# EphA2 mediates opening of the blood brain barrier in cerebral malaria

> **NIH NIH R01** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2021 · $356,155

## Abstract

Cerebral malaria (CM) is the leading cause of death in children infected with Plasmodium falciparum.
Approximately 20% of children admitted to hospital with CM will die. Breakdown of the blood brain barrier
(BBB) is a key feature of CM. Although the mechanisms behind this are not fully understood, it is clear that the
barrier can be disrupted by two mechanisms: apoptosis of endothelial cells and opening of the tight junctions.
The Plasmodium berghei ANKA mouse model of cerebral malaria (experimental cerebral malaria, ECM)
shares many features of human CM and has demonstrated a critical role for T cells in the development of this
condition. Previous work has suggested that cytotoxic T cells accumulate in the brain in response to
inflammation induced by sequestered Plasmodium infected red blood cells (iRBCs). Eph receptors are the
largest family of receptor tyrosine kinases. Here we propose that EphA2 is a critical molecule that facilitates
endothelial cell apoptosis by targeting ephrin A ligand-expressing T cell adhesion. This, along with binding of
soluble ephrin A ligands, initiates signaling pathways that induce opening of the tight junctions between
endothelial cells. The long-term goal of this project is to develop an adjunct therapy for CM based on blocking
the EphA2 molecule. Using the P. berghei ANKA model the objective of this proposal is to determine the
mechanism by which EphA2 leads to breakdown of the BBB during ECM. Analysis of the expression of ephrin
A ligands on PBMCs from children in Cameroon who have uncomplicated or cerebral malaria will determine
whether ephrin A ligand expression (soluble and on peripheral T cells) is correlated with the development of
CM. The central hypothesis of this proposal is that EphA2 is upregulated on brain endothelial cells upon
inflammation and mediates adhesion of ephrin A ligand T cells which in turn facilitates degranulation and
endothelial apoptosis. EphA2-mediated signaling pathways will be initiated by binding of T cell-bound and
soluble ephrin A ligands and this will mediate opening of tight junctions in the BBB. Our preliminary data shows
that EphA2-/- mice have an intact BBB and are resistant to death during ECM. We also show that there is
modulation of EphA2 and ephrin A ligands on brain endothelial cells and T cells, respectively. The rationale for
this research is that EphA2 could be a novel target for the development of an adjunctive therapy against CM.
The central hypothesis will be tested by pursuing the following three specific aims: 1) Test the hypothesis that
ligation of EphA2 expressed on brain endothelial cells induces opening of the endothelial junctions during CM
2) Test the hypothesis that EphA2 targets CD8+T cell degranulation and brain endothelial cell apoptosis in CM
and 3) Demonstrate that ephrin A ligand expression in the circulation (soluble and cell surface bound) is
elevated in P. falciparum-infected children with symptoms of CM. The approach is innovative because a r...

## Key facts

- **NIH application ID:** 10111575
- **Project number:** 5R01NS097819-05
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** Tracey Jane Lamb
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $356,155
- **Award type:** 5
- **Project period:** 2017-03-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10111575

## Citation

> US National Institutes of Health, RePORTER application 10111575, EphA2 mediates opening of the blood brain barrier in cerebral malaria (5R01NS097819-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10111575. Licensed CC0.

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