Induction of tumor necrosis factor-alpha and inducible nitric oxide synthase fails to prevent toxoplasmic encephalitis in the absence of interferon-gamma in genetically resistant BALB/c mice

Microbes Infect. 2000 Apr;2(5):455-62. doi: 10.1016/s1286-4579(00)00318-x.


Following infection with Toxoplasma gondii, certain strains of mice, such as BALB/c, are genetically resistant to development of toxoplasmic encephalitis (TE) and establish a latent chronic infection as do humans. Thus, these animals appear to be a suitable model to analyze the mechanism of resistance to TE. Since the mechanism for their genetic resistance is unknown, we examined the role of interferon-gamma (IFN-gamma) tumor necrosis factor-alpha (TNF-alpha) and inducible nitric oxide synthase (iNOS) in the resistance using BALB/c-background IFN-gamma-deficient (IFN-gamma(-/-)) mice. IFN-gamma(-/-) and control mice were infected with the ME49 strain of T. gondii and treated with sulfadiazine to establish chronic infection. After discontinuing sulfadiazine, the IFN-gamma(-/-) mice all died, whereas the control mice all survived. Histological studies revealed remarkable inflammatory changes associated with large numbers of tachyzoites in brains of the IFN-gamma(-/-) mice but not in the control mice after discontinuation of sulfadiazine. Large amounts of mRNA for tachyzoite-specific SAG1 were detected in brains of only the IFN-gamma(-/-) mice. IFN-gamma mRNA was detected in brains of only the control mice, whereas mRNA for TNF-alpha and iNOS were detected in brains of both strains of mice. The amounts of the mRNA for TNF-alpha and iNOS did not differ between these mice. Treatment of IFN-gamma(-/-) mice with recombinant IFN-gamma prevented development of TE. These results demonstrate that IFN-gamma is crucial for genetic resistance of BALB/c mice against TE and that TNF-alpha and iNOS are insufficient to prevent TE in the absence of IFN-gamma.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antigens, Protozoan*
  • Antiprotozoal Agents / therapeutic use
  • Brain / metabolism
  • Brain / parasitology
  • Brain / pathology
  • Disease Models, Animal
  • Encephalitis / drug therapy
  • Encephalitis / parasitology*
  • Encephalitis / pathology
  • Female
  • Immunohistochemistry
  • Interferon-gamma / deficiency*
  • Interferon-gamma / therapeutic use
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Nitric Oxide Synthase / biosynthesis*
  • Nitric Oxide Synthase / genetics
  • Nitric Oxide Synthase / isolation & purification
  • Polymerase Chain Reaction
  • Protozoan Proteins / analysis
  • Protozoan Proteins / genetics
  • RNA, Messenger / analysis
  • Recombinant Proteins / therapeutic use
  • Sulfadiazine / therapeutic use
  • Toxoplasma*
  • Toxoplasmosis / drug therapy
  • Toxoplasmosis / parasitology*
  • Tumor Necrosis Factor-alpha / biosynthesis*
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / isolation & purification


  • Antigens, Protozoan
  • Antiprotozoal Agents
  • Protozoan Proteins
  • RNA, Messenger
  • Recombinant Proteins
  • SAG1 antigen, Toxoplasma
  • Tumor Necrosis Factor-alpha
  • Sulfadiazine
  • Interferon-gamma
  • Nitric Oxide Synthase