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Secrets of the Mutant Superantigens

Artificial mutations and computer simulations are giving researchers at Auckland University's School of Medicine a better understanding of some of the basic processes behind a group of toxins involved in food poisoning, and may provide hints of how to treat arthritis and diabetes.

Many people have experienced the gut wrenching effects of staphylococcal food poisoning at some stage -- aptly described as the "feeling you're going to die, followed by realization that you won't -- but wish you could!". A group of toxins collectively called superantigens are responsible for this unpleasant disorder. Superantigens are found in food inadvertently contaminated with Staphylococcus aureus, a very common bacteria. They are also made by Streptococcus pyogenes, another very common bacteria in people.

It is these superantigens which are being studied intensively by a research group led by Dr John Fraser, in Auckland's Department of Molecular Medicine. As well as food poisoning, superantigens cause life-threatening diseases such as toxic shock syndrome and scarlet fever, and have also been implicated in arthritis, diabetes and AIDS. Superantigens attack the T-lymphocyte cells which control our immune system. They bind to two key proteins on the surface of lymphocytes, the major histocompatibility complex (MHC) and the T cell receptor (TcR). This binding is so effective that the T lymphocyte is left in total disarray, incapable of responding to other antigens.

Fraser and his team use sophisticated molecular techniques to analyse the structure and function of superantigens. Gene mutagenesis (the art of introducing specific mutations in superantigen genes) is used to create mutant superantigens that are then tested for loss of function. X-ray crystallography is being used to determine their three-dimensional structure, and computer-simulated molecular modelling is used to build models to examine how changing the structure changes the function of the toxin molecule.

This work has yielded important findings about exactly how superantigens work and what they do to our immune system. For instance, despite the fact that all seven members of the superantigen family evolved from a common ancestral gene, each member has developed its own unique group of T lymphocytes which it targets. Moreover, the mechanism by which each one works is slightly different.

Staphylococcal enterotoxin B (SEB), for instance, has two binding sites, one for the MHC antigen and one for the TcR, while staphylococcal enterotoxin A (SEA) has three, one for TcR and two for MHC. The differences reflect the complex but very directed evolution of bacterial superantigens (the SEB gene is older than the SEA gene) and indicate how efficient the evolution of protein structure and function can be when the selection pressure is strong. Superantigens must be important for the bacteria, or there would be no need to dramatically alter protein structure while keeping their function the same.

From a medical standpoint, superantigens cause serious diseases and are key elements in the survival and pathology of S. aureus and S. pyogenes in humans. Producing modified deactivated versions will lead to possible vaccines for future treatment of some of these disorders. In addition, according to Fraser, their action shows us possible ways to treat autoimmune diseases such as arthritis and diabetes by using the potent and broad spectrum activity of superantigens to selectively "turn off" autoreactive T cells.