Logo image
Back
A Novel Core Genome-Encoded Superantigen Contributes to Lethality of Community-Associated MRSA Necrotizing Pneumonia
Journal article   Open access   Peer reviewed

A Novel Core Genome-Encoded Superantigen Contributes to Lethality of Community-Associated MRSA Necrotizing Pneumonia

Gillian J Wilson, Keun Seok Seo, Robyn A Cartwright, Timothy Connelley, Olivia N Chuang-Smith, Joseph A Merriman, Caitriona M Guinane, Joo Youn Park, Gregory A Bohach, Patrick M Schlievert, …
PLoS pathogens, Vol.7(10), pp.e1002271-e1002271
10/13/2011
DOI: 10.1371/journal.ppat.1002271
PMCID: PMC3192841
PMID: 22022262
url
https://doi.org/10.1371/journal.ppat.1002271View
Published (Version of record) Open Access

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. Staphylococcus aureus is a global pathogen, responsible for an array of different illnesses in humans and animals. In particular, community-associated methicillin-resistant S. aureus (CA-MRSA) strains of the pandemic USA300 clone have the capacity to cause lethal human necrotizing pneumonia, but the molecular basis for the enhanced virulence remains unclear. Bacterial superantigens (SAg) stimulate T-cell hyper-activation resulting in severe systemic illnesses such as toxic shock syndrome (TSS). However, all S. aureus SAgs identified to date are encoded by mobile genetic elements found only in a proportion of clinical isolates. Here, 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. Importantly, we report that SElX made by pandemic USA300 contributes to lethality in a rabbit model of human necrotizing pneumonia revealing a novel virulence determinant of severe CA-MRSA infection.
 Biology

Details

Metrics

49 Record Views
162 Times Cited - Web of Science
Logo image