Anthrax: Key anthrax 'door' found.
POSTED 23 OCT 2001
 

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slide of Bacillus anthracisThe wave of bioterrorism continues. Although anthrax is so rare that most doctors have not seen it, about 10 cases have been found in Washington, DC and New York.

Bacillus anthracis. Courtesy National Institutes of Health.

As the bacterial disease continues to claim victims, researchers today identified the door that anthrax toxin uses to enter and kill mammalian cells. Eventually, the discovery could lead to a treatment for inhaled anthrax. Today, by the time of diagnosis, the patient usually has a deadly dose of anthrax toxin, so antibiotics do not help at that point (skin anthrax, however, is much easier to treat).

By showing how anthrax toxin enters cells, the discovery points toward a new, precise way to monkey-wrench the disease mechanism. Adding the new receptor protein to the blood of an anthrax patient might bind up anthrax toxin so it could not enter cells. The protein could also be used to screen for anti-anthrax drugs.

Both accomplishments, unfortunately, remain in the future, stressed John Young, a cancer researcher at University of Wisconsin-Madison who helped make the discovery. The experiment, he emphasized, used cultures of rodent cells. The protein is in short supply, and animal and human experiments are yet to be done.

It's the toxins, stupid
Like many bacteria, anthrax kills by making toxins -- biological molecules that block biological processes or attack key systems. Whether you get anthrax through the lungs or skin, Bacillus anthracis attacks macrophages. Ironically, these are immune cells that normally eat anthrax and other bacteria.

illustration depicting how anthrax attacks

Is anthrax an immune disease? Perhaps, but rather than bog down in terminology, let's do something even more silly: meet the three anthrax toxins.

Protective antigen: binds to the newly found receptor and ferries lethal or edema factor into cells.

Edema factor: prevents macrophages from attacking bacteria.

Lethal factor: causes macrophages to swell and release toxic chemicals the macrophage uses to kill bacteria. The result can be untreatable toxic shock.

illustration depicting the possible treatment of anthrax

Cellular bandito
The broad outline of the anthrax attack has been known for a while, but the receptor was mysterious when Kenneth Bradley, a University of Wisconsin-Madison grad student who works in Young's lab at the McArdle Laboratory for Cancer Research, decided to find it two years ago.

Bradley took a group of rodent cells that were susceptible to anthrax toxin, a sure sign that they contained the anthrax receptor. He chemically mutated the cells and extracted those that became immune to anthrax -- a sign of problems with the receptor. "We looked for the rare event where they would be mutated, and have no functioning receptor," says Bradley. Then he added gobs of genes -- millions at a crack -- to the cells, looking for genes that would restore the receptor -- and susceptibility to the toxin.

By a process of elimination, Bradley pinpointed a gene that patterns the anthrax receptor. Finding the gene means he has also found the protein that forms the actual receptor.

Although the research was largely finished last summer, before the anthrax attacks, recent headlines have certainly made the work seem more urgent, says Young. Talks about moving the research ahead are already under way, and a joint patent application has been filed by Harvard Medical School, where some of the work began, and the Wisconsin Alumni Research Foundation.

Still, the idea of using the receptors to fight anthrax is now just a pretty theory, one that could be encumbered by homely facts down the line. Will blocking the receptors actually work? Unknown. Will adding receptors to the blood cause nasty side effects? Unknown. On the more fundamental level, why do mammalian cells have a port of entry for anthrax toxin, and what was the receptor's original purpose?

The discovery certainly demonstrates that much more remains to be learned about interactions between bacteria and their hosts. At some point, it could also become a "smart bomb" in the war against bioterror.

-- David Tenenbaum

 

      BIBLIOGRAPHY

Identification of the Cellular Receptor for Anthrax toxin,
Kenneth Bradley et al, Nature Online

 

 
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