Agonist Properties of a Microbial Superantigen Peptide

Pontzer, Carol H.; Griggs, Nathan D.; Johnson, Howard M.

doi:10.1006/bbrc.1993.1751

Cited by 14 publications

(9 citation statements)

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“…Although, as expected, both fragments were highly immunogenic in mice and produced the same ELISA titers against SEB as the genetically engineered vaccine candidate produced, neither fragment produced neutralizing antibody, and vaccination with these fragments did not protect against the WT BSAg. Peptides corresponding to different portions of BSAgs have been used with limited success to modulate immune responses (9,13,14). Recently, carboxyl-terminal peptides, including sequences highly conserved among BSAgs, have also been identified which provided extensive cross-protection against challenge with a number of BSAgs in rabbit and sensitized-mouse models (1,22).…”

Section: Discussionmentioning

confidence: 99%

Protection against Bacterial Superantigen Staphylococcal Enterotoxin B by Passive Vaccination

2002

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We investigated the ability of two overlapping fragments of staphylococcal enterotoxin B (SEB), which encompass the whole toxin, to induce protection and also examined if passive transfer of chicken anti-SEB antibodies raised against the holotoxin could protect rhesus monkeys against aerosolized SEB. Although both fragments of SEB were highly immunogenic, the fragments failed to protect mice whether they were injected separately or injected together. Passive transfer of antibody generated in chickens (immunoglobulin Y [IgY]) against the whole toxin suppressed cytokine responses and was protective in mice. All rhesus monkeys treated with the IgY specific for SEB up to 4 h after challenge survived lethal SEB aerosol exposure. These findings suggest that large fragments of SEB may not be ideal for productive vaccination, but passive transfer of SEB-specific antibodies protects nonhuman primates against lethal aerosol challenge. Thus, antibodies raised in chickens against the holotoxin may have potential therapeutic value within a therapeutic window of opportunity after SEB encounter.The staphylococcal enterotoxins (SEs) are a family of bacterial superantigens (BSAgs) produced by Staphylococcus aureus. These protein toxins bind to major histocompatibility complex (MHC) class II molecules and, with less affinity, to the T-cell antigen receptors without MHC molecules, resulting in intense stimulation of the immune system that triggers acute pathological effects (8,11,20). BSAgs are associated with several serious diseases, including food poisoning, bacterial arthritis, and lethal toxic shock syndrome (7, 12). In addition, viral infections may predispose patients to toxic shock syndrome caused by BSAg-associated secondary streptococcal or staphylococcal infection (4, 16). The main component of the intoxication process depends on the ability of BSAgs to activate a large number of T cells, causing a massive release of inflammatory cytokines (7,20).Because SEs can cause severe pathologies and are considered potential biowarfare agents, there is considerable need to develop vaccines and therapeutic approaches capable of eliminating their toxicity. Previously, we showed that genetically altered staphylococcal enterotoxin A (SEA) and SEB inactivated by a site-directed mutagenesis strategy and lacking superantigenic effects were highly immunogenic in mice and rhesus monkeys (2,20,21). These recombinant vaccines elicited neutralizing antibodies that were detected in in vitro surrogate assays and protected the vaccinees against wild-type (WT) SEA and SEB. The experiments reported here were initiated to find fragments of SEB that could be used for vaccine purposes and to examine the suitability of passive immunotherapy with anti-SEB antibody developed in chickens (immunoglobulin Y [IgY]) against lethal effects of SEB in mice and rhesus monkeys. The data presented here highlight a useful therapeutic maneuver that could be employed to reduce or eliminate BSAg-mediated toxic shock syndrome and possibly other associated disorders. M...

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Section: Discussionmentioning

confidence: 99%

Protection against Bacterial Superantigen Staphylococcal Enterotoxin B by Passive Vaccination

2002

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“…Different methods have been used to determine the sites by which SAGs interact with both MHC class II molecules and TCR. These include peptide binding and inhibition assays (24,27), site-directed mutagenesis, the use of recombinant proteins BALB/C splenic cells (3.5 ϫ 10 5 /well) and purified human PBMC cells from donor 1 (HD1) or donor 2 (HD2) (10 5 /well each) were stimulated for 72 h with different SEAs in the presence or absence of anti-SEA MAbs. Cellular proliferation was then determined by measuring [ 3 H]thymidine incorporation.…”

