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PubMed1997

Oligosaccharide-derivatized dendrimers: defined multivalent inhibitors of the adherence of the cholera toxin B subunit and the heat labile enterotoxin of E. coli to GM1.

Poly(propylene imine) dendrimers having four or eight primary amino groups and a Starburst (PAMAM) dendrimer having eight primary amino groups were used as core molecules, to which phenylisothiocyanate derivatized (PITC) galbeta1-3galNAcbeta1-4[sialic acid alpha2-3]-galbeta1-4glc (oligo-GM1) residues were covalently attached to yield multivalent oligosaccharides. The synthesis of the oligo-GM1-PITC derivatized dendrimers was monitored using high performance thin layer chromatography, infrared spectroscopy, sialic acid content, and mass spectroscopy. The ability of multivalent oligo-GM1-PITC dendrimers to inhibit the binding of 125I-labeled cholera toxin B subunit and the heat labile enterotoxin of E. coli to GM1-coated microtiter wells was determined. IC50s obtained for the oligo-GM1-PITC dendrimers, GM1, and the oligosaccharide moiety of GM1 indicated that the derivatized dendrimers inhibited binding of the choleragenoid and the heat labile enterotoxin to GM1-coated wells at a molar concentration five- to 15-fold lower than native GM1 and more than 1,000-fold lower than that of the free oligosaccharide.

Animals↗

PubMed2000

Severe atopic dermatitis is associated with sensitization to staphylococcal enterotoxin B (SEB).

BACKGROUND: Staphylococcus aureus has been identified as a possible trigger factor in atopic dermatitis (AD). Some 30-60% of S. aureus strains isolated from patients with AD are able to produce exotoxins with superantigenic properties, mostly staphylococcal enterotoxins A, B, C, and D (SEA-D) and toxic shock syndrome toxin-1 (TSST-1). Recently, it was demonstrated that the presence of IgE antibodies to SEA and SEB is correlated with the severity of skin lesions in children with AD. To determine the relevance of staphylococcal enterotoxins in adult patients with AD, we investigated the relationship between the severity of skin lesions and sensitization to SEA and SEB. METHODS: Clinical severity was determined by the SCORAD index. Circulating IgE antibodies to SEA and SEB, serum eosinophil cationic protein (ECP) levels, and urine eosinophil protein X (EPX) levels were measured. RESULTS: The skin condition was significantly worse in patients sensitized to SEB than in unsensitized patients. Serum ECP and urine EPX levels were found to be significantly higher in SEB-sensitized patients, confirming the higher degree of cutaneous inflammation. CONCLUSIONS: Our results demonstrate a relationship between severity of skin lesions and sensitization to SEB in adult patients with AD, but a relationship between disease activity and sensitization to SEA could not be shown.

Adolescent↗

PubMed2000

Comparison of serum specific IgE antibodies to staphylococcal enterotoxins between atopic children with and without atopic dermatitis.

BACKGROUND: The skin of patients with atopic dermatitis (AD) exhibits a striking susceptibility to colonization and infection by Staphylococcus aureus. The exotoxins secreted by S. aureus can act as superantigens and classic allergens, inducing the production of functionally relevant specific IgE antibodies. The aim of this study was to compare the levels and positive rates of serum staphylococcal enterotoxin A (SEA)- and staphylococcal enterotoxin B (SEB)-specific IgE between atopic children with and without AD. METHODS: Sixty children with AD, 55 children with respiratory allergy without AD, and 24 nonatopic healthy children were studied. The levels and positive rates of serum SEA- and SEB-specific IgE were compared among three groups. The correlation between the levels or positive rates of serum SEA/SEB-specific IgE and the severity of AD or the presence of previous skin infections was studied. RESULTS: The children with AD had significantly higher levels and positive rates of serum SEA- and SEB-specific IgE than the atopic children without AD (P < 0.001) and the nonatopic children (P < 0.001). There was no significant difference in the levels and positive rates of serum SEA- and SEB-specific IgE between the atopic children without AD and the nonatopic children. With or without adjustment for the potential confounding effect of total serum IgE levels, the levels and positive rates of serum SEA- and SEB-specific IgE were significantly correlated with severity of AD (P <0.005), but they were not significantly different between AD children with and without previous skin infections. CONCLUSIONS: SEA and SEB may contribute to chronic inflammation and exacerbation of AD through the IgE-mediated immune response.

