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De novo pyrimidine biosynthesis is required for virulence of Toxoplasma gondii

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  • Barbara A. Fox

    (Dartmouth Medical School)

  • David J. Bzik

    (Dartmouth Medical School)

Abstract

Toxoplasma gondii is a ubiquitous protozoan parasite that is responsible for severe congenital birth defects and fatal toxoplasmic encephalitis in immunocompromized people1. Fundamental aspects of obligate intracellular replication and pathogenesis are only now beginning to emerge for protozoan parasites. T. gondii has a fragmented pathway for salvaging pyrimidine nucleobases derived from the parasite or host cell, and this limited pyrimidine salvage capacity is funnelled exclusively through uracil phosphoribosyltransferase2,3. Disrupting the function of this enzyme does not affect the growth of T. gondii tachyzoites4, which suggests that the de novo pyrimidine biosynthesis pathway may be necessary for growth. We have examined the virulence of T. gondii mutants that lack carbamoyl phosphate synthetase II (uracil auxotrophs) to determine whether de novo pyrimidine biosynthesis is required in vivo. Here we show that T. gondii uracil auxotrophs are completely avirulent not only in immune-competent BALB/c mice but also in mice that lack interferon-γ. A single injection of the uracil auxotroph into BALB/c mice induces long-term protective immunity to toxoplasmosis. Our findings indicate the significance of the de novo pyrimidine biosynthesis pathway for the virulence of parasitic protozoa, and suggest routes for developing vaccines and chemotherapy.

Suggested Citation

  • Barbara A. Fox & David J. Bzik, 2002. "De novo pyrimidine biosynthesis is required for virulence of Toxoplasma gondii," Nature, Nature, vol. 415(6874), pages 926-929, February.
  • Handle: RePEc:nat:nature:v:415:y:2002:i:6874:d:10.1038_415926a
    DOI: 10.1038/415926a
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    Cited by:

    1. Xuefang Guo & Nuo Ji & Qinghong Guo & Mengting Wang & Huiyu Du & Jiajia Pan & Lihua Xiao & Nishith Gupta & Yaoyu Feng & Ningbo Xia, 2024. "Metabolic plasticity, essentiality and therapeutic potential of ribose-5-phosphate synthesis in Toxoplasma gondii," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    2. Céline Christiansen & Deborah Maus & Ellen Hoppenz & Mateo Murillo-León & Tobias Hoffmann & Jana Scholz & Florian Melerowicz & Tobias Steinfeldt & Frank Seeber & Martin Blume, 2022. "In vitro maturation of Toxoplasma gondii bradyzoites in human myotubes and their metabolomic characterization," Nature Communications, Nature, vol. 13(1), pages 1-15, December.

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