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Impaired resistance to the development of toxoplasmic encephalitis in interleukin-6-deficient mice
Y Suzuki1, S Rani, O Liesenfeld
1Department of Immunology and Infectious Diseases, Research Institute, Palo Alto Medical Foundation, California 94301, USA. ML.SUZ@forsythe.Stanford.edu
Abstract:
The role of interleukin-6 (IL-6) in the pathogenesis of toxoplasmic encephalitis (TE) was examined by using IL-6-targeted mutant (IL-6(-/-)) mice. At 4 and 8 weeks after infection with the ME49 strain of Toxoplasma gondii, significantly greater numbers of T. gondii cysts and areas of inflammation associated with tachyzoites were observed in brains of IL-6(-/-) mice than in those of control mice. Large areas of necrosis were observed only in brains of IL-6(-/-) mice. Tachyzoites were frequently detected in the areas of necrosis, suggesting that necrosis was caused by proliferation of the parasite. These results indicate that IL-6 is protective against development of TE by preventing formation of T. gondii cysts and proliferation of tachyzoites in brains of infected mice. Whereas in brains of control mice, large numbers of inflammatory cells were always observed in areas where tachyzoites were detected, in brains of IL-6(-/-) mice, only small numbers of inflammatory cells were observed in many areas with tachyzoites. Lymphocyte preparations isolated from brains of infected control mice had significantly higher ratios of gamma/delta T cells and CD4+ alpha/beta T cells but lower ratios of CD8+ alpha/beta T cells compared to those of infected IL-6(-/-) mice. There were no differences in the ratios of these T-cell subsets in spleens between these mice. The amounts of mRNA for gamma interferon (IFN-gamma) detected by reverse transcriptase PCR were significantly smaller in brains of IL-6(-/-) mice than in those of control mice, whereas amounts of IL-10 mRNA were greater in the former than in the latter. IL-6 mRNA was detected only in infected control mice. The protective activity of IL-6 against development of TE appears to be through its ability to stimulate IFN-gamma production and induce infiltration and accumulation of different T-cell subsets in brains of infected mice.
Insights
Interleukin-6 (IL-6) protects against toxoplasmic encephalitis (TE) by limiting parasite growth and inflammation. Mice lacking IL-6 showed increased parasite cysts, necrosis, and altered T-cell responses in the brain.
Area of Science:
- Immunology
- Neuroscience
- Infectious Diseases
Background:
- Toxoplasmic encephalitis (TE) is a severe opportunistic infection caused by Toxoplasma gondii.
- The role of specific cytokines, like interleukin-6 (IL-6), in TE pathogenesis remains incompletely understood.
Purpose of the Study:
- To investigate the protective role of interleukin-6 (IL-6) in the development of toxoplasmic encephalitis (TE).
- To elucidate the mechanisms by which IL-6 influences parasite burden, brain pathology, and immune cell responses during T. gondii infection.
Main Methods:
- Utilized IL-6-deficient (IL-6(-/-)) mice and wild-type control mice infected with the ME49 strain of T. gondii.
- Assessed parasite burden (cysts and tachyzoites), brain inflammation, and necrosis at 4 and 8 weeks post-infection.
- Analyzed T-cell subset populations (gamma/delta, CD4+ alpha/beta, CD8+ alpha/beta) in brain and spleen using lymphocyte preparations.
- Quantified mRNA levels of key cytokines, including gamma interferon (IFN-gamma) and IL-10, via reverse transcriptase PCR.
Main Results:
- IL-6(-/-) mice exhibited significantly higher T. gondii cyst numbers and inflammatory areas compared to controls.
- Necrosis was prominent in IL-6(-/-) mice brains, associated with tachyzoite proliferation.
- Brains of IL-6(-/-) mice showed reduced inflammatory cell infiltration and altered T-cell subset ratios (lower gamma/delta and CD4+ alpha/beta, higher CD8+ alpha/beta).
- Lower IFN-gamma and higher IL-10 mRNA levels were observed in IL-6(-/-) mice brains, with IL-6 mRNA detected only in controls.
Conclusions:
- IL-6 plays a crucial protective role in controlling T. gondii infection in the brain, preventing cyst formation and tachyzoite proliferation.
- IL-6 appears to mediate its protective effects by promoting IFN-gamma production and orchestrating appropriate T-cell infiltration and accumulation in the brain.
- Deficiency in IL-6 leads to exacerbated neuropathology, characterized by increased parasite burden and necrosis, suggesting IL-6 as a potential therapeutic target for TE.