Adolescent↗

PubMed1989

High-affinity binding of staphylococcal enterotoxins A and B to HLA-DR.

Staphylococcal enterotoxins A-E (refs 1-3), toxic shock toxin (TST-1) (ref. 1), a product of Mycoplasma arthritidis and the Mls antigens provoke dramatic T-cell responses. All are extremely potent polyclonal mitogens stimulating a large proportion of both murine and human CD4+ and CD8+T cells although activity is tightly restricted by major histocompatibility complex (MHC) class II antigens. The murine T-cell response to staphylococcal enterotoxin B (SEB) has recently been shown to involve only those T cells expressing T-cell receptor V beta 3, 8.1, 8.2 and 8.3 domains, a situation which closely mimics the response to Mls antigens. This paper examines the initial events in SEA and SEB T-cell activation and shows that MHC restriction results from a direct high affinity binding by intact SEA and SEB to the same site on MHC class II HLA-DR antigens.

Binding Sites↗

PubMed1991

Programmed cell death and extrathymic reduction of Vbeta8+ CD4+ T cells in mice tolerant to Staphylococcus aureus enterotoxin B.

Clonal deletion and functional inactivation of self-reactive cells have been invoked as mechanisms underlying intrathymic development of T-cell tolerance. The relative importance of these mechanisms in the development of tolerance of more mature, peripheral T cells either to self or to exogenous antigens is unclear, although recent data relate the development of T-cell tolerance in the periphery to clonal anergy. We have now investigated the induction of extrathymic tolerance using BALB/c mice that were made tolerant to Staphylococcus aureus enterotoxin B, a superantigen which specifically interacts in such mice with T cells bearing V beta 8 antigen receptors. Both euthymic and athymic mice made tolerant to S. aureus enterotoxin B had a markedly reduced number of V beta 8.1,2+ CD4+ peripheral T cells. This reduction was accompanied by genomic DNA fragmentation that is associated with cell death. These results indicate that a deletional mechanism can contribute to the induction of T-cell tolerance in peripheral lymphoid cells.

Animals↗

PubMed1992

Lactose binding to heat-labile enterotoxin revealed by X-ray crystallography.

Recognition of the oligosaccharide portion of ganglioside GM1 in membranes of target cells by the heat-labile enterotoxin from Escherichia coli is the crucial first step in its pathogenesis, as it is for the closely related cholera toxin. These toxins have five B subunits, which are essential for GM1 binding, and a single A subunit, which needs to be nicked by proteolysis and reduced, yielding an A1-'enzyme' and an A2-'linker' peptide. A1 is translocated across the membrane of intestinal epithelial cells, possibly after endocytosis, upon which it ADP-ribosylates the G protein Gs alpha. The mechanism of binding and translocation of these toxins has been extensively investigated, but how the protein is orientated on binding is still not clear. Knowing the precise arrangement of the ganglioside binding sites of the toxins will be useful for designing drugs against the diarrhoeal diseases caused by organisms secreting these toxins and in the development of oral vaccines against them. We present here the three-dimensional structure of the E. coli heat-labile enterotoxin complexed with lactose. This reveals the location of the binding site of the terminal galactose of GM1, which is consistent with toxin binding to the target cell with its A1 fragment pointing away from the membrane. A small helix is identified at the carboxy terminus of A2 which emerges through the central pore of the B subunits and probably comes into contact with the membrane upon binding, whereas the A1 subunit is flexible with respect to the B pentamer.

Bacterial Toxins↗

PubMed1992

Crystal structure of staphylococcal enterotoxin B, a superantigen.

