Linking EPCR-Binding PfEMP1 to Brain Swelling in Pediatric Cerebral Malaria

Anne Kessler, Selasi Dankwa, Maria Bernabeu, Visopo Harawa, Samuel A. Danziger, Fergal Duffy, Sam D. Kampondeni, Michael J. Potchen, Nicholas Dambrauskas, Vladimir Vigdorovich, Brian G. Oliver, Sarah E. Hochman, Wenzhu B. Mowrey, Ian J.C. MacCormick, Wilson L. Mandala, Stephen J. Rogerson, D. Noah Sather, John D. Aitchison, Terrie E. Taylor, Karl B. SeydelJoseph D. Smith, Kami Kim

Research output: Contribution to journalArticlepeer-review

Abstract

Brain swelling is a major predictor of mortality in pediatric cerebral malaria (CM). However, the mechanisms leading to swelling remain poorly defined. Here, we combined neuroimaging, parasite transcript profiling, and laboratory blood profiles to develop machine-learning models of malarial retinopathy and brain swelling. We found that parasite var transcripts encoding endothelial protein C receptor (EPCR)-binding domains, in combination with high parasite biomass and low platelet levels, are strong indicators of CM cases with malarial retinopathy. Swelling cases presented low platelet levels and increased transcript abundance of parasite PfEMP1 DC8 and group A EPCR-binding domains. Remarkably, the dominant transcript in 50% of swelling cases encoded PfEMP1 group A CIDRα1.7 domains. Furthermore, a recombinant CIDRα1.7 domain from a pediatric CM brain autopsy inhibited the barrier-protective properties of EPCR in human brain endothelial cells in vitro. Together, these findings suggest a detrimental role for EPCR-binding CIDRα1 domains in brain swelling.
Original languageEnglish
Pages (from-to)601-614.e5
JournalCell Host & Microbe
Volume22
Issue number5
Early online date26 Oct 2017
DOIs
Publication statusPublished - 8 Nov 2017

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