Reasonable Rascal
02-11-02, 23:11
Experts Dissect Last Layer of Anthrax Toxin [edited]
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Scientists have worked out the exact 3-dimensional structure of the edema factor, the last of 3 toxins produced by the anthrax bacterium. The knowledge should help in understanding how the edema factor works and in devising drugs to block it. With the 3 toxin components deciphered, biologists are beginning to understand the extraordinary cunning with which the anthrax bacterium first stifles the body's immune system by blocking the signals that coordinate its usual defense against bacterial invasion.
The structures of the other 2, known as lethal factor and protective antigen, have already been worked out by the same technique, known as X-ray crystallography.
The structure of the edema factor, so called because it causes swelling, was worked out by Chester L. Drum of the University of Chicago, working with Dr. Wei-Jen Tang, also at the university, and Dr. Andrew Bohm of Tufts
University. They describe their work in a recent issue of the journal Nature. [24 January, "Structural basis for the activation of anthrax adenyl cyclase exotoxin by calmodulin," 415:396-402]
When a spore is ingested by a grazing animal, or slips through a break in the skin, it is swiftly engulfed by a macrophage. The anthrax spores germinate into bacteria, burst out into the bloodstream, and flood the body
with their 3 toxins. Protective antigen serves as the attack vehicle for the other 2 toxins. The protective antigen proteins assemble in clusters of 7, forming a barrel-shaped structure with a docking site for either edema factor or lethal factor, the other 2 members of the toxic troika.
The toxin-laden barrels seek and enter many kinds of cell, but macrophages seem to be their principal target. Edema factor is activated as soon as it meets calmodulin, a common component of cells. It grabs both ends of the calmodulin, changing shape as it does so. The activated edema factor [a.k.a. 'edema toxin'] is able to generate cyclic AMP, a small messenger chemical widely used within cells, synthesizing it a thousand times as fast as the cell itself does. Cyclic AMP quickly reaches abnormally high levels,
blocking them from performing their usual role of sending out cytokines to alert the immune system to a bacterial invasion.
Lethal factor, the other anthrax toxin, also inhibits cytokine production, though through a different mechanism. "The bacterium is stifling the immune response completely, so that the body doesn't know it is being infected," said Dr. Robert C. Liddington of the Burnham Institute in Torrey Pines, Calif. Dr. Liddington worked out the structure of lethal factor last year.
Experts are uncertain how anthrax delivers its coup de grace. One idea is that the macrophages are suddenly killed, releasing a flood of pent-up cytokines. The cytokines, which cause a useful inflammatory response in
small doses, are lethal en masse. Vessels leak, blood pressure drops, organs fail and the victim dies from septic shock. But another anthrax expert, Dr. John Collier of Harvard Medical School, said it was not yet
clear that the macrophages produced cytokines, and that anthrax might kill
by some other means.
With the victim's death, the immune system is immobilized. The anthrax bacteria are free to grow and devour the body's nutrients until they run out of food. Their lethal orgy ended, they turn back into spores and wait
patiently to repeat the cycle.
[Byline: Nicholas Wade] New York Times
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Scientists have worked out the exact 3-dimensional structure of the edema factor, the last of 3 toxins produced by the anthrax bacterium. The knowledge should help in understanding how the edema factor works and in devising drugs to block it. With the 3 toxin components deciphered, biologists are beginning to understand the extraordinary cunning with which the anthrax bacterium first stifles the body's immune system by blocking the signals that coordinate its usual defense against bacterial invasion.
The structures of the other 2, known as lethal factor and protective antigen, have already been worked out by the same technique, known as X-ray crystallography.
The structure of the edema factor, so called because it causes swelling, was worked out by Chester L. Drum of the University of Chicago, working with Dr. Wei-Jen Tang, also at the university, and Dr. Andrew Bohm of Tufts
University. They describe their work in a recent issue of the journal Nature. [24 January, "Structural basis for the activation of anthrax adenyl cyclase exotoxin by calmodulin," 415:396-402]
When a spore is ingested by a grazing animal, or slips through a break in the skin, it is swiftly engulfed by a macrophage. The anthrax spores germinate into bacteria, burst out into the bloodstream, and flood the body
with their 3 toxins. Protective antigen serves as the attack vehicle for the other 2 toxins. The protective antigen proteins assemble in clusters of 7, forming a barrel-shaped structure with a docking site for either edema factor or lethal factor, the other 2 members of the toxic troika.
The toxin-laden barrels seek and enter many kinds of cell, but macrophages seem to be their principal target. Edema factor is activated as soon as it meets calmodulin, a common component of cells. It grabs both ends of the calmodulin, changing shape as it does so. The activated edema factor [a.k.a. 'edema toxin'] is able to generate cyclic AMP, a small messenger chemical widely used within cells, synthesizing it a thousand times as fast as the cell itself does. Cyclic AMP quickly reaches abnormally high levels,
blocking them from performing their usual role of sending out cytokines to alert the immune system to a bacterial invasion.
Lethal factor, the other anthrax toxin, also inhibits cytokine production, though through a different mechanism. "The bacterium is stifling the immune response completely, so that the body doesn't know it is being infected," said Dr. Robert C. Liddington of the Burnham Institute in Torrey Pines, Calif. Dr. Liddington worked out the structure of lethal factor last year.
Experts are uncertain how anthrax delivers its coup de grace. One idea is that the macrophages are suddenly killed, releasing a flood of pent-up cytokines. The cytokines, which cause a useful inflammatory response in
small doses, are lethal en masse. Vessels leak, blood pressure drops, organs fail and the victim dies from septic shock. But another anthrax expert, Dr. John Collier of Harvard Medical School, said it was not yet
clear that the macrophages produced cytokines, and that anthrax might kill
by some other means.
With the victim's death, the immune system is immobilized. The anthrax bacteria are free to grow and devour the body's nutrients until they run out of food. Their lethal orgy ended, they turn back into spores and wait
patiently to repeat the cycle.
[Byline: Nicholas Wade] New York Times