The three-dimensional structure of staphylococcal enterotoxin B, which is both a toxin and a super-antigen, has been determined to a resolution of 2.5 A. The unusual main-chain fold containing two domains may represent a general motif adopted by all staphylococcal enterotoxins. The T-cell receptor binding site encompasses a shallow cavity formed by both domains. The MHCII molecule binds to an adjacent site. Another cavity with possible biological activity was also identified.

Animals↗

PubMed1996

A sigma ligand, SR 31747A, potently modulates Staphylococcal enterotoxin B-induced cytokine production in mice.

Sigma receptors originally described in distinct regions of the central nervous system are expressed on cells of the immune system. A sigma ligand, SR 31747A, was observed here to inhibit in vitro the Staphylococcal enterotoxin B (SEB)-driven lymphocyte proliferation. In mice, the drug confers a potent protection against the lethality induced by SEB, stimulates the SEB-induced serum release of interleukin (IL)-10 and inhibits at the same time the systemic release of IL-2, IL-4, granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-6 and tumour necrosis factor-alpha (TNF-alpha). The enhancement of IL-10 production by this compound is also effective in nude mice treated with SEB, indicating that IL-10 of T-cell origin is not involved in this process. The finding that a sigma ligand protects against the SEB-induced toxicity provides insights into the clinical use of this family of compounds, particularly in food poisoning and septic shock where Staphylococcal enterotoxins are involved. The observation that this compound stimulates IL-10 synthesis indicates that it could be a potent regulatory agent of chronic inflammatory diseases.

Animals↗

PubMed1998

Staphylococcal enterotoxin B inhibits the production of interleukin-4 in a human mast-cell line HMC-1.

Staphylococcal enterotoxins belong to the recently characterized group of immunocytotropic bacterial superantigens that are potent mitogens for human T cells. Superantigens are presented, but without intracellular processing, to T cells by monocyte/macrophages, Langerhans' cells and keratinocytes via the class II major histocompatibility complex (MHC) molecules. Superantigens have been demonstrated to act as potent inducers of several proinflammatory cytokines in the antigen-presenting cells such as interleukin-1 (IL-1) and tumour necrosis factor-alpha (TNF-alpha). As mast cells participate in the pathogenesis of several inflammatory skin disorders such as atopic dermatitis (AD), which is often aggravated by staphylococcal infections, we studied the effect of staphylococcal enterotoxin B (SEB) superantigen on the histamine release and IL-4 expression in a human mast-cell line (HMC-1). Incubation of SEB (50 micrograms/ml) with HMC-1 cells for 45 min, could not induce any histamine release. The HMC-1 cells were also stimulated with various concentrations of SEB (0, 1, 10, 20, 50 micrograms/ml) for 1, 2, 3 and 4 days. Clear dose-dependent inhibition of IL-4 protein production and release was observed on day 4 without any observed effect on cell viability. Compared with unstimulated HMC-1 cells, after 50 micrograms/ml SEB stimulation, the IL-4 mRNA levels decreased steadily in the 2, 6, 18 and 24 hr samples in repeated experiments as measured with the reverse transcription polymerase chain reaction (RT-PCR) method. In comparison, a biphasic decrease in TNF-alpha expression was found. Our results show that an human leukaemic mast cells, superantigen stimulation downregulates the production of IL-4.

Cell Degranulation↗

PubMed1998

Diarrhoeal enterotoxin production by psychrotrophic Baccillus cereus present in reconstituted milk-based infant formulae (MIF).

One hundred reconstituted milk-based infant formulae (MIF) representative of 10 leading brands available in many European Economic Community countries were examined for psychrotrophic Bacillus cereus and for the presence of diarrhoeal enterotoxin. Of the 38 B. cereus isolates recovered from MIF, one, four and 16 strains grew at 4, 6 and 8 degrees C after 15 d. One (2.6%), two (5.3%) and six (15.8%) of the isolates were identified as potential psychrotrophic food poisoning strains as they were both enterotoxigenic and exhibited good growth at 4, 6 and 8 degrees C, respectively. Enterotoxin was not detected in MIF in which less than 5.36 log10 cfu of B. cereus ml-1 had grown. While psychrotrophic enterotoxigenic B. cereus strains occur occasionally in MIF, brief storage of reconstituted MIF at the recommended refrigeration temperature of 4 degrees C will allow this product to remain safe for consumption.

