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Potential bioweapon, Brucella suis, is sequenced

In the 1950s, the US military developed artillery shells and bombs armed with a bacterium that causes a debilitating flu-like disease in humans. Now, three decades after those weapons were destroyed, scientists have sequenced the genome of the organism—a pathogen typically found in pigs called Brucella suis.

Detail of electron micrograph of Brucella. View full.

There are six species of Brucella bacteria, four of which can infect humans but are primarily animal pathogens. They cause brucellosis, a disease that leads to abortions and stillbirths in pigs, cattle, and goats. Humans with brucellosis experience long-term spiking fevers that are rarely fatal unless the infected person has an immune deficiency.

Brucella suis is on the "B" list of organisms considered potential bioweapons by the Centers for Disease Control and Prevention in Atlanta, Georgia. The bacterium can be delivered as an aerosol, making it relatively easy to disseminate. An outbreak of infections would be difficult to detect because the earliest signs are flu-like symptoms.

The sequencing of the Brucella suis genome began in the summer of 2001, before the terrorist attacks and anthrax deaths. These events did not accelerate the research, but they "certainly gave us a heightened awareness of how Brucella suis might be used," says Ian T. Paulsen of The Institute for Genomic Research (TIGR) of Rockville, Maryland, where the sequencing was done.

The US Defense Advanced Research Projects Agency, or DARPA—part of the Defense Department—funded the project under its program to sequence biological warfare agents. The grant, which came through the National Institutes of Health, mandates the publication of the genome sequence. But the information is unlikely to advance the aims of terrorists, according to the researchers.

"This type of genome data will be far more valuable to someone working on vaccines than to someone working on developing weapons," says Paulsen. His team and their collaborators are currently mining the genome sequence for new targets for human vaccines and therapies.

The Maltese Goat by Edward Caruana-Dingli.

Brucella suis infections are treatable, but the course of antibiotics can last nine months or more. Even with the antibiotics, the infection is difficult to eliminate entirely; treating an outbreak of brucellosis would be expensive because patients would need to be on antibiotics for extended periods of time.

"Brucellosis is like having the flu times ten," says Stephen M. Boyle of the Virginia Polytechnic Institute and State University in Blacksburg, who is a member of the research team. "You're basically in bed and debilitated, though it's not life-threatening unless you have some other condition."

The surprise of the study was the similarity between this animal pathogen and some plant pathogens and microbes that live symbiotically with plants. Despite their preferences for different kingdoms, the various organisms share genes, genomic structures and biological pathways.

For many Brucella genes, the closest matches were with a plant pathogen (Agrobacterium tumefaciens) and a plant symbiont (Mesorhizobium loti). When the researchers investigated the biology of these organisms, they found similar pathways, particularly for the metabolism of plant-derived compounds.

If Brucella suis can metabolize compounds in soil associated with plants, then this may explain its ability to survive outside human and animal hosts. It appears that the plant and animal pathogens may share a common ancestor—a soil bacterium.

"From my perspective, the study's most interesting findings are the similarity in genome sequence and in biological pathways between the plant and animal pathogens," says Paulsen. Comparing these species may yield insights into how the pathogens select a preferred host and how they cause disease.

The genomes of four Brucella species will soon be available. The US Department of Agriculture, under the direction of Shirley Halling, is sequencing the cattle pathogen Brucella abortus, and TIGR and its collaborators will soon begin work on Brucella ovis, which only infects male sheep. The Brucella suis study is published in Proceedings of the National Academy of Sciences.

‘Sir David Bruce discovered Brucella melitensis on the island of Malta in 1887’

These four genomes may help explain how the bacteria evolved to have predilections to infect certain hosts, and it appears that very few genes may make the difference. Only about three percent of the genome differs between Brucella suis and the goat pathogen Brucella melitensis, which was published last December.

"Having the genomes means we can now go in and systematically ask which genes allow Brucella to preferentially infect different animals," says Boyle.

These differences may also be important in developing vaccines. Boyle's group has shown, for instance, that genetic differences influence the effectiveness of a modified Brucella in eliciting a protective immune response in cattle.

"Brucellosis is still with us," says Boyle. "The cattle disease is officially eradicated in the U.S. and Western Europe, but it is endemic in other parts of the world."

A British army surgeon, Sir David Bruce, discovered Brucella melitensis on the island of Malta in 1887. He realized that soldiers were becoming ill from drinking milk from infected goats. The disease in sheep and goats is still a problem in the Mediterranean and parts of Asia, Africa, and Latin America.

In the fifties and sixties, the US military did extensive research on Brucella suis and developed a way to 'weaponize' the pathogen. They created extensive stocks of artillery and bombs that were destroyed when the Army abandoned its biological weapons program in 1969.

"The US Army quite liked Brucella suis because they were hoping the pathogen would give them a way of debilitating people without killing them," says Paulsen. "The Soviets were less interested in this pathogen because they wanted lethal agents."

"I'm not sure anyone knows what other countries may or may not have been up to with these pathogens," Paulsen adds.

See related GNN article
»Sequencing Brucella melitensis, an obscure candidate for biological warfare

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Paulsen, I.T. et al. The Brucella suis genome reveals fundamental similarities between animal and plant pathogens and symbionts. Proc Natl Acad Sci USA. Published online September 23, 2002.
DelVecchio, V.G. et al. The genome sequence of the facultative intracellular pathogen Brucella melitensis. Proc Natl Acad Sci USA 99, 443-448 (January 8, 2002).

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