Studies Point Way to New Anthrax Therapies

Research excites officials, but won't help in current outbreak

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By
HealthDay Reporter

WEDNESDAY, Oct. 24, 2001 (HealthDayNews) -- Two new studies in the journal Nature give scientists a window onto the way anthrax bacteria kills its cellular prey. The findings could help researchers come up with more effective treatments or vaccines against the potentially deadly germ, though experts say any clinical benefit from the work is far off.

"You can't rush the science, but when the science points you in the right direction, then you can start rushing," says Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, who attended a press conference on the work. "What we have here is the basis to do some very serious translation" of basic science into therapies.

Nature says it released the papers, both of which appear as research letters, ahead of their Nov. 8 publication date because of the intense interest in anthrax. America is on high alert for the infection, which has now cropped up in Florida, New York, New Jersey and Washington, D.C., where two postal workers died from the inhaled form of the disease.

The death toll from inhaled anthrax is now three, including the first victim in Florida earlier this month. Several others have the skin form of the illness, which typically responds well to antibiotics.

Anthrax attacks its hosts with three toxins. Two of these, lethal factor (LF) and edema factor (EF) do the deadly work. The third, protective antigen (PA), acts like a molecular "syringe" to inject LF and EF into host cells. The anthrax vaccine given to U.S. troops relies largely on PA for its protection against the disease.

For humans, inhaled anthrax's targets macrophages, white blood cells that patrol for invaders like germs and viruses.

When breathed in, anthrax spores penetrate deep into the airways, where they are attacked by macrophages. But the spores germinate and start producing more bacteria, literally bursting the macrophages, releasing the toxins and allowing the infection to spread rapidly. Although antibiotics can kill individual anthrax germs, they're powerless against the toxins. Experts say the ideal therapy would block the action of anthrax's toxins.

In one new study, John Young of the University of Wisconsin-Madison and colleagues at Harvard University say they've identified the precise portal through which anthrax toxins enter macrophages. The key is a protein called anthrax toxin receptor (ATR), which binds with PA.

"For more than a decade now the scientific community has been wondering what is the identify of this receptor," says Young.

The work is based on earlier experiments aimed at finding clues to how viruses reproduce and how certain cells had become resistant to viral infection. The researchers saw that cells without ATR became resistant to anthrax toxin. Returning ATR restored their susceptibility to the poison.

Young's group then engineered a key snippet of ATR, which they mixed with rodent cells and anthrax toxin. They found the cells were totally protected from the poison, which had bound harmlessly to the receptor fragments.

"The protective antigen now is soaked up by a sponge, which mops up the toxin and prevents it from attaching to cell surfaces," says Young. However, he says the receptor fragment has been tested only on cells in a plastic lab dish and not yet in any animals.

Young's group also found that ATR appears to be related to another gene and its protein, called TEM8, which is elevated in patients with colorectal cancer.

The second report, by Robert Liddington of the Burnham Institute in La Jolla, Calif., gives scientists a close-up view of the structure of LF, the enzyme that gives anthrax part of its punch.

Using a scanning technique called X-ray crystallography, Liddington and his colleagues mapped LF and saw that it binds with a group of molecules called mitogen-activated protein kinase kinase (MAPKK). LF splits these MAPKK compounds, which are important in cell signaling, and fatally disrupts healthy cell communication.

At the core of LF's virulence is a deep gulf into which MAPKK can nestle, and a lone zinc atom that ultimately triggers the cleaving. "If we could stop the action of this toxin, then we could save some lives," Liddington says.

R. John Collier, a Harvard University anthrax expert, says his lab has been working on a number of potential therapies to neutralize PA, LF and EF that might work in tandem with antibiotics. Two approaches,including a "dominant negative inhibitor," disrupt the PA syringe and keep it from injecting the two other toxins into target cells.

Collier says Harvard is "in active negotiations" with drug companies to develop these therapies commercially.

What To Do

To read more about anthrax, check the Centers for Disease Control and Prevention.

For more on defending against bioterrorism, visit the Center for Civilian Biodefense Studies or the Association for Professionals in Infection Control and Epidemiology.

For more on the various bioterror weapons, try the American Medical Association.

For more on anthrax and the mail, try the U.S. Postal Service.

SOURCES: Interviews with John Young, Ph.D., professor of cancer research, University of Wisconsin-Madison; Robert Liddington, Ph.D., professor, Burnham Institute, La Jolla, Calif.; R. John Collier, Ph.D., professor of microbiology and molecular genetics, Harvard University, Boston, and Anthony Fauci, M.D., director, National Institute of Allergy and Infectious Diseases, Rockville, Md.; Nov. 8, 2001, Nature

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