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Cell Host Microbe. 2017 Nov 8;22(5):601-614.e5. doi: 10.1016/j.chom.2017.09.009. Epub 2017 Oct 26.

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

Author information

1
Department of Medicine, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, NY 10461, USA.
2
Center for Infectious Disease Research, Seattle, WA 98109, USA.
3
Malawi-Liverpool Wellcome Trust Clinical Research Programme, Blantyre BT3, Malawi; University of Malawi, College of Medicine, Biomedical Department, Blantyre BT3, Malawi.
4
Blantyre Malaria Project, Blantyre BT3, Malawi.
5
Department of Imaging Sciences, University of Rochester, Rochester, NY 14642, USA.
6
Department of Medicine, New York University Langone Health, New York, NY 10016, USA.
7
Malawi-Liverpool Wellcome Trust Clinical Research Programme, Blantyre BT3, Malawi; Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh EH16 4SB, UK; Department of Eye and Vision Sciences, University of Liverpool, Liverpool L69 3BX, UK.
8
Malawi-Liverpool Wellcome Trust Clinical Research Programme, Blantyre BT3, Malawi; University of Malawi, College of Medicine, Biomedical Department, Blantyre BT3, Malawi; Academy of Medical Sciences, Malawi University of Science and Technology, Thyolo BT3, Malawi.
9
Department of Medicine at the Doherty Institute, The University of Melbourne, Melbourne, VIC 3000, Australia.
10
Blantyre Malaria Project, Blantyre BT3, Malawi; Department of Osteopathic Medical Specialities, College of Osteopathic Medicine, Michigan State University, East Lansing, MI 48824, USA.
11
Blantyre Malaria Project, Blantyre BT3, Malawi; Department of Osteopathic Medical Specialities, College of Osteopathic Medicine, Michigan State University, East Lansing, MI 48824, USA. Electronic address: seydel@msu.edu.
12
Center for Infectious Disease Research, Seattle, WA 98109, USA; Department of Global Health, University of Washington, Seattle, WA 98195, USA. Electronic address: joe.smith@cidresearch.org.
13
Department of Medicine, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, NY 10461, USA. Electronic address: kamikim@health.usf.edu.

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.

KEYWORDS:

EPCR; PfEMP1; Plasmodium falciparum; brain swelling; cerebral malaria; var

Comment in

PMID:
29107642
PMCID:
PMC5783720
[Available on 2018-11-08]
DOI:
10.1016/j.chom.2017.09.009
[Indexed for MEDLINE]

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