Use a Parasite to Fight a Parasite

Applied Genetics News,  March, 2002  

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Dartmouth Medical School (Hanover, NH 03755 USA; Tel: 603/646- 1110; Website: www.dartmouth.edu) geneticists have discovered how to weaken a common human parasite to prevent disease in an animal model after infection by the normal parasite. Barbara A. Fox, a research associate, and David J. Bzik, associate professor of microbiology and immunology, found that inactivating a single enzyme in a key biochemical pathway prevented Toxoplasma gondii from causing disease. Their work is reported in the February 21 issue of Nature.

The T. gondii parasite, most commonly spread through undercooked meat and sometimes by cats, causes toxoplasmosis. While this disease generally poses no problems in infected people, it can be life threatening in immune-compromised patients and cause severe birth defects in newborns from primary infections during pregnancy. T. gondii belongs to a family of parasites that include the human pathogens Cryptosporidium parvum, also a danger for immune-compromised patients, and Plasmodium falciparum, a cause of virulent malaria that kills more than two million children worldwide each year.

Fox and Bzik have devised a mutant T. gondii strain that causes no disease and, more important, provides protection against the normal parasite. "Because of the extraordinary ability of this mutant parasite to infect the animal host without apparent ill effects, this mutant could be used as a prototype vaccine strain," says Bzik.

"This parasite is amenable to further genetic manipulation; it has an amazing ability to elicit a strong immune response that is likely to be beneficial for certain vaccines targeted against other challenging infectious diseases or cancer," adds Fox.

"Parasites have been around a long time and have become very proficient at stealing things from their host, if they can. This parasite seemed to rely on just one pathway for obtaining some of the key components of its genetic material. Most other organisms have retained two functional pathways: they can make components new (de novo), or they can salvage them from their nutrient environment," Bzik explains.

Bzik and Fox knocked out the first and key regulatory enzyme, carbamoyl phosphate synthetase II, in the de novo pyrimidine pathway. Inactivating "this enzyme made the parasite completely dependent on the pyrimidine uracil for its growth in the laboratory. These results suggest that pyrimidines are limited in the host cell, explaining why these parasites have retained the ability to synthesize these essential (genetic) precursors," says Fox.

Millions of the new mutant parasites inoculated into mice do no harm; all mice survive without any sign of disease. "More surprisingly, this mutant parasite was equally avirulent in mice with severe immune deficiency," says Fox, "It is the only known T. gondii parasite strain that does not cause disease in immune- deficient animals."

Building on the vaccine possibility, the researchers immunized mice with a single dose of their mutant strain. Weeks later they challenged the immunized mice with a lethal dose of a highly virulent T. gondii parasite. "The mice were completely protected from a lethal challenge infection. "These mutants may offer great potential as a strategy for vaccine development," Fox says

"The parasite carbamoyl phosphate synthetase II enzyme is an attractive target for the design of drugs to treat infections from this family of parasites," says Bzik. "The pyrimidine pathway may ultimately prove to be a weakness of protozoan parasites."

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