Apr. 30, 2001 Boston, MA -— A study by Harvard Medical School researchers in the April 27 Science suggests a mutation in the anthrax toxin, which prevents poisoning, may lead to a double-pronged pharmaceutical that is equally effective as a vaccine and as a faster-acting and more broadly protective therapy than currently available.
Death from anthrax is due to the toxin produced by the bacteria. In its airborne form, just a teaspoonful of anthrax could wipe out hundreds of people. Though rarely a natural threat to humans, anthrax is especially dangerous as a potential weapon in terrorism and biological warfare.
Though a vaccine exists, most people have no vaccine-induced immunity to anthrax because the rarity of infection makes a mass vaccination program impractical. Yet current therapies demand that any unvaccinated person exposed to the bug receive antibiotic therapy before symptoms occur. Otherwise, the victim with systemic anthrax dies rapidly. The discovery by R. John Collier and colleagues may offer a better way to fight back before or after infection.
The researchers tested whether they could prevent infection using forms of the anthrax bacterium with a mutation in a toxin subunit dubbed "protective antigen." When protective-antigen mutants were injected together with a normally lethal mix of toxin, rats did not develop any symptoms of poisoning. The protective-antigen variants "totally protected the animals, whereas the control animals became moribund within 90 minutes," says Collier, the Maude and Lillian Presley Professor of Microbiology and Molecular Genetics at the Medical School. "We’re most encouraged about the experiments in rats. The results are remarkable."
The protective-antigen mutants are good candidates for an anthrax therapy because the normal form of protective antigen in and of itself is already known to be safe in humans: it is the major component of the current anthrax vaccine, the use that gave the subunit its name.
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 more potent protective-antigen mutants can be made. Future efficacy studies using a mouse model of anthrax infection will be performed at U.S. Army laboratories in Maryland.
This study was supported by the National Institutes of Health and the Foundation Philippe.
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