Tumour necrosis factor-α and macrophages inPlasmodium berghei-induced cerebral malaria

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.