PMID:22022262

Citation	Wilson, GJ, Seo, KS, Cartwright, RA, Connelley, T, Chuang-Smith, ON, Merriman, JA, Guinane, CM, Park, JY, Bohach, GA, Schlievert, PM, Morrison, WI and Fitzgerald, JR (2011) A novel core genome-encoded superantigen contributes to lethality of community-associated MRSA necrotizing pneumonia. PLoS Pathog. 7:e1002271
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.
Links	PubMed PMC3192841 Online version:10.1371/journal.ppat.1002271
Keywords	Animals; Cattle; Community-Acquired Infections/epidemiology; Community-Acquired Infections/microbiology; Enterotoxins/genetics; Evolution, Molecular; Genetic Variation; Humans; Interspersed Repetitive Sequences; Methicillin-Resistant Staphylococcus aureus/genetics; Methicillin-Resistant Staphylococcus aureus/immunology; Methicillin-Resistant Staphylococcus aureus/metabolism; Methicillin-Resistant Staphylococcus aureus/pathogenicity; Molecular Sequence Data; Phylogeny; Pneumonia, Staphylococcal/epidemiology; Pneumonia, Staphylococcal/microbiology; Rabbits; Superantigens/genetics; Virulence Factors/genetics
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
STAAE:A6QE83	Contributes to	GO:0009405: pathogenesis	ECO:0000314:		P		Figure 4: SEIX stimulates growth of human and rabbit lymphocytes, showing impact on immune system.	complete CACAO 3665
STAAU:G0Z026		GO:0009405: pathogenesis	ECO:0000315:		P		The experiment compared the ability of wild type, mutant and repaired strains to cause lethal necrotizing pneumonia in a rabbit model. As seen in figure 6c, animals receiving wild type LAC, all 11 rabbits succumbed within 4 days, compared to 2 of 11 receiving LAC Δselx. Importantly, 4 of 4 rabbits infected with the repaired strain LAC Δselx rep succumbed within 4 days. As seen in figure 6d, body temperatures were recorded in the first 24 h of the experiment, and animals receiving strain LAC demonstrated significantly higher body temperatures than animals receiving the SElX-deficient strain LAC Δselx and LAC Δselx rep had wild type levels of pyrogenicity.	complete CACAO 4218
STAAU:G0Z026	involved_in	GO:0009405: pathogenesis	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete

References

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