http://www.nytimes.com/2002/01/29/health/anatomy/29TOXI.html
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January 29, 2002 Experts Dissect Last Layer of Anthrax Toxin
By NICHOLAS WADE
The structures of the other two, known as lethal factor and protective
antigen, have already been worked out by the same technique, known as X-ray
crystallography, an arduous way of visualizing structures too small to be
picked up by light. With the three 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 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 the current issue of the journal
Nature. Anthrax spends most of its time as an invisible spore, lurking in soil.
When a spore is inhaled by a grazing animal, or slips through a break in the
skin, it is swiftly engulfed by a macrophage, a type of cell that patrols the
body surfaces for invaders. The anthrax spores, however, are specialized to destroy their captors.
They germinate into bacteria, burst out into the bloodstream, and flood the
body with their three toxins. Protective antigen, so named before its true
role was understood, serves as the attack vehicle for the other two toxins.
The protective antigen proteins assemble in clusters of seven, forming a
barrel-shaped structure with a docking site for either edema factor or lethal
factor, the other two members of the toxic troika. The toxin-laden barrels seek and enter many kinds of cell, but macrophages
again seem to be their principal target. Mr. Drum and his colleagues have
found that the edema factor, which is harmless while inside the bacterium, is
activated as soon as it bumps into a common component of cells known as
calmodulin. It grabs both ends of the calmodulin, changing shape as it does
so. The activated edema factor is able to generate a small messenger chemical
widely used within cells, synthesizing it a thousand times as fast as the cell
itself does. The messenger, known as cyclic AMP, quickly reaches abnormally high
levels, which derange the macrophages and block 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 grāce. 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. Dr. Drum said it took him nearly four years to work out the structure of
the edema factor, a protein he said some ancestral anthrax bacterium may have
hijacked from an animal cell many millennia ago. Knowledge of the exact structure of the three toxins should speed the
search for new drugs, which are likely to be used in combination with
antibiotics. Dr. Liddington said drugs against lethal factor might be ready
to test in 18 months. |
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