Functional Analysis of the TCR Binding Domain of Toxic Shock Syndrome Toxin-1 Predicts Further Diversity in MHC Class II/Superantigen/TCR Ternary Complexes

McCormick, John K.; Tripp, Timothy J.; Llera, Andrea S.; Sundberg, Eric J.; Dinges, Martin M.; Mariuzza, Roy A.; Schlievert, Patrick M.

doi:10.4049/jimmunol.171.3.1385

Cited by 46 publications

(48 citation statements)

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“…They exhibit superantigen activity, stimulating polyclonal T-cell proliferation through coligation between major histocompatibility complex class II molecules on antigen-presenting cells (APC) and the variable portion of the T-cell antigen receptor ␤ chain or ␣ chain (TCR V␤ and TCR V␣, respectively), with no need for prior APC processing (4,13,21,22,37,39). The pattern of V␤/V␣ activation is specific to each superantigen (4,12).…”

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confidence: 99%

Staphylococcal Enterotoxin-Like Toxins U2 and V, Two New Staphylococcal Superantigens Arising from Recombination within the Enterotoxin Gene Cluster

et al. 2006

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To test the hypothesis that the Staphylococcus aureus enterotoxin gene cluster (egc) can generate new enterotoxin genes by recombination, we analyzed the egc locus in a broad panel of 666 clinical isolates of S. aureus. egc was present in 63% of isolates, confirming its high prevalence. The archetypal organization of the egc locus, consisting of five enterotoxin genes plus two pseudogenes, was found in 409 of 421 egc-positive strains. The egc locus was incomplete in a few strains and occasionally harbored an insertion sequence and transposase genes. These strains may represent evolutionary intermediates of the egc locus. One strain with an atypical egc locus produced two new enterotoxins, designated SElV and SElU2, generated by (i) recombination between selm and sei, producing selv, and (ii) a limited deletion in the ent1-ent2 pseudogenes, producing selu2. Recombinant SElV and SElU2 had superantigen activity, as they specifically activated the T-cell families V␤ 6, V␤ 18, and V␤ 21 (SElV) and V␤ 13.2 and V␤ 14 (SElU2). Immunoscope analysis showed a Gaussian CDR3 size distribution of T-cell receptor V␤ chain junctional transcripts of expanded V␤ subsets in toxin-stimulated cultures, reflecting a high level of polyclonality. These data show that egc is indeed capable of generating new superantigen genes through recombination.Staphylococcus aureus produces a large variety of exotoxins, including staphylococcal enterotoxins A to E (SEA to SEE), SEG to SER, and SEU; staphylococcal enterotoxin-like toxins (SEls); and toxic shock syndrome (TSS) toxin-1 (5, 23). These toxins are responsible for specific acute clinical syndromes such as TSS (due to both TSS toxin-1 SEs and SEls), food poisoning (due to SEs), and staphylococcal scarlet fever (considered a mild form of TSS) (10,26,34).All these toxins share certain structural and biological properties, suggesting that they derive from a common ancestor (16,21). They exhibit superantigen activity, stimulating polyclonal T-cell proliferation through coligation between major histocompatibility complex class II molecules on antigen-presenting cells (APC) and the variable portion of the T-cell antigen receptor ␤ chain or ␣ chain (TCR V␤ and TCR V␣, respectively), with no need for prior APC processing (4,13,21,22,37,39). The pattern of V␤/V␣ activation is specific to each superantigen (4, 12). T-cell/APC activation by these toxins leads to the release of various cytokines/lymphokines and interferon, enhances endotoxic shock, and causes T-and B-cell immunosuppression, all of which may undermine the immune response against bacterial infection (5, 10, 25).All the genes encoding these toxins are harbored by mobile elements, including bacteriophages, pathogenicity islands, genomic islands, and plasmids (10,20,28,36). Only the enterotoxin gene cluster (egc) is organized as an operon, consisting of two enterotoxin genes (seg and sei), three enterotoxinlike genes with proven superantigenic activity but not emetic properties (selo, selm and seln), and two pseudogenes (ent1 and -2). This ...