Animals↗

PubMed1999

Production of enterotoxins and toxic shock syndrome toxin by Staphylococcus aureus isolated from bovine mastitis in Brazil.

The production of toxic shock syndrome toxin 1 (TSST-1) and enterotoxins (SE) A, B, C and D by bovine mastitis isolates of Staphylococcus aureus was evaluated by immunodiffusion using the Optimum-Sensitivity Plate method. S. aureus strains were isolated from bovine mastitis in 23 dairy herds in the state of Minas Gerais, Brazil, during 1994-9. Of 127 isolates, 83 (65.04%) produced one or several toxins, and among them production of SE was found in 54 (43.0%) isolates, of which 1138 (29.09%) secreted enterotoxin identified as type D. TSST-1 was found in 5829 (45.723.0%) isolates.

Animals↗

PubMed1999

Rolipram inhibits staphylococcal enterotoxin B-mediated induction of the human skin-homing receptor on T lymphocytes.

The cutaneous lymphocyte-associated antigen defines T lymphocytes with cutaneous tropism under inflammatory conditions. Bacterial infections participate in cutaneous inflammations, such as atopic dermatitis or psoriasis. Bacterial superantigens, such as staphylococcal enterotoxin B, can activate peripheral blood mononuclear cells to induce effector T cells bearing the T cell skin homing receptor cutaneous lymphocyte-associated antigen via enhancement of interleukin-12 production. We have identified and characterized the anti-inflammatory effects of different phosphodiesterase inhibitors on this system. Our data indicate that the selective type 4 phosphodiesterase inhibitor rolipram inhibits the Staphylococcal enterotoxin B-mediated generation of cutaneous lymphocyte-associated antigen positive CD3+ cells from peripheral blood mononuclear cells by reducing interleukin-12 production in a concentration-dependent manner. Conversely, type 3 phosphodiesterase or type 5 phosphodiesterase selective inhibitors were not effective. The rolipram inhibitory effect was on interleukin-12 production, as exogenously added interleukin-12 could revert rolipram suppression. These results suggest that selective type 4 phosphodiesterase inhibition may have beneficial effects on T cell mediated skin inflammatory processes characterized by the presence of bacterial infections, that are thought to exacerbate ongoing skin inflammation.

Animals↗

PubMed1990

Induction of specific clonal anergy in human T lymphocytes by Staphylococcus aureus enterotoxins.

The exotoxins produced by certain strains of Staphylococcus aureus are able to stimulate powerful polyclonal proliferative responses and to induce nonresponsiveness by clonal deletion of T lymphocytes expressing the appropriate T-cell antigen receptor V beta gene products. This paper examines the ability of S. aureus enterotoxins to modulate the responsiveness of human CD4+ T lymphocytes with defined antigen specificity. It was observed that certain S. aureus toxins were able to activate and induce anergy in hemagglutinin-reactive T cells expressing V beta 3+ elements. After exposure to S. aureus enterotoxins A, B, and D in the absence of antigen-presenting cells, the T cells failed to respond to their natural ligand presented in an immunogenic form, despite enhanced proliferation to exogenous interleukin 2. The S. aureus toxin-induced anergy was associated with modulation of T-cell membrane receptors; down-regulation of the T-cell antigen receptor was concomitant with enhanced expression of CD2 and CD25. Interestingly, CD28 was increased only on stimulation, suggesting this protein may be differentially expressed by activated and anergic T cells. These results indicate that bacterial toxins are able to induce antigen-specific nonresponsiveness in human T cells, the application of which may be relevant in the regulation of T cells expressing a particular family of V beta gene products.

