Population analysis of staphylococcus aureus reveals a cryptic, highly prevalent superantigen selw that contributes to the pathogenesis of bacteremia

Manouk Vrieling, Stephen W. Tuffs, Gonzalo Yebra, Marleen Y. van Smoorenburg, Joana Alves, Amy C. Pickering, Joo Youn Park, Nogi Park, David E. Heinrichs, Lindert Benedictus, Timothy Connelley, Keun Seok Seo, John K. McCormick, J.R. Fitzgerald*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Staphylococcal superantigens (SAgs) are a family of secreted toxins that stimulate T cell activation and are associated with an array of diseases in humans and livestock. Most SAgs produced by Staphylococcus aureus are encoded by mobile genetic elements, such as pathogenicity islands, bacteriophages, and plasmids, in a strain-dependent manner. Here, we carried out a population genomic analysis of >800 staph-ylococcal isolates representing the breadth of S. aureus diversity to investigate the distribution of all 26 identified SAg genes. Up to 14 SAg genes were identified per isolate with the most common gene selw (encoding a putative SAg, SElW) identified in 97% of isolates. Most isolates (62.5%) have a full-length open reading frame of selw with an al-ternative TTG start codon that may have precluded functional characterization of SElW to date. Here, we demonstrate that S. aureus uses the TTG start codon to translate a potent SAg SElW that induces Vβ-specific T cell proliferation, a defining feature of classical SAgs. SElW is the only SAg predicted to be expressed by isolates of the CC398 lineage, an important human and livestock epidemic clone. Deletion of selw in a representative CC398 clinical isolate, S. aureus NM001, resulted in complete loss of T cell mitogenicity in vitro, and in vivo expression of SElW by S. aureus increased the bacterial load in the liver during bloodstream infection of SAg-sensitive HLA-DR4 transgenic mice. Overall, we re-port the characterization of a novel, highly prevalent, and potent SAg that contributes to the pathogenesis of S. aureus infection. IMPORTANCE Staphylococcus aureus is an important human and animal pathogen associated with an array of diseases, including life-threatening necrotizing pneumonia and infective endocarditis. The success of S. aureus as a pathogen has been linked in part to its ability to manipulate the host immune response through the secretion of toxins and immune evasion molecules. The staphylococcal superantigens (SAgs) have been studied for decades, but their role in S. aureus pathogenesis is not well understood, and an ap-preciation for how SAgs manipulate the host immune response to promote infection may be crucial for the development of novel intervention strategies. Here, we character-ized a widely prevalent, previously cryptic, staphylococcal SAg, SElW, that contributes to the severity of S. aureus infections caused by an important epidemic clone of S. aureus CC398. Our findings add to the understanding of staphylococcal SAg diversity and function and provide new insights into the capacity of S. aureus to cause disease.

Original languageEnglish
Article numbere02082-20
Pages (from-to)1-13
Number of pages13
JournalmBio
Volume11
Issue number5
DOIs
Publication statusPublished - 1 Sep 2020
Externally publishedYes

Keywords

  • Evolution
  • Pathogenesis
  • Staphylococcus aureus
  • Superantigens
  • T cells

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