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.
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.
Suzuki
Y
Y
Department of Immunology and Infectious Diseases, Research Institute, Palo Alto Medical Foundation, Palo Alto, California 94301, USA.
Kang
H
H
Parmley
S
S
Lim
S
S
Park
D
D
D000818:Animals; D000953:Antigens, Protozoan; D000981:Antiprotozoal Agents / Q000627:therapeutic use; D001921:Brain / Q000378:metabolism / Q000469:parasitology / Q000473:pathology; D004195:Disease Models, Animal; D004660:Encephalitis / Q000188:drug therapy / Q000469:parasitology* / Q000473:pathology; D005260:Female; D007150:Immunohistochemistry; D007371:Interferon-gamma / Q000172:deficiency* / Q000627:therapeutic use; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D019001:Nitric Oxide Synthase / Q000096:biosynthesis* / Q000235:genetics / Q000302:isolation & purification; D016133:Polymerase Chain Reaction; D015800:Protozoan Proteins / Q000032:analysis / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D011994:Recombinant Proteins / Q000627:therapeutic use; D013411:Sulfadiazine / Q000627:therapeutic use; D014122:Toxoplasma; D014123:Toxoplasmosis / Q000188:drug therapy / Q000469:parasitology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics / Q000302:isolation & purification
D000953:Antigens, Protozoan; D000981:Antiprotozoal Agents; D015800:Protozoan Proteins; D012333:RNA, Messenger; D011994:Recombinant Proteins; C047168:SAG1 antigen, Toxoplasma; D014409:Tumor Necrosis Factor-alpha; D013411:Sulfadiazine; D007371:Interferon-gamma; D019001:Nitric Oxide Synthase