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Microbiology
From Mutation to Medication?
Faulty Toxin Sabotages Anthrax Infection
The speed and ease with which the anthrax bacterium, Bacillus anthracis, can cause death make it one of the most dangerous of biological weapons. A vaccine for humans exists, but the rarity of infection makes mass vaccination impractical. Unless antibiotics are given before symptoms develop, an unvaccinated victim usually dies within a few days.
The illustration shows the assembly and entry of anthrax toxin into the cell. Single molecules of the protective antigen (PA) toxin subunit bind to one another to form a doughnut-shaped pre-pore on the cell's surface. The other toxin subunits, lethal factor (LF) and edema factor (EF), bind to the pre-pore, and this complex is endocytosed. In the acidic environment of the endosome, the pre-pore inserts into the membrane and allows LF and EF to enter the cytoplasm, where they wreak havoc on the cell. The pink PA represents a mutant form generated by the authors, which acts as a dominant-negative PA (DN-PA). The presence of a DN-PA in the PA pre-pore prevents the formation of a mature pore, barring entry of LF and EF into the cytoplasm. The blockage of LF and EF inhibits their toxic activities. Illustration by Jeff Cleary
Now, researchers at HMS have identified a potential new anthrax therapy. Developed by R. John Collier, the Maude and Lillian Presley professor of microbiology and molecular genetics, and postdocs Bret Sellman and Michael Mourez, the approach may lead to a double-duty drug that acts as an equally effective preventive vaccine and also a more versatile cure. The study appears in the April 27
Science.
B. anthracis secretes the three subunits of its toxin—protective antigen, lethal factor, and edema factor—into the bloodstream of its host. Seven protective-antigen molecules then assemble into a pre-pore. The pre-pore undergoes a change in shape, forming a mature pore that allows lethal factor and edema factor to enter cells. Once inside, these toxin subunits destroy the cell, paving the way to disease.
R. John Collier, Michael Mourez, and Bret Sellman (l to r) developed this new potential anthrax therapy. Photo by Pam Murray
The authors generated mutants of protective antigen that assembled with normal protective-antigen molecules to form a pre-pore, but they inhibited the otherwise normal pre-pore from maturing. The researchers hypothesized that these mutants might thereby serve as an anthrax therapy because they would block edema factor and lethal factor from entering the cell.
To test their hypothesis the group injected rats with a normally lethal mix of protective antigen and lethal factor and a protective-antigen mutant. The protective-antigen variants "totally protected the animals, whereas the control animals became moribund within 90 minutes," said Collier.
Variants of protective antigen are particularly good candidates for an anthrax therapy. Normal protective antigen is already known to be safe in humans since it is the major component of the current anthrax vaccine. Mutant protective antigen also elicits an immune response equivalent to that generated by normal protective antigen. Therefore, it may fill the bill as both an anthrax vaccine and treatment.
Some other disease-causing bacteria also form a pore similar to that of B. anthracis. So "it may be possible to generalize this approach to certain other diseases," Collier said.
—Heather Ettinger
Copyright 2001 by the President and Fellows of Harvard College
