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Tumour necrosis factor-alpha and macrophages in Plasmodium berghei-induced cerebral malaria
J H Curfs1, C C Hermsen, P Kremsner
1Department of Medical Microbiology, Catholic University of Nijmegen, The Netherlands.
Abstract:
The effect of tumour necrosis factor-alpha on malaria-infected mice was studied. C57Bl/6J mice infected with Plasmodium berghei K173 exhibited an increased sensitivity to exogenous TNF. Injection of 15 micrograms TNF was lethal to some of the animals when given 5-7 days after infection, while when given later on in the infection (i.e. days 8-10) amounts as low as 2.5 micrograms TNF appeared to be lethal in all mice. The pathology in infected mice treated with TNF resembled that found in the brains of infected mice dying with cerebral malaria. Infected mice treated with TNF, however, also developed severe pathological changes in other organs. On the contrary, treatment with sublethal amounts of TNF (1.0 micrograms or less) given on days 8 and 9 after infection, protected mice against the development of cerebral malaria. In addition, infected mice exhibited and enhanced sensitivity for treatment with lipopolysaccharide (LPS). Sublethal amounts of LPS, however, did not prevent mortality as in TNF-treated mice (LPS-treated mice died at about the same time as infected mice that developed cerebral malaria), but no cerebral haemorrhages were found in the majority of LPS treated, infected animals. Treatment with dexamethasone during infection protected mice against the development of cerebral malaria, but did not suppress their increased sensitivity to exogenous TNF. Treatment of mice with liposome-encapsulated dichloromethylene diphosphonate (lip-Cl2MDP), used to eliminate macrophages (an important source of TNF), prevented the development of cerebral malaria, but only when given before day 5 of infection. Mice protected by treatment with lip-Cl2MDP, however, remained sensitive for LPS on the eighth day of infection.
Insights
Tumor necrosis factor-alpha (TNF) exacerbates malaria severity in mice, but low doses protect against cerebral malaria. Macrophage depletion prevents cerebral malaria but not LPS sensitivity.
Area of Science:
- Immunology
- Pathology
- Infectious Diseases
Background:
- Malaria infection in C57Bl/6J mice with Plasmodium berghei K173.
- Tumor necrosis factor-alpha (TNF) plays a complex role in malaria pathogenesis.
- Increased sensitivity to exogenous TNF in malaria-infected mice.
Purpose of the Study:
- To investigate the dose-dependent effects of TNF on malaria-infected mice.
- To explore the protective and detrimental roles of TNF in cerebral malaria.
- To evaluate the impact of lipopolysaccharide (LPS), dexamethasone, and macrophage depletion on malaria pathology.
Main Methods:
- Administration of varying doses of TNF to infected mice at different infection stages.
- Treatment with LPS, dexamethasone, and liposome-encapsulated dichloromethylene diphosphonate (lip-Cl2MDP).
- Assessment of mortality, pathology (especially cerebral malaria), and organ damage.
Main Results:
- Exogenous TNF administration was lethal at higher doses and later stages of infection.
- Sublethal TNF doses protected against cerebral malaria but not overall mortality.
- LPS treatment reduced cerebral hemorrhages but did not prevent mortality.
- Dexamethasone prevented cerebral malaria but not TNF hypersensitivity.
- Macrophage depletion (lip-Cl2MDP) before day 5 prevented cerebral malaria.
Conclusions:
- TNF exhibits a dual role in malaria, potentially protective at low doses against cerebral malaria.
- Macrophage-derived TNF is critical in the development of cerebral malaria.
- Malaria-infected mice show altered responses to immunomodulatory agents like TNF and LPS.