The Importance of S. aureus Superantigens in Human Diseases

Objective: Staphylococcus aureus is a common and important cause of a myriad of serious human infections. The organisms superantigens toxins are causes of many of these diseases. This review discusses the physicochemical and biological properties of superantigens, their roles in human diseases, assays for antibodies against the superantigens, and assays for the superantigen proteins and DNA.

Results: Staphylococcal superantigens include toxic shock syndrome toxin-1, staphylococcal enterotoxin serotypes A to E and G, and staphylococcal superantigen-like serotypes I and K to X. The first human cells staphylococcal superantigens interact with are epithelial cells through the immune co-stimulatory molecule, CD40, and keratinocytes through CD40 and gp130. After penetration into the circulation, superantigens are potent pyrogens, they amplify the lethal effects of Gram-negative endotoxin, and they cause massive T lymphocyte proliferation and macrophage activation, leading to the classic cytokine storm. The “big three” superantigens, toxic shock syndrome toxin-1 and enterotoxins B and C, are important causes of toxic shock syndrome and necrotizing pneumonia after influenza, and are highly associated with infective endocarditis, atopic dermatitis, diabetes mellitus type 2, bullous pemphigoid, numerous autoimmune diseases, and certain types of cancer. Patients who develop serious infections as a result of sero-susceptibility to superantigens do not develop immunity to the toxins as determined by enzyme-linked immunosorbent assays. Commercially-available intravenous immunoglobulins have high titers of protective antibodies. Superantigens associated with human diseases can be assayed for by combinations of antibody-based assays (in body fluids other than blood, and on skin) and polymerase chain reaction, both for detection and quantification. Quantitative polymerase chain reaction has recently been used to demonstrate superantigen DNA in human urine and blood.

Conclusion: Staphylococcal superantigens are known causes of human diseases. Additionally, the proteins are associated with many other human diseases where they have been conclusively shown to be causative. We know how to determine antibodies against superantigens, and we have assays to detect and quantify the superantigens.

Implications: Our ability to measure antibodies to superantigens and detect and quantify the superantigens in humans have allowed us to show that staphylococcal superantigens are important causes of serious infections. Furthermore, these reagents have allowed us to associate staphylococcal superantigens with many other common infections and conditions. This may lead to studies to vaccinate humans against toxoids of at least the three major superantigens, toxic shock syndrome toxin-1 and enterotoxins B and C.