Parasite histones are toxic to brain endothelium and link blood barrier breakdown and thrombosis in cerebral malaria

Moxon, C. A. et al. (2020) Parasite histones are toxic to brain endothelium and link blood barrier breakdown and thrombosis in cerebral malaria. Blood Advances, 4(13), pp. 2851-2864. (doi: 10.1182/bloodadvances.2019001258) (PMID:32579667) (PMCID:PMC7362376)

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Microvascular thrombosis and blood-brain barrier (BBB) breakdown are key components of cerebral malaria (CM) pathogenesis in African children and are implicated in fatal brain swelling. How Plasmodium falciparum infection causes this endothelial disruption and why this occurs, particularly in the brain, is not fully understood. In this study, we have demonstrated that circulating extracellular histones, equally of host and parasite origin, are significantly elevated in CM patients. Higher histone levels are associated with brain swelling on magnetic resonance imaging. On postmortem brain sections of CM patients, we found that histones are colocalized with P falciparum-infected erythrocytes sequestered inside small blood vessels, suggesting that histones might be expelled locally during parasite schizont rupture. Histone staining on the luminal vascular surface colocalized with thrombosis and leakage, indicating a possible link between endothelial surface accumulation of histones and coagulation activation and BBB breakdown. Supporting this, patient sera or purified P falciparum histones caused disruption of barrier function and were toxic to cultured human brain endothelial cells, which were abrogated with antihistone antibody and nonanticoagulant heparin. Overall, our data support a role for histones of parasite and host origin in thrombosis, BBB breakdown, and brain swelling in CM, processes implicated in the causal pathway to death. Neutralizing histones with agents such as nonanticoagulant heparin warrant exploration to prevent brain swelling in the development or progression of CM and thereby to improve outcomes.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Seydel, Dr Karl and McGuinness, Dr Dagmara and Moxon, Dr Christopher
Authors: Moxon, C. A., Alhamadi, Y., Storm, J., Toh, J. M.H., McGuinness, D., Ko, J. Y., Murphy, G., Lane, S., Taylor, T. E., Seydel, K. B., Kampondeni, S., Potchen, M., O'Donnell, J. S., O'Regan, N., Wang, G., García- Cardeña, G., Molyneux, M., Craig, A., Abrams, S. T., and Toh, C.-H.
College/School:College of Medical Veterinary and Life Sciences > School of Infection & Immunity
Journal Name:Blood Advances
Publisher:American Society of Hematology
ISSN (Online):2473-9529
Published Online:24 June 2020
Copyright Holders:Copyright © 2020 The American Society of Hematology
First Published:First published in Blood Advances 4(13):2851-2864
Publisher Policy:Reproduced in accordance with the publisher copyright policy

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
170547The Wellcome Centre for Molecular Parasitology ( Core Support )Andrew WatersWellcome Trust (WELLCOTR)104111/Z/14/ZRIII - Parasitology