Human cerebral malaria and the blood-brain barrier.
Malaria represents a continuing and major global health challenge and our understanding of how the Plasmodium parasite causes severe disease and death remains poor. One serious complication of the infection is cerebral malaria, a clinically complex syndrome of coma and potentially reversible encephalopathy, associated with a high mortality rate and increasingly recognised long-term sequelae in survivors. Research into the pathophysiology of cerebral malaria, using a combination of clinical and pathological studies, animal models and in vitro cell culture work, has focussed attention on the blood-brain barrier (BBB). This represents the key interface between the brain parenchyma and the parasite, which develops within an infected red cell but remains inside the vascular space. Studies of BBB function in cerebral malaria have provided some evidence for parasite-induced changes secondary to sequestration of parasitised red blood cells and host leukocytes within the cerebral microvasculature, such as redistribution of endothelial cell intercellular junction proteins and intracellular signaling. However, the evidence for a generalised increase in BBB permeability, leading to cerebral oedema, is conflicting. As well as direct cell adhesion-dependent effects, local adhesion-independent effects may activate and damage cerebral endothelial cells and perivascular cells, such as decreased blood flow, hypoxia or the effects of parasite toxins such as pigment. Finally, a number of systemic mechanisms could influence the BBB during malaria, such as the metabolic and inflammatory complications of severe disease acting 'at a distance'. This review will summarise evidence for these mechanisms from human studies of cerebral malaria and discuss the possible role for BBB dysfunction in this complex and challenging disease.
Medana
Isabelle M
IM
Malaria Research Group, Nuffield Department of Clinical Laboratory Sciences, Oxford University, Oxford, UK.
Turner
Gareth D H
GD
D000818:Animals; D015415:Biomarkers / Q000134:cerebrospinal fluid; D001812:Blood-Brain Barrier / Q000276:immunology / Q000469:parasitology / Q000503:physiopathology*; D004730:Endothelium, Vascular / Q000469:parasitology / Q000648:ultrastructure; D006790:Host-Parasite Interactions; D006801:Humans; D016779:Malaria, Cerebral / Q000276:immunology / Q000469:parasitology / Q000503:physiopathology*; D010963:Plasmodium falciparum / Q000472:pathogenicity*
D015415:Biomarkers