EphA2 contributes to disruption of the blood-brain barrier in cerebral malaria

Thayer K. Darling; Patrice N. Mimche; Christian Bray; Banlanjo Umaru; Lauren M. Brady; Colleen Stone; Carole Else Eboumbou Moukoko; Thomas E. Lane; Lawrence S. Ayong; Tracey J. Lamb

doi:10.1371/journal.ppat.1008261

EphA2 contributes to disruption of the blood-brain barrier in cerebral malaria

Thayer K. Darling, Patrice N. Mimche, Christian Bray, Banlanjo Umaru, Lauren M. Brady, Colleen Stone, Carole Else Eboumbou Moukoko, Thomas E. Lane, Lawrence S. Ayong, Tracey J. Lamb

Research output: Contribution to journal › Article › peer-review

9 Citations (Scopus)

Abstract

Disruption of blood-brain barrier (BBB) function is a key feature of cerebral malaria. Increased barrier permeability occurs due to disassembly of tight and adherens junctions between endothelial cells, yet the mechanisms governing junction disassembly and vascular permeability during cerebral malaria remain poorly characterized. We found that EphA2 is a principal receptor tyrosine kinase mediating BBB breakdown during Plasmodium infection. Upregulated on brain microvascular endothelial cells in response to inflammatory cytokines, EphA2 is required for the loss of junction proteins on mouse and human brain microvascular endothelial cells. Furthermore, EphA2 is necessary for CD8+ T cell brain infiltration and subsequent BBB breakdown in a mouse model of cerebral malaria. Blocking EphA2 protects against BBB breakdown highlighting EphA2 as a potential therapeutic target for cerebral malaria.

Original language	English
Article number	e1008261
Journal	PLoS Pathogens
Volume	16
Issue number	1
DOIs	https://doi.org/10.1371/journal.ppat.1008261
Publication status	Published - 2020
Externally published	Yes

ASJC Scopus subject areas

Parasitology
Microbiology
Immunology
Molecular Biology
Genetics
Virology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1371/journal.ppat.1008261

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title = "EphA2 contributes to disruption of the blood-brain barrier in cerebral malaria",

abstract = "Disruption of blood-brain barrier (BBB) function is a key feature of cerebral malaria. Increased barrier permeability occurs due to disassembly of tight and adherens junctions between endothelial cells, yet the mechanisms governing junction disassembly and vascular permeability during cerebral malaria remain poorly characterized. We found that EphA2 is a principal receptor tyrosine kinase mediating BBB breakdown during Plasmodium infection. Upregulated on brain microvascular endothelial cells in response to inflammatory cytokines, EphA2 is required for the loss of junction proteins on mouse and human brain microvascular endothelial cells. Furthermore, EphA2 is necessary for CD8+ T cell brain infiltration and subsequent BBB breakdown in a mouse model of cerebral malaria. Blocking EphA2 protects against BBB breakdown highlighting EphA2 as a potential therapeutic target for cerebral malaria.",

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note = "Funding Information: This work was funded by grants from the National Institute of Neurological Disorders and Stroke (R21NS085382 and R01NS097819), the Emory Egleston Children{\textquoteright}s Research Fund, and Royal Society to TJL. TKD was supported by training grants T32AI007610, T32AI106699, and individual fellowship F31NS098736. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of this manuscript. Publisher Copyright: {\textcopyright} 2020 Darling et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.",

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doi = "10.1371/journal.ppat.1008261",

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AU - Stone, Colleen

AU - Moukoko, Carole Else Eboumbou

AU - Lane, Thomas E.

AU - Ayong, Lawrence S.

AU - Lamb, Tracey J.

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EphA2 contributes to disruption of the blood-brain barrier in cerebral malaria

Abstract

ASJC Scopus subject areas

UN SDGs

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