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Removing Enzyme Turns Potent Parasite into Pussycat

Weakening germs could lead to new drugs or vaccines, study says

WEDNESDAY, Feb. 20, 2002 (HealthDayNews) -- Nobody likes a hanger-on, especially when it's a parasitic organism.

Now, new research has shed light on how one particular parasite does its dirty work, revealing a way to weaken the organism and raising hopes for new therapies and vaccines against other parasites.

The findings focused on Toxoplasma gondii, a parasite that is generally harmless to healthy people but can cause neurological problems in people with weakened immune systems and birth defects in unborn babies. T. gondii is also a cousin of the parasite that causes malaria.

The study, conducted by researchers at Dartmouth Medical School, appears in tomorrow's issue of Nature.

In its natural form, T. gondii is deadly to mice, with a single organism capable of killing any species of mouse within seven to 10 days. Senior investigator David J. Bzik, an associate professor of microbiology and immunology, looked specifically at how the parasite uses uracil, one of the basic chemical building blocks of life.

T. gondii gets uracil using a "biosynthesis" pathway, converting other chemicals into uracil. As a backup, it can "salvage" uracil from its host, but it's not particularly good at this.

So what would happen if its primary supply line of uracil were cut off? The researchers found that by deleting the gene that produces an enzyme crucial to the parasite's ability to make uracil, T. gondii becomes entirely dependent on salvaging uracil from its host.

Although the parasite isn't completely cut off from the compound, this difference radically alters its effect.

The researchers found this weakened version of T. gondii couldn't survive when injected into mice. While the normal version of the parasite would kill the animals, mice injected with the altered parasite not only survived, but developed a strong immunological response to the full-strength parasite. Over time, the animals remained parasite-free.

The altered parasite was so weakened it didn't even kill severely immune-compromised mice.

"We made parasites that failed to survive in animals, which also provided protective immunity when used in animal vaccinations," Bzik says. "The findings have important implications for … a new approach for vaccination against infections caused by parasites."

"The infection by these crippled parasites does serve to stimulate an effective immune response," says David S. Roos, director of the Genomics Institute at the University of Pennsylvania. "That makes these parasites an interesting candidate for an anti-Toxoplasma vaccine, for example."

"It is conceivable that this sort of strategy might provide clues as to how to develop an anti-malarial vaccine," Roos adds.

The study could also lead to new drugs that target specific parasitic enzymes and interfere with infections, Bzik says, noting that both T. gondii and Cryptosporidium parvum, another related parasite, are implicated in HIV-related infections.

What To Do: Find out more about T. gondii from Ohio State University or Iowa State University.

SOURCES: Interviews with David J. Bizk, Ph.D., associate professor, Department of Microbiology and Immunology, Dartmouth Medical School, Lebanon, N.H.; David S. Roos, Ph.D., professor, Department of Biology, director, Genomics Institute, University of Pennsylvania, Philadelphia; Feb. 21, 2002, Nature
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