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Biologists on Front Lines vs. Bioterror

By Sean Henahan, Access Excellence

Cambridge, MA (10/05/01)- The recent mysterious outbreak of anthrax in Florida heightens concern about bioterrorism among an already anxious public. New findings reported by Harvard biologists in two leading scientific journals may help explain how anthrax does it damage and could lead to new strategies to prevent infection.

Anthrax Facts

Bacillus anthracis (above)
A spore forming, rod-shaped bacterium.

Three clinical forms:
-cutaneous
-inhalation
-gastrointestinal

Symptoms of inhalation anthrax:
- Flu-like aches & pains
- Fever, malaise, fatigue
- cough and mild chest discomfort followed by severe difficulty breathing

Diagnosis:
-Isolating the bacteria from blood, other body fluids or skin lesions
-Measuring specific antibodies late in the course of the disease

Pathogenesis:
The disease occurs when spores enter lungs, migrate to the lymph nodes, change to the bacterial form, multiply, and produce toxins. These toxins cause bleeding and destruction of structures in the middle of the chest (medical term: hemorrhagic necrotizing mediastinitis).

Treatment:
Treatment for the inhalational form is usually not effective after symptoms are present. Other forms are treated with antibiotics.

Sources: CDC, DOD

The term anthrax refers to the disease caused by infection with the bacterium Bacillus anthracis, a large, gram-positive, nonmotile, spore-forming bacterial rod. Anthrax infection is exceedingly rare in the US, with only a handful of cases reported in the past 100 years. These typically involve those who work with livestock or who have been in touch with infected hides or wool from outside the US. Anthrax can infect the human body by three routes- the skin (contact with infected animals) , the gastrointestinal tract (eating of contaminated meat) or through the lungs (inhalation of anthrax spores). The recent cases in Florida involved inhalation, the rarest and most dangerous route of transmission.

One reason anthrax is so deadly is that it produces toxins that wreak havoc on the human immune system. These toxins destroy macrophages, key defensive cells in the human immune system. Harvard Medical School researcher William F. Dietrich and colleagues identified a gene that appears to makes some strains of mice resistant to anthrax infection.They determined that the mice that were less susceptible to anthrax infection had a different version of a protein produced by the gene Kif1C that transports molecules in macrophages. By gaining an better understanding of how anthrax disables macrophages, the researchers hope to open the way for discovering ways to protect people from infection.

"While the effects of anthrax lethal toxin on cells are quite complicated, the primary impact of the toxin is on the body's macrophages. The rest of the physiological impact of the disease on humans and animals seems to be secondary to those effects. The bacterium has evolved this mode of attack since, as a key weapon in the body's innate immune system, macrophages would gobble up the bacteria. Wiping out this first line of defense allows the bacteria to proliferate unchecked. Our finding in mice represents a new insight into a specific mechanism of toxin action in a well-defined model. Since this biology is conserved across species, we believe that studying this mechanism in mice will tell us a lot about the infection process in other species, including humans,"said Dr. Dietrich.

Single Nucleotide Makes the Difference

Working with molecular biologists at the Whitehead Institute, Dietrich employed DNA sequencing tools to compare mouse and human genome databases to isolate the genes. They then carefully compared the genes, looking for sequence differences between susceptible and resistant strains. They found that single nucleotide changes in the Kif1C gene appeared to be associated with greater or less resistance to infection. An experiment in which they increased the level of resistance to infection by inserting a resistant allele of Kif1C into susceptible macrophages confirmed the original observation.

The Kif1C gene codes for a transport protein related to kinesins. Kinesins, sometimes called motor proteins, carry molecules along cellular microtubules. The researchers believe that the polymorphisms in the Kif1C gene alter the ability of the protein to do its part in protecting the macrophage from the anthrax toxin.

"Research by other groups has indicated that anthrax toxin kills macrophages by inducing a runaway reaction called an oxidative burst. We speculate that this kinesin protein might be transporting either the elements that are part of this oxidative burst, or the actual oxidative compounds themselves. Or, the protein may be ensuring the prompt and appropriate delivery of compounds that protect the macrophage against its own oxidative bursts. So, while the subtle mutations that we see in Kif1C probably don't affect the macrophages in their normal functioning, the decrease in efficiency during the stress of intoxication by the anthrax toxin can mean the difference between death and survival of the macrophage," said Dietrich.

Further studies should clarify the effects of the polymorphisms and yield even more insight into the effects of the toxin. While Dietrich does not see immediate clinical benefits from the new findings, he does see the beginning of an important research pathway.

