Summary
Brain swelling is the 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.
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