Development of engineered vaccines effective against structurally related bacterial superantigens

Ulrich, Robert G.; Olson, Mark A.; Bavari, Sina

doi:10.1016/s0264-410x(98)00176-5

Cited by 91 publications

(125 citation statements)

References 26 publications

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“…Third, the serum of many healthy individuals contains antibodies, which can neutralize the T-cell-stimulatory effects of superantigens; 85 of 100 human serum samples fully inhibited the T-cell proliferation induced by all 11 isoforms of the streptococcal superantigen SMEZ, and the remaining 15 serum samples at least partially neutralized a subset of the variants (33). In mice, such antibodies have been shown to protect the animals from the toxic effects of superantigens as well as from the lethal consequences of S. aureus infection (1,20,26,35). In humans, lack of detectable antibodies to toxic shock syndrome-associated superantigens in the serum was predictive of susceptibility to toxic shock syndrome (34,36), and there is evidence that intravenous immunoglobulin preparations improve the survival of patients with streptococcal toxic shock syndrome (8,15,29).…”

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confidence: 99%

egc -Encoded Superantigens from Staphylococcus aureus Are Neutralized by Human Sera Much Less Efficiently than Are Classical Staphylococcal Enterotoxins or Toxic Shock Syndrome Toxin

et al. 2004

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PCR was employed to determine the presence of all known superantigen genes (sea, seq, and tst) and of the exotoxin-like gene cluster (set) in 40 Staphylococcus aureus isolates from blood cultures and throat swabs; 28 isolates harbored superantigen genes, five on average, and this strictly correlated with their ability to stimulate T-cell proliferation. In contrast, the set gene cluster was detected in every S. aureus strain, suggesting a nonredundant function for these genes which is different from T-cell activation. No more than 10% of normal human serum samples inhibited the T-cell stimulation elicited by egc-encoded enterotoxins (staphylococcal enterotoxins G, I, M, N, and O), whereas between 32 and 86% neutralized the classical superantigens. Similarly, intravenous human immunoglobulin G preparations inhibited egc-encoded superantigens with 10-to 100-fold-reduced potency compared with the classical enterotoxins. Thus, there are surprisingly large gaps in the capacity of human serum samples to neutralize S. aureus superantigens.Staphylococcus aureus persists as a commensal microorganism in 10 to 30% of the population, but the organism is also a common cause of food poisoning and infections of different severity such as skin abscesses and wound infections, osteomyelitis, endocarditis, pneumonia, toxic shock syndrome, and staphylococcal scarlet fever (21). S. aureus is one of the most frequent causes of hospital-acquired infections, and the emergence and spread of multiresistant strains give rise to concern. The pathogenicity of S. aureus is multifactorial, and the versatility of this organism is underscored by recent clinical studies (4,14,16,31,37,38).Superantigens activate large subpopulations of T lymphocytes by directly cross-linking certain T-cell receptor V␤ domains with conserved structures on major histocompatibility complex class II molecules (32). They belong to the most potent T-cell mitogens known and can induce massive systemic cytokine release, leading to the symptoms of toxic shock syndrome (22). Among the virulence factors of S. aureus are the staphylococcal enterotoxins, the causative agents of food poisoning. They also act as superantigens. Whole-genome sequencing of several S. aureus clinical isolates has revealed that all 17 known staphylococcal enterotoxins (staphylococcal enterotoxins A to E and G to Q and toxic shock syndrome toxin 1) are encoded on mobile genetic elements together with other virulence factors (3,18,40). For example, the recently described enterotoxin gene cluster egc, which contains the five superantigen genes seg, sei, sem, sen, and seo, as well as two pseudogenes is located on the genomic island SaPI3 (18).egc is special in that it functions as an operon and its genes are transcribed into a single polycistronic mRNA (13). In addition, a large cluster of up to 11 genes with sequence homology to superantigens has been discovered on the genomic island SaPI2; they have been termed staphylococcal exotoxinlike genes, or set (3,10,18,39). For an overview of the organization ...

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egc -Encoded Superantigens from Staphylococcus aureus Are Neutralized by Human Sera Much Less Efficiently than Are Classical Staphylococcal Enterotoxins or Toxic Shock Syndrome Toxin

et al. 2004

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“…A vaccine developed by site-specific mutagenesis provided safer and more effective vaccines. The most effective vaccine (SEBvax) was designed with mutations in the MHC class II binding region so that the vaccine no longer was capable of cross-linking T cells to APCs (Ulrich et al, 1998). The military is no longer funding development of SEBvax.…”

Section: Vaccinesmentioning

confidence: 99%

Staphylococcal Enterotoxins, Stayphylococcal Enterotoxin B and Bioterrorism

Hale¹

2012

Bioterrorism

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“…Comparative structural and biochemical studies carried out during the 1990s focused on the development of nontoxic, recombinant immunogens capable of eliciting a protective immune response against multiple SAg toxins ( 83,104). Ulrich et al at USAMRIID attempted to inactivate SE by modifying three structural regions of the toxin that are involved in HLA-DR1 binding: a polar pocket created by three ß-strand elements of the ß-barrel domain of the toxin, a hydrophobic reverse turn, and a disulfide-bonded loop (104).…”

Section: Engineered Se Vaccinesmentioning

confidence: 99%

“…Ulrich et al at USAMRIID attempted to inactivate SE by modifying three structural regions of the toxin that are involved in HLA-DR1 binding: a polar pocket created by three ß-strand elements of the ß-barrel domain of the toxin, a hydrophobic reverse turn, and a disulfide-bonded loop (104).…”

Section: Engineered Se Vaccinesmentioning

confidence: 99%