The mutant protective-antigen molecules can elicit an immune response in rats equivalent to that produced by normal protective antigen. In the future, mutant protective antigen may fill the bill as both an anthrax vaccine and treatment, negating the need for two separate pharmaceuticals.

The anthrax bacterium normally secretes three toxin components into the bloodstream: protective antigen, lethal factor, and edema factor. These assemble into the toxin on the outside surface of human cell membranes. In order for symptoms to develop, lethal factor and edema factor must move to the cell interior.

Normally, seven protective-antigen molecules form a doughnut-shaped channel that enables lethal factor and edema factor to cross the usually impenetrable cell membrane and enter the cytoplasm. There, they disrupt normal cell function. The protective-antigen mutants identified by Collier and colleagues most likely act by blocking the formation of a normal protective-antigen channel.

The presence of just one mutant protective-antigen molecule in an otherwise normal channel may be potent enough to disrupt the entire channel. A mutant protective antigen, therefore, can block the toxic effects of anthrax even when it is outnumbered by normal protective antigen molecules. The three most potent protective-antigen variants that Collier identified fully prevented development of symptoms when present in a one-to-four ratio with normal protective antigen.

To wield their tools of destruction, certain other disease-causing bacteria, such as Staphylococcus, also require the formation of doughnut-like structures similar to the protective-antigen channel. Therefore, "it may be possible to generalize this approach to other diseases" Collier says.

One challenge to developing this approach as a therapy is devising a strategy to determine efficacy in humans. The researchers are now determining whether
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Contact: John Lacey
john_lacey@hms.harvard.edu
617-432-0441
Harvard Medical School
26-Apr-2001