Journal
CELL HOST & MICROBE
Volume 22, Issue 5, Pages 601-+Publisher
CELL PRESS
DOI: 10.1016/j.chom.2017.09.009
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Funding
- NIH [K08MH089848, T32 AI 070117, R01AI34969, R01AI114766, R01HL130488, P41GM109824]
- NIH National Center for Advancing Translational Science (NCATS) Einstein-Montefiore CTSA [TL1TR001072]
- Burroughs Wellcome Fund
- National Health and Medical Research Council of Australia [1061993]
- Michigan State University College of Osteopathic Medicine
- National Health and Medical Research Council of Australia [1061993] Funding Source: NHMRC
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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 CIDR alpha 1.7 domains. Furthermore, a recombinant CIDR alpha 1.7 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 CIDR alpha 1 domains in brain swelling.
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