Takes two to tango: Neutralization of staph toxins

Contact: Shelley Thompson, shelley@lanl.gov, (505) 665-7778

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LOS ALAMOS, N.M., May 23, 2001 -- Scientists at the Department of Energy's Los Alamos National Laboratory are researching a new approach for neutralizing deadly toxins released by pathogenic bacteria, such as those that cause anthrax and plague.

The scientists' initial efforts focus on staphylococcus aureus, or staph, whose toxin is responsible for a variety of skin diseases, toxic shock syndrome and a quarter of all food poisoning cases in the United States each year.

The researchers have designed and laboratory-tested a decoy molecule, or receptor-mimicking molecule, that stops the spread of the bacteria's toxin by preferentially binding the toxin, keeping it from binding to the immune system's cells. This research may in time lead to methods for fighting virulence factors from harmful viruses, such as HIV that causes AIDS.

"The decoy molecules are better suited to protect the body's immune system from attack than currently used antibodies," said Goutam Gupta a structural biologist who led the research project. "Ideally, the decoys could offer a faster-acting, more effective alternative to stop the toxins. If all goes well with further research, the decoy could be given to patients suffering from food poisoning or toxic shock syndrome. It could also be given prior to possible exposure to biowarfare agents like anthrax."

Staph bacteria attack the body and elicit effects by releasing a toxin designed to subvert the immune system. Typical treatment for a staph infection involves antibiotics, but staph is growing increasingly resistant to antibiotics. Los Alamos researchers have taken a novel approach to blocking the staph toxin by building a decoy molecule that mimics the toxin's binding sites on antigen-presenting cells and helper T cells. The staph toxin attaches to the decoy instead of the immune cells preventing it from setting off its harmful chain of events.

Typically bacterial toxins or antigens -- molecules that cause an immune response -- are quickly targeted by the body's immune system and cleared by its antibodies. Specialized immune cells called antigen-presenting cells -- which label foreign invaders for other cells to attack -- engulf a toxin molecule, process it and display an inactive portion of it on its cell surface. This process activates other immune cells called helper T cells that call into action a host of other immune system cells, including cells that produce antibodies to inactivate the toxin.

The staph toxin, which is classified as a superantigen, however does not follow the same cellular process. The superantigen bypasses the normal route of antigen processing by binding as an intact protein to the receptors on both the APC and the helper T cell. This binding over-stimulates the immune system causing T cell proliferation and a massive production of cytokines -- chemical mediators released by cells that affect the behavior of other cells -- resulting in cellular toxicity. This over-stimulated immune response is ineffective at fighting the infection, turns the body against itself and can lead to shock and even death.

The researchers genetically engineered a decoy protein molecule consisting of the two sites on the immune cell receptors to which the staph toxin binds. "The resulting protein can be attached to the surface of a liposome -- a fatty hollow sphere or vesicle -- and given by injection, or orally. Because it does not contain the binding sites for normal antigens, it does not interfere with the normal immune function," says Gupta. "The beauty of these mimics is that they can be given in advance, if someone were worried about possible future exposure, and they will be cleared within three days without leaving any side-effects." Since it binds to the staph toxin with an affinity similar to that of the immune cell receptors, the decoy molecule will only have to be administered in concentrations comparable to that of the immune cell receptors. "The decoy molecules, with or without bound toxins, are cleared by the liver in about three days."

To create the decoy, the researchers identified the sequences of the staph genome that enable the toxin to bind the human immune cells. They then connected those sequences together to make an artificial gene for the decoy molecule and inserted it into an E coli bacterium that then manufactured the decoy for them.

The Los Alamos scientists plan to extend their research to the suite of staph toxins that attack the immune cells using the same mechanisms as the bacterium staphylococcus aureus's toxin. The liposome vesicles coated with the appropriate decoy molecules will be laboratory-tested to determine their ability to neutralize staph toxins and then tested in animals.

The research is published in the April 10 issue of Biochemistry -- a peer reviewed journal of the American Chemical Society, the world's largest scientific society. The scientists have applied for a patent.

The research was funded by the U.S. Department of Energy and the Defense Advanced Research Project Agency, part of the U.S. Department of Defense.

Los Alamos National Laboratory is operated by the University of California for the U.S. Department of Energy's National Nuclear Security Administration.

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