Researchers at Harvard Medical School and the University of Wisconsin Medical School in Madison said Tuesday they have discovered a protein receptor thought to be the first contact between the anthrax toxin and the cells it eventually will kill.
In a separate study, researchers at Harvard Medical School and The Burnham Institute in La Jolla, Calif. discovered the three-dimensional structure of the lethal part of the anthrax toxin. Both studies have been underway for several years, and both were funded by the National Institutes of Health.
The two research papers also will appear in the Nov. 8 issue of Nature and in Tuesday's online edition of the magazine.
The scientists said an effective antidote to anthrax is needed because once the flu-like symptoms of inhalation anthrax become apparent, it generally is too late for medical help.
That is because anthrax infects the body in two stages. First, the bacterium gets into the body through the nose, intestines or skin, but stays outside individual cells in the body. At that stage it is treatable by antibiotics. In the second stage the anthrax toxin gets through the wall of the cell, where it can no longer be treated with antibiotics.
The anthrax bacterium secretes three toxin components into the blood stream. Once they are inside the cell, two of them disrupt the normal activity of the cell. The third creates a hole for the other two to use to tunnel further into the cell.
By knowing where the receptor is and how the toxin gets through it and into the cell, it may be possible to develop new treatments, including drugs that keep the toxin from entering cells and others that block its ability to disrupt the normal activities of the cells.
"If there's any good news about anthrax, it's that we now have a far more detailed understanding of it at the cellular and molecular levels," said John Collier, co-author of both studies and a professor of microbiology and molecular genetics at Harvard Medical School.
Collier said Harvard University already is in active negotiations with several companies to develop the findings into products.
The scientists also made a fragment of the anthrax toxin receptor protein in the laboratory. They said they discovered the lab-made fragment blocks the anthrax from binding to the cell's surface. That finding may lead to a treatment, because the blockage interrupts the fatal sequence of events during which the anthrax toxin kills cells.
"Our short-term goals are to study the mechanism of toxin uptake through the anthrax toxin receptor, and to make enough of the toxin-blocking form of the receptor so that it can be tested in animals," said John Young, professor of cancer research at UW-Madison and senior author of the paper.
Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, said the findings are "very important."
"What we have here is the basis to do some very serious translation of this into drugs," he said. "This is part of the contribution of basic research to public health."
"This [the receptor] is really important, because it provides a direct target for drug intervention," said William Dietrich, assistant professor of genetics at Harvard Medical School and an expert on genetic differences in individual susceptibility to anthrax toxin.
The findings may lead to both better preventive and therapeutic drugs.
"It may be possible to make better vaccines to protect against infection, and to design therapies to stop the progression of the disease once someone is infected," said Kevin Killeen, senior director of bacterial viruses at Avant Immunotherapeutics Inc., a Needham, Mass. biotechnology company.
Avant recently licensed components of its vaccine technology to DynPort Vaccine Co., which is developing vaccines for anthrax and other contagious diseases for the U.S. Department of Defense.
(Written by Lori Valigra in Cambridge, Mass.)
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