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Scientists unlock major clue about how anthrax kills

University Of Chicago : 24 January, 2002  (Technical Article)
Scientists have worked out the exact three-dimensional structure of edema factor, the last of three components in the deadly toxin produced by the anthrax bacterium. The knowledge should help both in understanding how edema factor works and in devising drugs to block it.
The structures of the other two components, known as lethal factor and protective antigen, have already been worked out by the technique known as X-ray crystallography, an arduous way of visualizing atomic-scale 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, and then kills its host, perhaps by forcing the sudden release of the pent-up immune signals and throwing the body into septic shock.

The structure of edema factor was worked out by Dr. Chester L. Drum of the University of Chicago, working with Dr. Wei-Jen Tang, also at Chicago, 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 years in the soil until some grazing animal disturbs it. When a spore is inhaled, or slips through a break in the skin, it is swiftly engulfed by a macrophage, a type of cell that patrols the body's surfaces for invaders and hauls captives to the nearest lymph node for identification.

The anthrax spores, however, are specialized to destroy their captors. They germinate into bacteria, burst out and infect the bloodstream, multiplying rapidly in its sea of nutrients.

The proliferating microbes then flood the body with their three toxins. Protective antigen, so named before its true role was understood, is 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 out and enter many kinds of cell, but macrophages again seem to be their principal target. Edema factor, so called because it causes swelling, binds to a common constituent of human cells known as calmodulin. Dr. Drum and his colleagues have found that edema factor grabs both ends of the calmodulin, bending the protein in a way that disrupts its usual functions.

Edema factor itself changes structure as it binds calmodulin, and in so doing becomes able to generate a small messenger chemical widely used within cells.

The abnormally high levels of the messenger, known as cyclic AMP, derange the macrophages and block them from performing their usual role of alerting the immune system to a bacterial invasion. Though the details are still unclear, it seems that swamping the cell with cyclic AMP inhibits another agent whose role is to switch on production of cytokines, the agents used by the macrophages to alert the immune system.

Lethal factor, the other anthrax toxin, inhibits the cytokine-production agent through a different mechanism. 'The bacterium is stifling the immune reponse 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 gríce. One idea is that the stricken macrophages produce their immune-alerting cytokines but do not export them until they themselves are killed. The cytokines, which cause a useful inflammatory response in small doses, can be lethal when uncontrolled. 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 is not yet clear that the macrophages produce cytokines, and that septic shock may not be anthrax's exact method of murder.

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 edema factor, a protein he believes 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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