Severe Human Malaria Research Articles

A Primate Model for Severe Human Malaria with Cerebral Involvement: Plasmodium coatneyi-Infected Macaca fuscata

To develop an animal model for severe human malaria, we carried out clinical and pathologic observations of Japanese monkeys (Macaca fuscata) infected with Plasmodium coatneyi. Two monkeys, eight and nine months of age, were used in this experiment. After inoculation with the parasite, both monkeys developed a fulminating acute infection with high parasitemia (20-28.2%) and became moribund with typical signs of severe malaria. In the splenectomized Japanese monkey, sequestered infected erythrocytes blocked brain capillaries. Electron microscopic studies on brain tissues revealed electron-dense knobs protruding from the membrane of infected erythrocytes that formed focal junctions with the cerebral capillary endothelial cells. These findings were remarkably similar to those seen in human cases. Prominent sequestration of the infected erythrocytes was uniformly distributed in capillaries of the lungs and heart. The nonsplenectomized Japanese monkey developed acute anemia with a packed cell volume of 6%, but blockage of brain capillaries was minimal. However, sequestered, infected erythrocytes were evident in capillaries of the heart and lungs of this animal. Our study showed that the Japanese monkey is highly susceptible to P. coatneyi infection and that this system provides a model for the study of severe human malaria.

Increased lymphotoxin in human malarial serum, and the ability of this cytokine to increase plasma interleukin-6 and cause hypoglycaemia in mice: implications for malarial pathology

The origin of illness and pathology in malaria is now largely attributed to high levels of circulating tumour necrosis factor (TNF), released from cells of macrophage lineage after triggering by the products of malarial schizogony. The role of lymphocytes and their products in malarial pathology is not yet known. This paper reports the presence of a related cytokine, lymphotoxin, which is produced only by lymphocytes, in the serum of malarial patients. This is the first report of raised serum levels of lymphotoxin in a systemic disease state. When injected into mice, recombinant human lymphotoxin induced hypoglycaemia and increased serum levels of interleukin-6. These changes, which are seen in severe experimental and human malaria, were also provoked by TNF. Both of these cytokines acted synergistically with interleukin-1, which has also been reported to be raised in malaria, to produce these alterations. These observations imply that lympotoxin, as well as TNF, may contribute to the hypoglycaemia and raised serum interleukin-6 observed in malaria. This reduces the likelihood of effectively blocking the pathology of this disease by the use of neutralizing antibody directed against just one member of this family of functionally overlapping mediators.