Whether a computer bug or a tapeworm, parasites are organisms that evolve to exploit their surroundings in many kinds of system. Biological parasites cause many of the world's crippling diseases, such as malaria and sleeping sickness, and show a remarkable diversity of intracellular and extracellular habitats, from gut to liver to eye. Toxoplasma gondii, a member of the protozoan Apicomplexa group of intracellular parasites, causes toxoplasmosis in humans and animals. In the 21 February issue of Nature, Barbara Fox and David Bzik show that T. gondii parasites that lack a crucial pyrimidine biosynthetic pathway become severely weakened and cannot survive when injected into mice.

Parasites rely on their hosts for nutrients and have lost many of the anabolic pathways for generating the basic building blocks of life. T. gondii relies completely on its host for obtaining purines (adenine and guanine), but has retained the ability to synthesize pyrimidines (cytosine, thymidine and uracil). To generate pyrimidines, T. gondii relies on converting uridine monophosphate into cytodine and thymidine monophosphates for use in making nucleic acids. Uracil can be salvaged from the host and is converted into uridine monophosphate, but it can also be synthesized from scratch. By using targeted gene insertion to eliminate carbamoyl phosphate synthetase II (CPSII) — the first enzyme in the uracil synthesis pathway — Fox and Bzik found that the parasite becomes dependent on an external supply of uracil for growth. When uracil is abundant in the environment, the pyrimidine requirements of T. gondii are satisfied.

Surprisingly, the in vivo situation turned out to be different. Wild-type T. gondii is usually lethal when injected into mice, but the uracil-dependent mutant T. gondii strains were unable to kill their mouse hosts. The result was the same even if severely immunodeficient mice were used. These data indicate that the mutant parasites were hindered by pyrimidine nutrient limitation and not by immune control in the host. The short supply of pyrimidines in animal tissues gives us a clue as to why parasites have retained the ability to synthesize these molecules. Importantly, the mutant parasites acted as a vaccine in normal mice and allowed them to survive subsequent infection with the highly virulent wild-type T. gondii.

This study is important for several reasons. First, the development of uracil-dependent T. gondii strains might allow safe and reliable vaccination of livestock. Second, this could represent a broad-ranging immunization approach to treating other protozoan parasites by severely attenuating their virulence. Finally, because pyrimidine biosynthesis is now known to be an obligate T. gondii pathway, enzymes in that cascade are attractive therapeutic targets for drug design and chemotherapy. The CPSII enzyme has unique structural and kinetic properties that differentiate it from the mammalian enzyme, so it might be possible to design inhibitors of CPSII that selectively disrupt pyrimidine synthesis in the parasite but not the host.