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Loss of endothelial protein C receptors links coagulation and inflammation to parasite sequestration in cerebral malaria in African children

Christopher A. Moxon, Samuel C. Wassmer, Danny A. Milner Jr., Ngawina V. Chisala, Terrie E. Taylor, Karl B. Seydel, Malcolm E. Molyneux, Brian Faragher, Charles T. Esmon, Colin Downey, Cheng-Hock Toh, Alister G. Craig, Robert S. Heyderman

Key points

  • In cerebral malaria, infected erythrocytes (IE) cause loss of protein C receptors and a highly localized microvascular coagulopathy.

  • Low cerebral constitutive expression of these receptors - EPCR and TM - may explain the brain's vulnerability to IE-dependent pathology.

Abstract

Cerebral malaria (CM) is a major cause of mortality in African children and the mechanisms underlying its development, namely how malaria-infected erythrocytes (IE) 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, co-localized 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 non-fatal 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.

  • Submitted March 14, 2013.
  • Accepted May 17, 2013.