Team locates anthrax-receptor protein.
The findings, slated for release in the Nov. 8 issue of NATURE, were unveiled this week as infections from letter-borne anthrax spores continue to crop up across the eastern United States.
In hosts such as people and livestock, the anthrax bacterium emerges from its protective spore and begins to grow. It releases the three components of its toxin--known as lethal factor, edema factor, and protective antigen (PA)--which assemble on cell surfaces. First to attach is PA, which binds to a receptor protein on a cell. Next, PA is cleaved by an enzyme there. Then, the other two toxin components attach to PA and gain entry into the cell. Once inside, lethal factor triggers the biochemical cascade that leads to anthrax's symptoms, which are most dangerous when the spores have been inhaled.
Until now, the protein serving as PA's docking station on cells was a mystery. John A.T. Young, a geneticist at the University of Wisconsin-Madison, and his colleagues searched for it by inducing mutations in hamster ovary cells. The researchers then mixed these mutant cells with PA. They found 10 cell lines to which PA couldn't bind, suggesting that these cells' PA receptors were absent or had been altered.
Drawing from a genetic library, the researchers began adding genes back to one of the cell lines to see which genes might restore the cell's binding to PA. They found such a gene. It encodes a cell-surface protein that the scientists dubbed anthrax toxin receptor.
The team then determined the part of the receptor to which PA binds. When they added extra copies of this receptor fragment to a mixture of rodent cells and anthrax toxin, the copies "soaked up the toxin and prevented it from attaching to the cell surfaces," Young says. If a drug were tailored to occupy this receptor site, it might thwart the disease, he says.
In a separate study, scientists reveal the three-dimensional shape of lethal factor and the mechanism it uses to sever a protein in cells, an action that triggers the disease. Knowing lethal factor's molecular shape might now enable scientists to design compounds that can disable it, says study coauthor Philip C. Hanna, a microbiologist at the University of Michigan in Ann Arbor.
Earlier this year, researchers reported progress on two other potential antidotes to anthrax toxin (SN: 5/12/01, p. 296; SN: 10/6/01, p. 212). All these studies are examples of "extraordinary, elegant science," says Anthony S. Fauci, director of the National Institute of Allergy and Infectious Diseases in Bethesda, Md. "It's incumbent upon us to do as much as we can to translate that into something that would [benefit] the public health," he says.