Antigens, CD↗

PubMed1991

In vivo T-cell activation by staphylococcal enterotoxin B prevents outgrowth of a malignant tumor.

Treatment of T cells with staphylococcal enterotoxins in vitro is known to activate T cells in a subset restricted manner based on beta-chain variable region (V beta) gene expression. In particular, staphylococcal enterotoxin B (SEB) activates T cells bearing V beta 7 or V beta 8. We examined the ability of SEB to activate T cells in vivo. Treatment of C3H mice with doses of SEB ranging from 5 to 250 micrograms resulted in a dose-dependent activation of V beta 8+ T cells as reflected by increased interleukin 2 receptor (IL-2R) expression, proliferation to exogenous IL-2 and allogeneic cells, and production of gamma interferon. SEB also caused proliferation of the CD8+ subset of V beta 8+ cells in vivo. Thus, T-cell activation by SEB in vivo appears to be specific since V beta 2+ cells (non-SEB reactive) did not show increases in IL-2R expression similar to those seen with V beta 8+ cells nor did they proliferate. We then studied the ability of these activated cells to potentiate the immune response to a malignant progressor tumor. Treatment of C3H mice with 50 micrograms of SEB at the time of inoculation with tumor fragments resulted in a statistically significant decrease in the frequency of tumor outgrowth. These data demonstrate that treatment of C3H mice with SEB results in specific activation of V beta 8+ cells in vivo and that these activated cells are capable of preventing the outgrowth of a malignant tumor.

Animals↗

PubMed1992

T-cell antigen receptor binding sites for the microbial superantigen staphylococcal enterotoxin A.

We have examined the interaction of the microbial superantigen staphylococcal enterotoxin A (SEA) with peptides corresponding to overlapping regions of the T-cell antigen receptor beta chain variable region V beta 3. SEA is known to stimulate murine T cells bearing certain V beta elements, among them V beta 3. Five peptides were synthesized representing amino acids 1-24, 20-44, 39-60, 57-77, and 74-95 of V beta 3. We demonstrate here that soluble V beta 3-bearing beta chains can bind to a complex of SEA and major histocompatibility complex class II and that the synthetic peptide V beta 3-(57-77) blocked this interaction. The peptide V beta 3-(57-77) also inhibited SEA-induced interferon-gamma production and SEA-induced proliferation of B10.BR spleen cells. Conversely, the peptide corresponding to amino acids 57-77 of V beta 8.2, a V beta element that is not recognized by SEA, decreased staphylococcal enterotoxin C-2-induced proliferation but did not affect SEA-induced proliferation. The peptide inhibition of SEA-induced function was due at least in part to inhibition of V beta 3-bearing T-cell activity, since the percentage of T cells reactive with an anti-V beta 3 monoclonal antibody was significantly reduced by V beta 3-(57-77). These data suggest that the region of V beta 3 encompassing amino acids 57-77 is an area that displays the appropriate sequence and conformation for binding of the SEA molecule and blocking of the resultant interaction with the T-cell antigen receptor.

Amino Acid Sequence↗

PubMed1992

Distinct binding sites on HLA-DR for invariant chain and staphylococcal enterotoxins.

During biosynthesis, class II molecules of the major histocompatibility complex exist as complexes of the polymorphic alpha and beta chains in association with trimers of the invariant chain (Ii). The nonpolymorphic Ii contains sequences necessary for proper targeting of class II to endosomal compartments, where Ii is degraded. Ii also prevents the premature association of antigenic peptides with class II molecules. It is not known whether the effect of Ii on peptide binding extends to other ligands of class II, specifically exogenous superantigens. Cells expressing a mutant Ii molecule stably associated with HLA-DR at the cell surface were tested for their ability to interact with staphylococcal toxins. Most toxins (staphylococcal enterotoxins A-E and exfoliative toxin) were found to bind to cells expressing this alpha beta Ii complex with levels comparable to cells expressing only alpha beta chains at the cell surface. Cells expressing surface alpha beta Ii complexes stimulated polyclonal populations of peripheral blood T cells in association with these toxins. Binding of toxic shock syndrome toxin (TSST) and subsequent stimulation of T cells were reduced by the presence of the Ii. This reduction was not due to an alteration in the repertoire of T cells responding to TSST in the presence of Ii. Data from experiments with a T-cell clone suggest that interactions between class II molecules and T-cell antigen receptors occur during staphylococcal enterotoxin-mediated stimulation and that surface Ii does not interfere with such interactions.

