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Role of TNF and IL-1 in infections with Toxoplasma gondii
H R Chang1, G E Grau, J C Pechère
1Department of Microbiology, University of Geneva Medical School, Switzerland.
Abstract:
Mice lethally infected with the C56 strain of Toxoplasma gondii and treated with purified recombinant murine tumour necrosis factor (TNF, 1 microgram/day/mouse for 8 days), recombinant human interleukin-1 (IL-1 alpha or IL-1 beta, 100 ng/day/mouse for 5 days) or a single dose of a combination of TNF (1 microgram/mouse) and IL-1 alpha or IL-1 beta (100 ng/mouse) were significantly protected against death (P less than 0.05-0.001, as compared with untreated infected controls). Mice infected with 100,000 tachyzoites of the highly virulent RH strain of T. gondii released serum TNF in relation to the time after infection and were primed to secrete an enhanced level of serum TNF upon stimulation with bacterial lipopolysaccharide (LPS). In vitro studies showed that interferon-gamma (IFN-gamma) increased the antimicrobial activity of murine peritoneal macrophages whereas TNF, IL-1 alpha and IL-1 beta did not. TNF, however, synergized with the anti-toxoplasmic effect provided by IFN-gamma and this activity was blocked by anti-TNF antibodies. IFN-gamma induced the production of TNF and the anti-toxoplasmic effect provided by IFN-gamma seemed to be dependent partly on the production of TNF. We conclude that TNF and IL-1 may play a significant role in modulating the host's immune defence against T. gondii infection.
Insights
Tumor necrosis factor (TNF) and interleukin-1 (IL-1) protect mice against lethal Toxoplasma gondii infection. Interferon-gamma (IFN-gamma) enhances macrophage antimicrobial activity, partly through TNF production, suggesting a role for these cytokines in host defense.
Area of Science:
- Immunology
- Parasitology
- Infectious Diseases
Background:
- Toxoplasma gondii is a significant human pathogen.
- The host immune response to T. gondii infection is complex and involves various cytokines.
- Tumor necrosis factor (TNF) and interleukin-1 (IL-1) are key inflammatory mediators.
Purpose of the Study:
- To investigate the protective effects of TNF and IL-1 against T. gondii infection in mice.
- To explore the role of TNF and IL-1 in the context of other immune mediators like interferon-gamma (IFN-gamma).
- To elucidate the mechanisms by which these cytokines modulate host defense against T. gondii.
Main Methods:
- Mice were infected with lethal doses of T. gondii (C56 or RH strains).
- Mice were treated with recombinant murine TNF, human IL-1 alpha, IL-1 beta, or combinations thereof.
- Serum cytokine levels were measured after infection and lipopolysaccharide (LPS) stimulation.
- In vitro studies assessed the antimicrobial activity of murine peritoneal macrophages treated with cytokines and IFN-gamma.
Main Results:
- Treatment with TNF and/or IL-1 significantly protected mice against lethal T. gondii infection.
- Infected mice exhibited increased serum TNF levels and enhanced TNF production upon LPS stimulation.
- IFN-gamma increased macrophage antimicrobial activity, while TNF, IL-1 alpha, and IL-1 beta did not directly.
- TNF synergized with IFN-gamma's anti-toxoplasmic effect, an activity blocked by anti-TNF antibodies.
- IFN-gamma-induced anti-toxoplasmic activity was partly dependent on TNF production.
Conclusions:
- TNF and IL-1 play a significant role in protecting the host against T. gondii infection.
- IFN-gamma enhances macrophage function against T. gondii, partly via induction of TNF.
- These findings highlight the intricate interplay of cytokines in T. gondii host defense.