Abstract
Bacterial superantigens (SAg) stimulate T-cell hyper-activation resulting in immune modulation and severe systemic illnesses such as Staphylococcus aureus toxic shock syndrome. However, all known S. aureus SAgs are encoded by mobile genetic elements and are made by only a proportion of strains. Here, we report the discovery of a novel SAg staphylococcal enterotoxin-like toxin X (SElX) encoded in the core genome of 95% of phylogenetically diverse S. aureus strains from human and animal infections, including the epidemic community-associated methicillin-resistant S. aureus (CA-MRSA) USA300 clone. SElX has a unique predicted structure characterized by a truncated SAg B-domain, but exhibits the characteristic biological activities of a SAg including Vβ-specific T-cell mitogenicity, pyrogenicity and endotoxin enhancement. In addition, SElX is expressed by clinical isolates in vitro, and during human, bovine, and ovine infections, consistent with a broad role in S. aureus infections of multiple host species. Phylogenetic analysis suggests that the selx gene was acquired horizontally by a progenitor of the S. aureus species, followed by allelic diversification by point mutation and assortative recombination resulting in at least 17 different alleles among the major pathogenic clones. Of note, SElX variants made by human- or ruminant-specific S. aureus clones demonstrated overlapping but distinct Vβ activation profiles for human and bovine lymphocytes, indicating functional diversification of SElX in different host species. Importantly, SElX made by CA-MRSA USA300 contributed to lethality in a rabbit model of necrotizing pneumonia revealing a novel virulence determinant of CA-MRSA disease pathogenesis. Taken together, we report the discovery and characterization of a unique core genome-encoded superantigen, providing new insights into the evolution of pathogenic S. aureus and the molecular basis for severe infections caused by the CA-MRSA USA300 epidemic clone.
Highlights
Staphylococcus aureus is responsible for an array of diseases including life-threatening toxinoses such as toxic shock syndrome (TSS) and necrotizing pneumonia
We report the discovery of a unique core genome-encoded SAg (SElX) which was acquired by an ancestor of the S. aureus species and which has undergone genetic and functional diversification in pathogenic clones infecting humans and animals
We report that staphylococcal enterotoxin-like toxin X (SElX) made by pandemic USA300 contributes to lethality in a rabbit model of human necrotizing pneumonia revealing a novel virulence determinant of severe community-associated methicillin-resistant S. aureus (CA-MRSA) infection
Summary
Staphylococcus aureus is responsible for an array of diseases including life-threatening toxinoses such as toxic shock syndrome (TSS) and necrotizing pneumonia. Characterized SAgs are small secreted proteins of 20 to 28 kDa in size, which share similar biochemical, structural, and immunobiological properties [1,2], but can be differentiated into 4 distinct subgroups according to their phylogenetic relatedness [3,4,5]. They share a compact 2-domain protein structure consisting of domain A which contains a long central a-helix and a C-terminal b-grasp motif, and the smaller domain B which contains an N-terminal oligonucleotide-oligosaccharide binding (OB) fold [1,2,5,6]. SAgs have the capacity to cause immune suppression by inducing T-cell anergy, and may contribute to bacterial persistence during chronic infection [10]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