Antigens, Bacterial↗

PubMed1993

Calcium influx mediated by the Escherichia coli heat-stable enterotoxin B (STB).

The heat-stable enterotoxin B (STB) of Escherichia coli is a 48-amino acid extracellular peptide that induces rapid fluid accumulation in animal intestinal models. Unlike other E. coli enterotoxins that elicit cAMP or cGMP responses in the gut [heat-labile toxin (LT) and heat-stable toxin A (STA), respectively], STB induces fluid loss by an undefined mechanism that is independent of cyclic nucleotide elevation. Here we studied the effects of STB on intracellular calcium concentration ([Ca2+]i), another known mediator of intestinal ion and fluid movement. Ca2+ and pH measurements were performed on different cell types including Madin-Darby canine kidney (MDCK), HT-29/C1 intestinal epithelial cells, and primary rat pituitary cells. Ca2+ and pH determinations were performed by simultaneous real-time fluorescence imaging at four emission wavelengths. This allowed dual imaging of the Ca(2+)- and pH-specific ratio dyes (indo-1 and SNARF-1, respectively). STB treatment induced a dose-dependent increase in [Ca2+]i with virtually no effect on internal pH in all of the cell types tested. STB-mediated [Ca2+]i elevation was not inhibited by drugs that block voltage-gated Ca2+ channels including nitrendipine, verapamil (L-type), omega-conotoxin (N-type), and Ni2+ (T-type). The increase in [Ca2+]i was dependent on a source of extracellular Ca2+ and was not affected by prior treatment of MDCK cells with thapsigargin or cyclopiazonic acid, agents that deplete and block internal Ca2+ stores. In contrast to these results, somatostatin and pertussis toxin pretreatment of MDCK cells completely blocked the STB-induced increase in [Ca2+]i. Taken together, these data suggest that STB opens a GTP-binding regulatory protein-linked receptor-operated Ca2+ channel in the plasma membrane. The nature of the STB-sensitive Ca2+ channel is presently under investigation.

Animals↗

PubMed2000

Extracellular DsbA-insensitive folding of Escherichia coli heat-stable enterotoxin STa in vitro.

To study the folding of human Escherichia coli heat-stable enterotoxin STh, we used the major protein subunit of CS31A fimbriae (ClpG) as a marker of STh secretion and a provider of a signal peptide. We established that STh genetically fused to the N or C terminus of ClpG was able to mobilize ClpG to the culture supernatant while still retaining full enterotoxicity. These features indicate that the STh activity was not altered by the chimeric structure and suggest that spatial conformation of STh in the fusion is close to that of the native toxin, thus permitting recognition and activation of the intestinal STh receptor in vivo. In contrast to other studies, we showed that disulfide bond formation did not occur in the periplasm through the DsbA pathway and that there was no correlation between DsbA and secretion, folding, or activity. This discrepancy was not attributable to the chimeric nature of STh since there was no effect of dsbA or dsbB mutations on secretion and activity of recombinant STh from which ClpG had been deleted. Periplasmic and lysate fractions of dsbA(+) and dsbA(-) cells did not have any STh activity. In addition, the STh chimera was exclusively found in an inactive reduced form intracellularly and in an active oxidized form extracellularly, irrespective of the dsbA background. Subsequently, a time course experiment in regard to the secretion of STh from both dsbA(+) and dsbA(-) cells indicated that the enterotoxin activity (proper folding) in the extracellular milieu increased with time. Overall, these findings provide evidence that STa toxins can be cell-released in an unfolded state before being completely disulfide-bonded outside the cell.

Amino Acid Sequence↗