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.

Pathophysiology and neurologic sequelae of cerebral malaria

“…In response to increased inflammation in eCM, Darling et al showed the relevance of the receptor tyrosine kinase EphA at the BBB endothelium [116]. Upregulation of EphA2 was shown to be required for the loss of BBB junction proteins both in eCM and in human brain microvascular endothelial cells and for infiltration of CD8+T cell into the brain in the eCM model.…”

“…However, clinical studies demonstrated that high erythropoietin levels are associated with extended coma and increased mortality [ 149 ]. As the BBB inflammation and loss of integrity also plays a central role in CM, a potential therapeutic approach of blocking EphA2 to protect the BBB from breakdown was suggested in recent eCM studies [ 116 ].…”

Ephs and Ephrins in Adult Endothelial Biology

“…In a study of Miao et al, it was shown that VEGF activates the intracellular PI3K/Akt and Erk1/2 signaling pathways resulting in the increased expression of EphA2 which then, in turn, contributes to an increase in paracellular permeability [38]. The role of (ephrinA1-induced) EphA2 forward signaling in reducing the endothelial barrier function has also been shown in several other in vitro and in vivo studies, where the increased expression of EphA2 increases vascular permeability, and reduced expression decreases (ephrinA1-induced) vascular permeability [28,37,39,75]. Opposite to the increase in vascular permeability upon EphA2 forward signaling, the exposure of endothelial cells to EphA4 recombinant protein could protect the endothelial barrier against TNFα-induced vascular leakage.…”

“…For example, the increased vascular permeability observed in different forms of induced lung injury in mice could be reduced by an EphA2 knockout, administration of recombinant EphA2 or EphA2 receptor blocking antibodies [39,96,97]. The breakdown of the blood-brain-barrier after traumatic brain injury or induced by cerebral malaria in mice, also marked by increased vascular leakage, could be prevented by knockout of EphB3 [56] or EphA2, respectively [75], while the induction of Eph signaling by administration of ephrinA1 after ischemia/reperfusion injury induced blood-brain-barrier damage. These ephrinA1-treated mice showed more inflammation and edema in the brain and had decreased neurological scores.…”

Ephrin receptor A2, the epithelial receptor for Epstein-Barr virus entry, is not available for efficient infection in human gastric organoids

“…This alludes to the physiological relevance of transfer infection of epithelial cells. EPHA2 receptor is upregulated by inflammatory cytokines [ 39 ] and has also been shown to play a role in the recruitment of leukocytes to the site of inflammation [ 39 – 41 ]. Similarly, certain integrins are activated by inflammatory cytokines and also aid the recruitment of leukocytes.…”