"We intend to look for these variations in human populations; to figure out what cargo this protein is carrying, and to learn why Kif1C is activated under anthrax intoxication," he said. "Once we understand such phenomena, we might be able to work toward clinical applications in terms of better diagnostics and treatments."

Synthetic Toxin Inhibitor

Another group at Harvard, led by John Collier in the department of microbiology and molecular genetics, has devised another approach to blocking the effects of the deadly toxins produced by the anthrax bacillus. By reviewing a large 'library' of peptides, Collier and colleagues found one peptide that interfered modestly with with the molecular assembly process of the anthrax toxin. This natural peptide formed the basis for the development of a synthetic compound that boosted the inhibitory activity of the peptide by about 7,500-fold.

The researchers then injected the compound into rats and exposed them to anthrax spore. The toxin inhibitor protected rats who were exposed to ten times the lethal dose of anthrax spores.

"Clinical anthrax is rare, but there is growing concern over the potential use of B. anthracis in biological warfare and terrorism. Although a vaccine against anthrax exists, various factors make mass vaccination impractical. The bacteria can be eradicated from the host by treatment with antibiotics, but because of the continuing action of the toxin, such therapy is of little value once symptoms have become evident. Thus, a specific inhibitor of the toxin's action might prove a valuable adjunct to antibiotic therapy," Collier noted.

It will be some time before either of the Harvard research projects progress to studies involving humans. Nevertheless, each of these projects suggests new avenues of research in the diagnosis and treatment not only of anthrax but of other infectious diseases and various cancers

Anthrax Vaccines

Louis Pasteur developed an animal vaccine for anthrax in In 1881. A human vaccine, made by the Bioport company, is also available. That vaccine is a cell-free filtrate vaccine, ie, it uses dead bacteria as opposed to live bacteria. A human live attenuated vaccine is produced and used in countries of the former Soviet Union. Such vaccines are considered unsuitable for use in humans by US health authorities. University of Texas Health Science Center are developing a new form of anthrax vaccine that could be taken in pill form based on a modified version of the salmonella bacteria. That bacteria disables the toxic element of salmonella, retaining its native ability to populate the human intestines. It is not expected to be ready for public use for at least five years.

The Bioport vaccine is the only one now on the market for humans. Currently, public health authorities recommend it only for those at risk of exposure through work (e.g. those who deal with livestock or hides) and some members of the military. One reason for this is probably that there is simply not enough vaccine to go around. US Health and Human Services Secretary Tommy G. Thompson recently announced that the government has no plans to acquire the vaccine for civilians. The vaccine itself has generated a lot of controversy. Some members of the military have refused to be vaccinated out of concern that the vaccine is dangerous. While the FDA says the vaccine is safe, the company that makes the vaccine has been in trouble with FDA over manufacturing purity issues.

Gas Masks? Antibiotics?

Concern over bioterror attacks with anthrax or other agents has boosted sales of gas masks and antibiotics among the public. The gas masks could protect against anthrax if the public had sufficient warning, but this may be unlikely considering that anthrax, like most biological agents, is invisible and odorless. Anthrax can be treated in the earliest, asymptomatic stages with antibiotics such as ciprofloxacin. However, detection of anthrax infection before symptoms develop requires sophisticated laboratory tests. Once symptoms of infection are present, antibiotics are considered to be of little use.

Nonetheless, current government strategy in the event of an anthrax attack would be to rely on massive stockpiles of antibiotics. Government authorities report that current medical supplies on hand would be sufficient to treat two million people for 60 days in the event of a massive anthrax attack. These supplies are in caches distributed around the country. Efforts are now underway to boost medical preparedness.

Don't Panic

While concern about a bioterror attack using aerosolized anthrax is at an all time high, experts note that such an attack would be very difficult to mount. A large amount of anthrax bacillus would first have to be prepared and 'weaponized'. It would then need to be delivered into the atmosphere and would be subject to the unpredictable patterns of wind and weather. Victims would have to inhale a sufficient amount of spores to become ill. The notorious Aum Shinriko cult attempted to release anthrax eight times in Tokyo without infecting a single person. Anthrax is not contagious, so those not affected would be able to assist those who were without fear of becoming infected. The current policy in the US is to educate the public, avoid a panic and ramp up coordinated public health emergency contingency plans.

Dr. Dietrich's research appears in the October 2001 issue of Current Biology. Dr. Collier's research appears in the October 2001 issue of Nature Biotechnology. Links to information about anthrax are listed below.

 

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