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

Kessler, A; Dankwa, S; Bernabeu, M; Harawa, V; Danziger, SA; Duffy, F; Kampondeni, SD; Potchen, MJ; Dambrauskas, N; Vigdorovich, V; Oliver, BG; Hochman, SE; Mowrey, WB; MacCormick, IJC; Mandala, WL; Rogerson, SJ; Sather, DN; Aitchison, JD; Taylor, TE; Seydel, KB; Smith, JD; Kim, K

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

Kessler, A Dankwa, S Bernabeu, M Harawa, V Danziger, SA Duffy, F Kampondeni, SD Potchen, MJ Dambrauskas, N Vigdorovich, V Oliver, BG

Hochman, SE Mowrey, WB MacCormick, IJC Mandala, WL Rogerson, SJ Sather, DN Aitchison, JD Taylor, TE Seydel, KB Smith, JD Kim, K

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Publication Type:: Journal Article
Citation:: Cell Host and Microbe, 2017, 22 (5), pp. 601 - 614.e5
Issue Date:: 2017-11-08

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Field	Value	Language
dc.contributor.author	Kessler, A	en_US
dc.contributor.author	Dankwa, S	en_US
dc.contributor.author	Bernabeu, M	en_US
dc.contributor.author	Harawa, V	en_US
dc.contributor.author	Danziger, SA	en_US
dc.contributor.author	Duffy, F	en_US
dc.contributor.author	Kampondeni, SD	en_US
dc.contributor.author	Potchen, MJ	en_US
dc.contributor.author	Dambrauskas, N	en_US
dc.contributor.author	Vigdorovich, V	en_US
dc.contributor.author	Oliver, BG https://orcid.org/0000-0002-7122-9262	en_US
dc.contributor.author	Hochman, SE	en_US
dc.contributor.author	Mowrey, WB	en_US
dc.contributor.author	MacCormick, IJC	en_US
dc.contributor.author	Mandala, WL	en_US
dc.contributor.author	Rogerson, SJ	en_US
dc.contributor.author	Sather, DN	en_US
dc.contributor.author	Aitchison, JD	en_US
dc.contributor.author	Taylor, TE	en_US
dc.contributor.author	Seydel, KB	en_US
dc.contributor.author	Smith, JD	en_US
dc.contributor.author	Kim, K	en_US
dc.date.issued	2017-11-08	en_US
dc.identifier.citation	Cell Host and Microbe, 2017, 22 (5), pp. 601 - 614.e5	en_US
dc.identifier.issn	1931-3128	en_US
dc.identifier.uri	http://hdl.handle.net/10453/125024
dc.description.abstract	© 2017 Elsevier Inc. 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. Brain swelling is associated with cerebral malaria mortality, but the parasite and host factors responsible for development of brain swelling are unknown. Kessler et al. demonstrate an association of low platelet count and EPCR-binding PfEMP1 with brain swelling in children with cerebral malaria.	en_US
dc.relation.ispartof	Cell Host and Microbe	en_US
dc.relation.isbasedon	10.1016/j.chom.2017.09.009	en_US
dc.subject.classification	Immunology	en_US
dc.title	Linking EPCR-Binding PfEMP1 to Brain Swelling in Pediatric Cerebral Malaria	en_US
dc.type	Journal Article
utslib.citation.volume	5	en_US
utslib.citation.volume	22	en_US
utslib.for	0605 Microbiology	en_US
utslib.for	1108 Medical Microbiology	en_US
pubs.embargo.period	Not known	en_US
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Life Sciences
pubs.organisational-group	/University of Technology Sydney/Strength - CHT - Health Technologies
utslib.copyright.status	closed_access
pubs.declined	2018-06-08T14:28:46.590+1000
pubs.issue	5	en_US
pubs.publication-status	Published	en_US
pubs.volume	22	en_US

Abstract:

© 2017 Elsevier Inc. 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. Brain swelling is associated with cerebral malaria mortality, but the parasite and host factors responsible for development of brain swelling are unknown. Kessler et al. demonstrate an association of low platelet count and EPCR-binding PfEMP1 with brain swelling in children with cerebral malaria.

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http://hdl.handle.net/10453/125024