title: Loss of endothelial protein C receptors links coagulation and inflammation to parasite sequestration in cerebral malaria in African children.
abstract: Cerebral malaria (CM) is a major cause of mortality in African children and the mechanisms underlying its development, namely how malaria-infected erythrocytes (IEs) cause disease and why the brain is preferentially affected, remain unclear. Brain microhemorrhages in CM suggest a clotting disorder, but whether this phenomenon is important in pathogenesis is debated. We hypothesized that localized cerebral microvascular thrombosis in CM is caused by a decreased expression of the anticoagulant and protective receptors thrombomodulin (TM) and endothelial protein C receptor (EPCR) and that low constitutive expression of these regulatory molecules in the brain make it particularly vulnerable. Autopsies from Malawian children with CM showed cerebral fibrin clots and loss of EPCR, colocalized with sequestered IEs. Using a novel assay to examine endothelial phenotype ex vivo using subcutaneous microvessels, we demonstrated that loss of EPCR and TM at sites of IE cytoadherence is detectible in nonfatal CM. In contrast, although clotting factor activation was seen in the blood of CM patients, this was compensated and did not disseminate. Because of the pleiotropic nature of EPCR and TM, these data implicate disruption of the endothelial protective properties at vulnerable sites and particularly in the brain, linking coagulation and inflammation with IE sequestration.
authors.affiliation: Malawi-Liverpool-Wellcome Clinical Research Programme, University of Malawi College of Medicine, Blantyre, Malawi. cmoxon@liverpool.ac.uk
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Moxon
authors.forename: Samuel C
authors.initials: SC
authors.lastname: Wassmer
authors.forename: Danny A
authors.initials: DA
authors.lastname: Milner
authors.forename: Ngawina V
authors.initials: NV
authors.lastname: Chisala
authors.forename: Terrie E
authors.initials: TE
authors.lastname: Taylor
authors.forename: Karl B
authors.initials: KB
authors.lastname: Seydel
authors.forename: Malcolm E
authors.initials: ME
authors.lastname: Molyneux
authors.forename: Brian
authors.initials: B
authors.lastname: Faragher
authors.forename: Charles T
authors.initials: CT
authors.lastname: Esmon
authors.forename: Colin
authors.initials: C
authors.lastname: Downey
authors.forename: Cheng-Hock
authors.initials: CH
authors.lastname: Toh
authors.forename: Alister G
authors.initials: AG
authors.lastname: Craig
authors.forename: Robert S
authors.initials: RS
authors.lastname: Heyderman
mesh_terms: D015703:Antigens, CD / Q000378:metabolism* / Q000502:physiology; D044383:Black People; D001777:Blood Coagulation / Q000276:immunology / Q000502:physiology*; D001921:Brain / Q000098:blood supply / Q000469:parasitology* / Q000473:pathology; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D015536:Down-Regulation; D000074283:Endothelial Protein C Receptor; D004730:Endothelium, Vascular / Q000378:metabolism*; D004912:Erythrocytes / Q000469:parasitology / Q000473:pathology; D005260:Female; D006801:Humans; D007223:Infant; D007249:Inflammation / Q000378:metabolism / Q000469:parasitology; D016779:Malaria, Cerebral / Q000097:blood / Q000276:immunology / Q000378:metabolism / Q000469:parasitology*; D008295:Malawi; D008297:Male; D011956:Receptors, Cell Surface / Q000378:metabolism* / Q000502:physiology; D018180:Thrombomodulin / Q000378:metabolism / Q000502:physiology
chemical_list: D015703:Antigens, CD; D000074283:Endothelial Protein C Receptor; C478370:PROCR protein, human; D011956:Receptors, Cell Surface; C546931:THBD protein, human; D018180:Thrombomodulin