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

Anne Kessler, Selasi Dankwa, Maria Bernabeu, Visopo Harawa, Samuel A. Danziger, Fergal Duffy, Sam D. Kampondeni, Michael J. Potchen, Nicholas Dambrauskas, Vladimir Vigdorovich, Brian G. Oliver, Sarah E. Hochman, Wenzhu Bi Mowrey, Ian J.C. MacCormick, Wilson L. Mandala, Stephen J. Rogerson, D. Noah Sather, John D. Aitchison, Terrie E. Taylor, Karl B. SeydelJoseph D. Smith, Kami Kim

Research output: Contribution to journalArticle

22 Citations (Scopus)

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. 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.

Original languageEnglish (US)
Pages (from-to)601-614.e5
JournalCell Host and Microbe
Volume22
Issue number5
DOIs
StatePublished - Nov 8 2017

Fingerprint

Cerebral Malaria
Brain Edema
Protein C
Pediatrics
Parasites
Blood Platelets
Mortality
Brain
Platelet Count
Neuroimaging
Biomass
Autopsy
Endothelial Cells

Keywords

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

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Virology

Cite this

Kessler, A., Dankwa, S., Bernabeu, M., Harawa, V., Danziger, S. A., Duffy, F., ... Kim, K. (2017). Linking EPCR-Binding PfEMP1 to Brain Swelling in Pediatric Cerebral Malaria. Cell Host and Microbe, 22(5), 601-614.e5. https://doi.org/10.1016/j.chom.2017.09.009

Linking EPCR-Binding PfEMP1 to Brain Swelling in Pediatric Cerebral Malaria. / Kessler, Anne; Dankwa, Selasi; Bernabeu, Maria; Harawa, Visopo; Danziger, Samuel A.; Duffy, Fergal; Kampondeni, Sam D.; Potchen, Michael J.; Dambrauskas, Nicholas; Vigdorovich, Vladimir; Oliver, Brian G.; Hochman, Sarah E.; Mowrey, Wenzhu Bi; MacCormick, Ian J.C.; Mandala, Wilson L.; Rogerson, Stephen J.; Sather, D. Noah; Aitchison, John D.; Taylor, Terrie E.; Seydel, Karl B.; Smith, Joseph D.; Kim, Kami.

In: Cell Host and Microbe, Vol. 22, No. 5, 08.11.2017, p. 601-614.e5.

Research output: Contribution to journalArticle

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 2017, 'Linking EPCR-Binding PfEMP1 to Brain Swelling in Pediatric Cerebral Malaria', Cell Host and Microbe, vol. 22, no. 5, pp. 601-614.e5. https://doi.org/10.1016/j.chom.2017.09.009
Kessler A, Dankwa S, Bernabeu M, Harawa V, Danziger SA, Duffy F et al. Linking EPCR-Binding PfEMP1 to Brain Swelling in Pediatric Cerebral Malaria. Cell Host and Microbe. 2017 Nov 8;22(5):601-614.e5. https://doi.org/10.1016/j.chom.2017.09.009
Kessler, Anne ; Dankwa, Selasi ; Bernabeu, Maria ; Harawa, Visopo ; Danziger, Samuel A. ; Duffy, Fergal ; Kampondeni, Sam D. ; Potchen, Michael J. ; Dambrauskas, Nicholas ; Vigdorovich, Vladimir ; Oliver, Brian G. ; Hochman, Sarah E. ; Mowrey, Wenzhu Bi ; MacCormick, Ian J.C. ; Mandala, Wilson L. ; Rogerson, Stephen J. ; Sather, D. Noah ; Aitchison, John D. ; Taylor, Terrie E. ; Seydel, Karl B. ; Smith, Joseph D. ; Kim, Kami. / Linking EPCR-Binding PfEMP1 to Brain Swelling in Pediatric Cerebral Malaria. In: Cell Host and Microbe. 2017 ; Vol. 22, No. 5. pp. 601-614.e5.
@article{3834d16cbbe24576a2b430c8e7038d42,
title = "Linking EPCR-Binding PfEMP1 to Brain Swelling in Pediatric Cerebral Malaria",
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. 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.",
keywords = "brain swelling, cerebral malaria, EPCR, PfEMP1, Plasmodium falciparum, var",
author = "Anne Kessler and Selasi Dankwa and Maria Bernabeu and Visopo Harawa and Danziger, {Samuel A.} and Fergal Duffy and Kampondeni, {Sam D.} and Potchen, {Michael J.} and Nicholas Dambrauskas and Vladimir Vigdorovich and Oliver, {Brian G.} and Hochman, {Sarah E.} and Mowrey, {Wenzhu Bi} and MacCormick, {Ian J.C.} and Mandala, {Wilson L.} and Rogerson, {Stephen J.} and Sather, {D. Noah} and Aitchison, {John D.} and Taylor, {Terrie E.} and Seydel, {Karl B.} and Smith, {Joseph D.} and Kami Kim",
year = "2017",
month = "11",
day = "8",
doi = "10.1016/j.chom.2017.09.009",
language = "English (US)",
volume = "22",
pages = "601--614.e5",
journal = "Cell Host and Microbe",
issn = "1931-3128",
publisher = "Cell Press",
number = "5",

}

TY - JOUR

T1 - Linking EPCR-Binding PfEMP1 to Brain Swelling in Pediatric Cerebral Malaria

AU - Kessler, Anne

AU - Dankwa, Selasi

AU - Bernabeu, Maria

AU - Harawa, Visopo

AU - Danziger, Samuel A.

AU - Duffy, Fergal

AU - Kampondeni, Sam D.

AU - Potchen, Michael J.

AU - Dambrauskas, Nicholas

AU - Vigdorovich, Vladimir

AU - Oliver, Brian G.

AU - Hochman, Sarah E.

AU - Mowrey, Wenzhu Bi

AU - MacCormick, Ian J.C.

AU - Mandala, Wilson L.

AU - Rogerson, Stephen J.

AU - Sather, D. Noah

AU - Aitchison, John D.

AU - Taylor, Terrie E.

AU - Seydel, Karl B.

AU - Smith, Joseph D.

AU - Kim, Kami

PY - 2017/11/8

Y1 - 2017/11/8

N2 - 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.

AB - 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.

KW - brain swelling

KW - cerebral malaria

KW - EPCR

KW - PfEMP1

KW - Plasmodium falciparum

KW - var

UR - http://www.scopus.com/inward/record.url?scp=85032590759&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85032590759&partnerID=8YFLogxK

U2 - 10.1016/j.chom.2017.09.009

DO - 10.1016/j.chom.2017.09.009

M3 - Article

C2 - 29107642

AN - SCOPUS:85032590759

VL - 22

SP - 601-614.e5

JO - Cell Host and Microbe

JF - Cell Host and Microbe

SN - 1931-3128

IS - 5

ER -