Pathogenesis of cerebral malaria--inflammation and cytoadherence

Abstract

Despite decades of research on cerebral malaria (CM) there is still a paucity of knowledge about what actual causes CM and why certain people develop it. Although sequestration of P. falciparum infected red blood cells has been linked to pathology, it is still not clear if this is directly or solely responsible for this clinical syndrome. Recent data have suggested that a combination of parasite variant types, mainly defined by the variant surface antigen, P. falciparum erythrocyte membrane protein 1 (PfEMP1), its receptors, coagulation and host endothelial cell activation (or inflammation) are equally important. This makes CM a multi-factorial disease and a challenge to unravel its causes to decrease its detrimental impact.

Keywords: PfEMP1; cerebral malaria; endothelium dysfunction; histopathology; inflammation.

Figure 1

Cerebral malaria—a multi-component disease. Cytoadherence of iRBC of the PfEMP1-DC8 and DC13 variants to endothelial receptors (like EPCR and ICAM-1) leads to sequestration and a reduction in microvascular flow. Binding to EPCR prevents activation of protein C, normally an inhibitor of thrombin generation. Increased thrombin affects various signaling pathways leading to loss of endothelial barrier function, increased TNF, Ang2/Ang1 ratio and von Willebrand factor (for a detailed description see Moxon et al., 2013). iRBC in the circulation and the rupture of iRBC elicits an immune response and the production of cytokines, Via various signaling pathways this leads to inflammation, an increased expression of endothelial receptors and therefore shedding of soluble endothelial receptors and ultimately to endothelial damage (see Miller et al., 2013). The leakage into the perivascular space affects astrocytes and pericytes leading to BBB impairment.