Section: Discussionmentioning

confidence: 99%

“…Some investigators localized the mitogenic activity of SEs to the N-terminal portion (5,18,24) while others blocked mitogenic function by deleting nine amino acid (aa) residues from the C-terminal region (22) or changed the V␤ specificity by mutation of one aa residue from this region (23). Several studies have also localized MHC class II binding to the amino terminus (13,18,25,26), but others have attributed MHC class II binding to the C-terminal portion of SEs (15,27). Recently, the structures of SE type B (SEB) and toxic shock syndrome toxin and their complexes with MHC class II molecules were elucidated by X-ray crystallography and the residues involved in these interactions identified (2,17,19,32).…”

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confidence: 99%

Mapping of Staphylococcal Enterotoxin A Functional Binding Sites and Presentation by Monoclonal Antibodies and Fusion Proteins

Mahana

1999

Infect Immun

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Staphylococal enterotoxins (SE) bind with high affinity to major histocompatibility complex (MHC) class II proteins and stimulate large number of T cells via the V␤ region of the T-cell receptor (TCR).To map the epitopes of SE type A (SEA) involved in MHC binding and cell proliferation, 20 specific anti-SEA monoclonal antibodies (MAbs) and two large glutathione S-transferase fusion proteins corresponding to the amino and carboxy termini, respectively, of SEA were used. The functionality of these antibodies was tested, by MHC binding inhibition, interleukin-2 production, and T-cell proliferation assays. Moreover, I studied the ability of the MAbs to present SEA in vitro to human and murine cells and their reactivity with the two fusion proteins. This study showed that all of the MAbs have a defined effect on one or both immunological properties of SEA and were able to present SEA to human and murine cells. However, one MAb (4H8) recognized SEA but without any interference with its biological activities. When the MAbs were tested to react with the two fusion proteins representing the SEA molecule, all of the MAbs were negative except for two. These results confirmed the presence of two functionally different binding sites of SEA with MHC class II molecules and the importance of the disulfide loop for the mitogenic activity of SEA. I further demonstrated that MAbs can present SEA to immune cells independent of the site recognized by the antibody and that the integrity of the SEA molecule is very important for its functions.

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“…Peptides derived from SAg protein sequences have been successfully used to map domains that are involved in T cell receptor and MHC class II binding, stimulation of cytokine production, and T cell proliferation (Pontzer et al, 1992(Pontzer et al, , 1993Jett et al, 1994;Kum et al, 2000). Several groups have sought to develop protection against toxic shock and other SAg-induced symptoms by injecting peptides derived from SAg to both interfere with SAg binding to the MHC class II and T cell receptors as well as to elicit antibodies that can recognize and clear SAgs from the body.…”

Section: Sag-derived Peptides Provide Protection Against Toxic Shockmentioning

confidence: 99%

Therapeutic approaches to superantigen‐based diseases: a review

Hong-Geller

Gupta

2003

J of Molecular Recognition

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Superantigens secreted by the bacterial pathogen Staphyloccocus aureus are extremely potent toxins that overstimulate the host immune system by binding to the MHC class II and T cell receptors and activating a large population of T cells. Superantigen infection has been shown to be the causative agents in acute diseases, food poisoning and toxic shock syndrome, and in more chronic conditions such as inflammatory skin diseases. In addition to the toll on public health, S. aureus superantigens also represent a potential biothreat to our national security. To address these risks, a number of different therapeutic strategies have been developed that target different aspects of the pathogenic mechanism of S. aureus and superantigen infection. These therapies, which encompass strategies as diverse as production of neutralizing antibodies, inhibitory peptide/receptor design and blockage of superantigen gene transcription, are being tested for treatment of established S. aureus infections in pre- and post-exposure scenarios. In this review, we will describe these different strategies and their efficacies in inhibition of superantigen-induced effects in the host, and present the future outlook for successfully producing therapies for superantigen-based disease.

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Agonist Properties of a Microbial Superantigen Peptide

Cited by 14 publications

References 0 publications

Protection against Bacterial Superantigen Staphylococcal Enterotoxin B by Passive Vaccination

Protection against Bacterial Superantigen Staphylococcal Enterotoxin B by Passive Vaccination

Mapping of Staphylococcal Enterotoxin A Functional Binding Sites and Presentation by Monoclonal Antibodies and Fusion Proteins

Therapeutic approaches to superantigen‐based diseases: a review

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