streptolysin S results in a zone of clearing surrounding colonies on the surface of blood agar. SLO is antigenic, resulting in SLO-specific antibodies that are useful for documenting recent exposure to group A Streptococcus.

Heterocyclic compound

A compound that has atoms of at least two different elements within its ring structure or structures. With respect to bioorganic chemistry, heterocycles contain one or more carbon atoms and at least one ring member other than carbon.

Carrier molecules

High-molecular-mass molecules, such as non-ionic detergents, albumin, α-lipoprotein, lipoteichoic acid and the RNase-resistant fraction of yeast RNA (RNA core), that can stabilize the haemolytic activity from a streptolysin S (SLS)-producing growing culture or resting cell suspension. SLS is irreversibly inactivated on separation from the carrier or on destruction of the carrier.

Trypan blue

A vital stain that is usually used to selectively colour dead tissue or cells blue. A defining feature of streptolysin S-like peptides is the fact that they are completely inactivated by trypan blue.

Thiazole/oxazole-modified microcins

(TOMMS). A structurally and functionally diverse family of ribosomally produced peptides with post-translationally installed heterocycles derived from Cys, Ser and Thr residues. These modifications rigidify the precursor peptide to endow biological function on the mature natural product.

Chromosome-walking studies

Studies using a technique to identify and characterize regions of DNA by the sequential isolation of overlapping DNA sequences, starting with a known fragment of DNA.

Bacteriocin

A small ribosomally synthesized, heat-stable peptide that is produced by one bacterium and is active against other, either in the same species (narrow spectrum) or across genera (broad spectrum).

Class I bacteriocins

Antimicrobial peptides that are extensively post-translationally modified in their active form, including the lantibiotic (lanthionine-containing) family of bacteriocins.

Microcin B17

(MccB17). A class I bacteriocin that is produced by strains of Escherichia coli and is active against closely related bacterial species, targeting the essential enzyme DNA gyrase.

Lowry-type

A designation for atypical, completely non-haemolytic group A Streptococcus strains, named after the initial isolation of such a strain (by James and McFarland in 1971) from an outbreak of rheumatic fever at Lowry Air Force Base, Colorado, USA.

Quorum sensing

A mechanism of communication between bacteria that requires the production and secretion of a signalling molecule which, when present at or above a critical threshold concentration, induces changes in gene expression in neighbouring cells.

Myositis

A general term for inflammation of the skeletal muscles.

Paracellular invasion

The translocation of pathogens across an epithelial barrier by passing between the host cells.

Natural combinatorial biosynthesis

The production of a library of related compounds by an organism. In the case of some thiazole/oxazole-modified microcin biosynthesis pathways, a single enzyme complex processes numerous substrates that have a common recognition motif but variable structural carboxyl termini. One striking example is the cyanobactin family of natural products.

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Molloy, E., Cotter, P., Hill, C. et al. Streptolysin S-like virulence factors: the continuing sagA. Nat Rev Microbiol 9, 670–681 (2011). https://doi.org/10.1038/nrmicro2624

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