Plasmodium berghei: cerebral malaria in CBA mice is not clearly related to plasma TNF levels or intensity of histopathological changes.

Plasmodium berghei ANKA infection in CBA/J mice leads to the development of cerebral malaria (CM) that kills 80-90% of the animals in 6-9 days. This model has been used to study the pathogenesis of CM, which is a major cause of morbidity and mortality in Plasmodium falciparum-infected individuals. The role of cytokines in the induction of CM in the murine model has been well documented, but most studies have been restricted to the peak of neurological manifestations. Here we used a sequential approach to compare mice that developed CM with those that developed no cerebral pathology. Animals were examined for systemic histopathological changes and plasma Tumor Necrosis Factor-alpha (TNF) levels. The objectives were (a) to further determine the importance of factors commonly associated with murine CM-such as elevated levels of TNF and the presence of hemorrhage and vascular plugging-by comparing mice at different stages of infection and/or with different outcomes following infection and (b) to examine the importance of systemic changes-course of parasitemia and histopathological alterations in brain, liver, and lungs-in the development of CM. The data suggest that (a) the clinical manifestation of CM appears to be associated with a wave of merozoite release on days 6-7, (b) murine CM does not present reliable histopathological indicators, (c) there is no topographic association between the occurrence of intravascular plugging and the hemorrhagic foci, (d) monocyte-monocyte and monocyte-endothelial cell adherence were the most expressive histopathological events and were not restricted to brain vessels, (e) blood levels of TNF are not indicative of the local tissue reaction, (f) adhesiveness of monocyte/endothelial cells fluctuate during infection and is dissociated from the lymphocyte homing to the liver, and (g) pulmonary megakaryocytosis (megakaryopoiesis?) is a late event in the lungs.