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

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-γ (IFN-γ) tumor necrosis factor-α (TNF-α) and inducible nitric oxide synthase (iNOS) in the resistance using BALB/c-background IFN-γ-deficient (IFN-γ(-/-)) mice. IFN- γ(-/-) 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-γ(-/-) 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-γ(-/-) 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-γ(-/-) mice. IFN-γ mRNA was detected in brains of only the control mice, whereas mRNA for TNF-α and iNOS were detected in brains of both strains of mice. The amounts of the mRNA for TNFα and iNOS did not differ between these mice. Treatment of IFN-γ(-/-) mice with recombinant IFN-γ prevented development of TE. These results demonstrate that IFN-γ is crucial for genetic resistance of BALB/c mice against TE and that TNF-α and iNOS are insufficient to prevent TE in the absence of IFN-γ. (C) 2000 Editions scientifiques et medicales Elsevier SAS.