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Staphylococcal Enterotoxin-Like Toxins U2 and V, Two New Staphylococcal Superantigens Arising from Recombination within the Enterotoxin Gene Cluster

et al. 2006

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“…Superantigens cross-bridge MHC class II molecules on antigen-presenting cells with variable region ␤ chains of TCRs (16,35,39,41,42). The consequence of superantigen cross-bridging of T cells with antigenpresenting cells is a massive systemic release of chemokines and cytokines from both the T cells, dominated by Th1 cell activation, and macrophages (16, 35, 39, 41, 42).…”

Section: Discussionmentioning

confidence: 99%

The Innate Immune System Is Activated by Stimulation of Vaginal Epithelial Cells withStaphylococcus aureusand Toxic Shock Syndrome Toxin 1

Ault²,

et al. 2005

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“…In addition, the Schlievert laboratory is approved by the Centers for Disease Control for handling such agents. Staphyloocccus aureus RN4220 (pCE107) was used as the source of the superantigen TSST-1 (26). Staphylococcal strain MNJA was the source of both the superantigen SEB and α-hemolysin (27).…”

Section: Bacteria Exotoxins and Chemicalsmentioning

confidence: 99%

Glycerol Monolaurate Inhibits the Effects of Gram-Positive Select Agents on Eukaryotic Cells

Peterson

Schlievert

2006

Biochemistry

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Many exotoxins of gram positive bacteria, such as superantigens (staphylococcal enterotoxins, toxic shock syndrome toxin-1 [TSST-1], and streptococcal pyrogenic exotoxins) and anthrax toxin are bioterrorism agents that cause diseases by immunostimulation or cytotoxicity. Glycerol monolaurate (GML), a fatty acid monoester found naturally in humans, has been reported to prevent synthesis of gram positive bacterial exotoxins. This study explored the ability of GML to inhibit the effects of exotoxins on mammalian cells and prevent rabbit lethality from TSS. GML (≥10 ug/ml) inhibited superantigen (5 ug/ml) immunoproliferation, as determined by inhibition of 3 H-thymidine incorporation into DNA of human peripheral blood mononuclear cells (1 × 10 6 cells/ml) as well as phospholipase Cγ1, suggesting inhibition of signal transduction. The compound (20 ug/ml) prevented superantigen (100 ug/ml) induced cytokine secretion by human vaginal epithelial cells (HVECs) as measured by ELISA. GML (250 ug) inhibited rabbit lethality due to TSST-1 administered vaginally. GML (10 ug/ml) inhibited HVEC and macrophage cytotoxicity by anthrax toxin, prevented erythrocyte lysis by purified hemolysins (staphylococcal α and β) and culture fluids containing streptococcal and Bacillus anthracis hemolysins, and was non-toxic to mammalian cells (up to 100 ug/ml) and rabbits (250 ug). GML stabilized mammalian cell membranes, as erythrocyte lysis was reduced in the presence of hypotonic aqueous solutions (0 to 0.05 M saline) or staphylococcal α and β-hemolysins when erythrocytes were pretreated with GML. GML may be useful in management of gram positive exotoxin illnesses; its action appears to be membrane stabilization with inhibition of signal transduction.Many gram positive bacterial pathogens produce exotoxins that are potential agents of bioterrorism and contribute to their abilities to cause human diseases (1-3). Examples include anthrax toxin made by Bacillus anthracis (2), superantigens produced by Staphylococcus aureus, including staphylococcal enterotoxins (SEs) 1 and toxic shock syndrome toxin-1 (TSST-1) (1), and superantigens produced by group A streptococci, including streptococcal pyrogenic exotoxins (SPEs) (3). Other exotoxins, such as staphylococcal α and β-hemolysins and streptolysins, are not agents of bioterrorism but have adjunct roles in virulence and can be used as model toxins to study mechanisms of cellular toxicity.

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Functional Analysis of the TCR Binding Domain of Toxic Shock Syndrome Toxin-1 Predicts Further Diversity in MHC Class II/Superantigen/TCR Ternary Complexes

Cited by 46 publications

References 45 publications

Staphylococcal Enterotoxin-Like Toxins U2 and V, Two New Staphylococcal Superantigens Arising from Recombination within the Enterotoxin Gene Cluster

Staphylococcal Enterotoxin-Like Toxins U2 and V, Two New Staphylococcal Superantigens Arising from Recombination within the Enterotoxin Gene Cluster

The Innate Immune System Is Activated by Stimulation of Vaginal Epithelial Cells withStaphylococcus aureusand Toxic Shock Syndrome Toxin 1

Glycerol Monolaurate Inhibits the Effects of Gram-Positive Select Agents on Eukaryotic Cells

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