@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 = "EPCR, PfEMP1, Plasmodium falciparum, brain swelling, cerebral malaria, 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 B.} 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",
note = "Funding Information: We thank the patients and their families who made this study possible. We thank Patricia Phula and the Blantyre Malaria Project (BMP) laboratory staff for help with sample collection and processing, Alice Liomba (BMP) for organizing data, Jack Gormley for the 2016 ophthalmoscopy, Matt Levy for sharing equipment, and Adriana Lippy for illustration. The study was made possible by NIH grants K08MH089848 and T32 AI 070117 (S.E.H.), R01AI34969 (T.E.T.), R01AI114766 and R01HL130488 (J.D.S.), and P41GM109824 (J.D.A.); NIH National Center for Advancing Translational Science (NCATS) Einstein-Montefiore CTSA TL1TR001072 (A.K.); the Burroughs Wellcome Fund (A.K.); grant 1061993 from the National Health and Medical Research Council of Australia (S.J.R.); and support from the Michigan State University College of Osteopathic Medicine (T.E.T.). Data in this paper are from a thesis submitted in partial fulfillment of the requirements for the Degree of Doctor of Philosophy in the Graduate Division of Medical Sciences at Albert Einstein College of Medicine – Yeshiva University. Funding Information: We thank the patients and their families who made this study possible. We thank Patricia Phula and the Blantyre Malaria Project (BMP) laboratory staff for help with sample collection and processing, Alice Liomba (BMP) for organizing data, Jack Gormley for the 2016 ophthalmoscopy, Matt Levy for sharing equipment, and Adriana Lippy for illustration. The study was made possible by NIH grants K08MH089848 and T32 AI 070117 (S.E.H.), R01AI34969 (T.E.T.), R01AI114766 and R01HL130488 (J.D.S.), and P41GM109824 (J.D.A.); NIH National Center for Advancing Translational Science (NCATS) Einstein-Montefiore CTSA TL1TR001072 (A.K.); the Burroughs Wellcome Fund (A.K.); grant 1061993 from the National Health and Medical Research Council of Australia (S.J.R.); and support from the Michigan State University College of Osteopathic Medicine (T.E.T.). Data in this paper are from a thesis submitted in partial fulfillment of the requirements for the Degree of Doctor of Philosophy in the Graduate Division of Medical Sciences at Albert Einstein College of Medicine – Yeshiva University. Publisher Copyright: {\textcopyright} 2017 Elsevier Inc.",
year = "2017",
month = nov,
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",
}
