Superantigenic Activity of emm3 Streptococcus pyogenes Is Abrogated by a Conserved, Naturally Occurring smeZ Mutation

Claire E Turner,Matthew T G Holden,Deborah L W Chong,Mary Sommerlad,Androulla Efstratiou,Brian G Spratt,Shiranee Sriskandan,Frances J Davies,Karen Mcgregor,Leili Farzaneh,Bruno Pichon,Laurence Van Melderen

doi:10.1371/journal.pone.0046376

Claire E Turner, Matthew T G Holden + Show 10 more

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https://doi.org/10.1371/journal.pone.0046376

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Abstract

Streptococcus pyogenes M/emm3 strains have been epidemiologically linked with enhanced infection severity and risk of streptococcal toxic shock syndrome (STSS), a syndrome triggered by superantigenic stimulation of T cells. Comparison of S. pyogenes strains causing STSS demonstrated that emm3 strains were surprisingly less mitogenic than other emm-types (emm1, emm12, emm18, emm28, emm87, emm89) both in vitro and in vivo, indicating poor superantigenic activity. We identified a 13 bp deletion in the superantigen smeZ gene of all emm3 strains tested. The deletion led to a premature stop codon in smeZ, and was not present in other major emm-types tested. Expression of a functional non-M3-smeZ gene successfully enhanced mitogenic activity in emm3 S. pyogenes and also restored mitogenic activity to emm1 and emm89 S. pyogenes strains where the smeZ gene had been disrupted. In contrast, the M3-smeZ gene with the 13 bp deletion could not enhance or restore mitogenicity in any of these S. pyogenes strains, confirming that M3-smeZ is non-functional regardless of strain background. The mutation in M3-smeZ reduced the potential for M3 S. pyogenes to induce cytokines in human tonsil, but not during invasive infection of superantigen-sensitive mice. Notwithstanding epidemiological associations with STSS and disease severity, emm3 strains have inherently poor superantigenicity that is explained by a conserved mutation in smeZ.

Highlights

Streptococcus pyogenes is a major human pathogen, responsible for a wide spectrum of clinical manifestations
To determine whether emm3 S. pyogenes strains might change in phenotype in vivo, during an infection, the superantigenic activity of S. pyogenes strains of different emm-types was compared in vivo using a murine intramuscular infection model; three representative strains were tested for each of the seven streptococcal toxic shock syndrome (STSS) emm-types
Invasive infections due to emm3 S. pyogenes are widely associated with increased disease severity and, in the UK, with risk of STSS compared with other emm-types [12,13,14,15]

Summary

Introduction

Streptococcus pyogenes is a major human pathogen, responsible for a wide spectrum of clinical manifestations. These range from non-invasive and self-limiting to severe, potentially lethal invasive infections complicated by streptococcal toxic shock syndrome (STSS). SMEZ is the most potent streptococcal superantigen described, produced in small amounts compared to other superantigens, [7,8,9,10] and the smeZ gene is present in the majority of S. pyogenes strains, with over 40 different alleles [8,11]. Studies in the USA, Canada, and elsewhere in Europe have highlighted an increased risk of death associated with M/emm S. pyogenes infection [13,14,15,16]

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