SHORT REPORT: LETHAL MALARIA IN CYTOSOLIC PHOSPHOLIPASE A2- AND PHOSPHOLIPASE A2IIA-DEFICIENT MICE

Lipid mediators play important roles in the pathogenesis of malaria. Phospholipase A2s are enzymes involved in the production of these mediators, and they function in inflammation. Among them, cytosolic phospholipase A2 (cPLA2) is a key enzyme in the metabolism of arachidonic acid, the first intermediate in the production of lipid mediators. Plasmodium berghei ANKA causes cerebral malaria in CL57B/6 mice, and we recently produced cPLA2- deficient mice with this background. With the expectation of reduced pathogenicity, we performed experimental infec- tion in these mice. Unexpectedly, the infected mice developed cerebral malaria and died at the same time as the control mice, while the parasitemia progressed similarly in both groups. These observations suggest that secretory PLA2s rather than cPLA2 may be involved in the aggravation, although possible compensation by the induction of other enzymes has not been excluded. The present findings are expected to help clarify the involvement of various phospholipase A2 si n malaria. Several lines of evidence indicate that lipid mediators known as eicosanoids are involved in the pathogenesis of ma- laria. Clark and Hunt showed that peritoneal macrophages from mice infected with murine malaria produced increased amounts of arachidonate metabolites. 1 A report of successful treatment of human cerebral malaria with prostaglandin I2 was followed by prevention of murine cerebral malaria by a stable prostaglandin I2 analog. 2,3 Intervention in murine ma- laria with aspirin, a prostaglandin synthesis inhibitor, sug- gested that prostaglandins are protective against cerebral ma- laria, while leukotrienes aggravate this disease. 4 In human malaria caused by Plasmodium falciparum, the levels of pros- taglandin E2 in plasma and cyclooxygenase-2 in blood mono- nuclear cells are inversely related to disease severity. 5 Focal