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

Autor:	Kessler A; Department of Medicine, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, NY 10461, USA., Dankwa S; Center for Infectious Disease Research, Seattle, WA 98109, USA., Bernabeu M; Center for Infectious Disease Research, Seattle, WA 98109, USA., Harawa V; Malawi-Liverpool Wellcome Trust Clinical Research Programme, Blantyre BT3, Malawi; University of Malawi, College of Medicine, Biomedical Department, Blantyre BT3, Malawi., Danziger SA; Center for Infectious Disease Research, Seattle, WA 98109, USA., Duffy F; Center for Infectious Disease Research, Seattle, WA 98109, USA., Kampondeni SD; Blantyre Malaria Project, Blantyre BT3, Malawi., Potchen MJ; Department of Imaging Sciences, University of Rochester, Rochester, NY 14642, USA., Dambrauskas N; Center for Infectious Disease Research, Seattle, WA 98109, USA., Vigdorovich V; Center for Infectious Disease Research, Seattle, WA 98109, USA., Oliver BG; Center for Infectious Disease Research, Seattle, WA 98109, USA., Hochman SE; Department of Medicine, New York University Langone Health, New York, NY 10016, USA., Mowrey WB; Department of Medicine, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, NY 10461, USA., MacCormick IJC; 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., Mandala WL; 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., Rogerson SJ; Department of Medicine at the Doherty Institute, The University of Melbourne, Melbourne, VIC 3000, Australia., Sather DN; Center for Infectious Disease Research, Seattle, WA 98109, USA., Aitchison JD; Center for Infectious Disease Research, Seattle, WA 98109, USA., Taylor TE; Blantyre Malaria Project, Blantyre BT3, Malawi; Department of Osteopathic Medical Specialities, College of Osteopathic Medicine, Michigan State University, East Lansing, MI 48824, USA., Seydel KB; 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., Smith JD; 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., Kim K; Department of Medicine, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, NY 10461, USA. Electronic address: kamikim@health.usf.edu.
Jazyk:	angličtina
Zdroj:	Cell host & microbe [Cell Host Microbe] 2017 Nov 08; Vol. 22 (5), pp. 601-614.e5. Date of Electronic Publication: 2017 Oct 26.
DOI:	10.1016/j.chom.2017.09.009
Abstrakt:	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. (Copyright © 2017 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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