In vitro studies on the pathogenesis of cerebral malaria

Malaria is caused by infection with the protozoan Plasmodium. About 40% of the world’s population is at risk, nearly all of them living in the least developed countries. While 300-500 million cases are reported per year, about 2 million people die annually. Most of the fatal cases develop severe malaria, which is a complication of Plasmodium fulciparum infection. Symptoms can include multi-organ dysfunction, anaemia, lung complications and cerebral malaria (CM). Although the pathogenesis is controversial, there are two main theories to explain the aetiology of CM: sequestration of parasitised red blood cells (pRBC) and leukocytes in the vasculature, and an over-reaction of the immune system. In the latter case, enhanced production of deleterious immune effectors such as cytokines is involved. Experimental models of CM (in vitro and in vivo) have been developed because clinical studies are hampered by ethical constraints and post-mortem human tissue is hard to obtain. CBA or C57BL/6 mice infected with Plasmodium berghei ANKA (PbA) succumb to murine CM and show progressive behavioural, histopathological and immunological changes. In contrast, Plasmodium berghei K173 (PbK)-infected C57BL/6 mice die due to anaemia and hyperparasitaemia, but without neurological symptoms. Although it is important to study the disease in the whole animal, in vitro studies are helpful to elucidate mechanisms at the cellular level. It is known that various cell types contribute to the pathogenesis of CM. In particular, endothelial cells lining the cerebral microvasculature are involved in the development of CM. They form part of the blood-brain barrier (BBB) which tightly regulates the traffic of substances and cells into the brain parenchyma to protect cerebral cells and to maintain the intemeuronal milieu. The permeability of the BBB is increased early after infection (day 3-4 p.i.) in the murine experimental model of CM. This might lead to an influx of deleterious substances into the cerebral parenchyma, causing the neurological symptoms observed. Changes at the microvascular endothelium are thought to contribute to the leakage of the BBB. In response to various stimulants ECs increase the expression of cellular adhesion molecules (CAM) on their surface. Cells such as leucocytes (in murine CM) and pRBCs (in human CM) adhere to the vessels, recruiting an immune response to the area