Anthrax toxin’s structure shown

By Raphael Satter

University researchers have discovered the three-dimensional structure of a key component of an anthrax toxin known as the edema factor. This breakthrough, published in yesterday’s issue of Nature, may lead to the creation of an effective antitoxin with the potential to save the lives of patients suffering from advanced cases of anthrax infection.

The study, conducted by Wei-Jen Tang, associate professor in the Ben May Institute for Cancer Research, and University graduate student Chester Drum along with Andrew Bohm of the Boston Biomedical Research Institute, used a technique known as X-ray crystallography to discover the shape of the toxin.

“This particular toxin makes cyclic AMP, so I worked on a protein that makes AMP, and we solved the structure,” said Tang, the director of the study.

The edema factor, one of the three anthrax toxin components, can release fluid into the lungs and cause death. The structures of the other two toxins, known as lethal factor and protective antigen, have already been worked out using similar techniques.

After the anthrax bacteria burst into the bloodstream, protective antigen allows the other two toxins to attack macrophage target cells. Edema factor is activated once it comes into contact with calmodulin, a protein normally present in the body’s cells. It then begins to produce cyclic AMP, a chemical that blocks cells from sending out the messenger proteins known as cytokines to alert the body of a bacterial invasion.

Lethal factor also stops production of cytokines so that the immune system is completely unaware of the infection. Once the host dies and the immune system is immobilized, the anthrax bacteria feast on the body’s nutrients. After doing so, they become dormant spores until the cycle is repeated in a different host.

The edema factor acts as a vehicle for the other two toxins and can make the lethal factor as much as 100 times more potent.

Tang said that if the edema factor can be neutralized, then the other toxins are weakened. “Removing the edema factor will significantly reduce the toxicity of the other two [toxins], and that can be sufficient to cure the patient,” said Tang.

Unlike antibiotics, an antitoxin based on Tang’s work would be effective well into the period of infection. This is particularly important because the symptoms of an anthrax infection are not apparent for several weeks, at which point it is too late for antibiotic treatment. Although antibiotics can kill the bacteria, anthrax makes lethal toxins that survive even after the bacteria are eradicated.

Tang first started researching the toxin three years ago, but his work has acquired a new significance after the anthrax attacks last October. According to Tang, anthrax has become the fifth most common word in the headlines in 2001. Anthrax, particularly pulmonary anthrax, is especially dangerous because of the ease with which it can be contracted and the difficulty in treating it once the symptoms occur.

“There is a silver lining behind the tragic mail attacks in October,” Tang said. “Although anthrax was seen as merely an agricultural problem, many scientists…had long realized the potential danger and have been working on this problem for a long time. Our government has also devoted significant resources to such study.”

Work will soon begin on finding a drug to neutralize the toxin. “We’re going to go after the antitoxin,” Tang said.

“We’re going to try structure-based inhibitor design; that’s the technology that we’re exploring right now. We’re also exploring drug throughput and designing a screening method.”

Tang admits it will take time before a treatment can be devised. “We’re still in a very early stage,” Tang said. “Typical drug screening can take five to 10 years.”