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The susceptibility of the human malaria parasite, Plasmodium falciparum, to killing in vitro by macrophage secretory products was investigated. The effect of 02 radicals and tumor necrosis factor on parasite viability was assessed both morphologically and by following the uptake of [3H]hypoxanthine. H202 produced by the interaction of glucose and glucose oxidase was found to reduce viability; this effect was reversed by the addition of exogenous catalase. Further studies indicated that the catalase level within the erythrocyte was not altered upon parasite invasion. 02 radicals produced during the xanthine-xanthine oxidase interaction also killed P. falciparum. The addition of various 02 radical scavengers (including catalase) did not reverse this effect; therefore, it was not possible to determine which of the 02 radicals were involved in the killing process. Samples from three different sources containing tumor necrosis factor, a nonspecific soluble mediator derived from Mycobacterium bovis BCG-activated macrophages treated with endotoxin, also killed the parasite. There was no evidence that tumor necrosis factor or the products of the xanthine-xanthine oxidase interaction caused damage to the erythrocyte membrane that could be implicated as an important aspect of the killing process. These findings all strongly suggest that such macrophage products play an important role in immunity to malaria. * Corresponding author. was assessed both morphologically and by measuring the uptake of [3H]hypoxanthine over a 24-h period after treatment. MATERIALS AND METHODS Parasites. P. falciparum (Wellcome/Liverpool strain) was maintained by routine cultivation procedures (26), using RPMI 1640 medium supplemented with 15% ARh+ human serum and N-tris(hydroxymethyl)methyl-2-aminoethane sul

In this review the old concept of severe malaria as a toxic disease is re-examined in the light of recent discoveries in the field of cytokines. Animal studies suggest that the induction of TNF by parasite-derived molecules may be partly responsible for cerebral malaria and anemia, while hypoglycaemia may be due to direct effects of similar molecules on glucose metabolism. These molecules appear to be phospholipids and we suggest that when fully characterized they might form the basis of antitoxic therapy for malaria.

A cosmid vector carrying the Epstein-Barr virus origin of replication, the EBNA-1 gene, the hygromycin phosphotransferase (hph) gene and pBR322 sequences has been constructed. This cosmid can replicate autonomously in the nucleus of human tissue culture cells, even when it carries a 35-kb long insert. The cosmid can be rescued from the transfected cells by cloning it directly into ampicillin-sensitive Escherichia coli. A gene for human tumour necrosis factor (TNF) cloned into this cosmid vector was introduced in tissue culture cells, where it was transcribed into mature mRNA.