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Aiming a knock-out blow at malaria

Bzik, left, and Fox manipulated Toxoplasma's DNA.

By Amos Esty

By knocking out a key gene in the -parasite Toxoplasma gondii, DMS researchers hope to strike a blow for global health. More than a billion people worldwide may be infected by Toxoplasma, which can cause damage to the central nervous system or death in infants and people with compromised immune systems. But the organism has added importance because it's a close relative of several other parasites, including Plasmodium, which causes malaria.

Model: David Bzik, Ph.D., a professor of microbiology and immunology, and Barbara Fox, a research associate in Bzik's lab, study Toxoplasma as a model organism that may help fight malaria and other diseases. In 2002, they created an attenuated, or weakened, strain of Toxoplasma that showed great promise as a vaccine. In a normal strain, Bzik says, even a single parasite can kill a mouse. But in the weakened strain, mice could withstand being injected with 10 million parasites. At the same time, the weakened strain prompted an immune response that protected the mice against infection by virulent strains of Toxoplasma.

But before the finding could be used, Bzik and Fox had to provide the exact sequence of the strain's genome. "The problem with the original attenuated strain . . . is that it's not defined genetically," Bzik says. "If you ultimately want to put anything into people, you have to have a genetic definition [of it] . . . and you have to show that it's safe and efficacious."

"It's really a major breakthrough," says microbiologist Bzik.

Genome: A peculiar behavior of the parasite frustrated Bzik and Fox's efforts. When Toxoplasma encounters foreign DNA, it randomly inserts that DNA into its genome in a process called nonhomologous end-joining (NHEJ), making it hard for scientists to manipulate the organism's DNA and target specific genes.

With their progress stymied, Bzik and Fox looked for a way to disrupt NHEJ. They thought it might be possible to identify-and knock out-a specific gene responsible for allowing Toxoplasma to exhibit this behavior. They spent a year trying without success to knock out the gene that produces the protein KU-70, part of the NHEJ pathway in other organisms. Then they tried it with another protein, KU-80, and found that the resulting strain of Toxoplasma was much less likely to exhibit NHEJ.

Bzik is excited by the possibilities opened up by the finding. "It's really a major breakthrough," he says. He explains that the immune response prompted by Toxoplasma is just what's needed to combat a host of diseases, including malaria, tuberculosis, HIV, and cancer. With the NHEJ problem solved, creating new strains of Toxoplasma for use against these diseases will be much easier.

Host: Shutting down the NHEJ pathway may also yield other dividends. "By taking a genetic approach to study what the parasite is doing to the host cell, we're actually going to learn a lot about the biology of our cells," Bzik says. "There's so much biological knowledge that can come out of this in the future."

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