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bioRxiv · 10.64898/2026.10.18.760006

Brain microvascular endothelial cell dysfunction during Plasmodium infection does not result from astrocyte-derived wingless-related integration site (Wnt)7a deficiency

Roedel, M.·Brooks, N.·Andersen, J. N.·Cornwall, D. H.·Doddavaram, R.·Chastang, K.·Rubner, L.·Liu, T.·Lamb, T.
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Abstract

Breakdown of the blood brain barrier is a key event leading to vasogenic edema that underpins pediatric cerebral malaria. Brain microvascular endothelial cells (BMECs) downregulate junction proteins in response to Plasmodium-infected red blood cells (iRBCs). Very little is known about how glial cell activation in Plasmodium infection dysregulates astrocyte-derived steady state signals that control BMEC junction expression. Astrocytes from mice infected with Plasmodium berghei ANKA (PbA) exhibit transcriptional changes dominated by interferon signaling pathways. Downregulation of wingless-related integration site (Wnt)7a transcription in astrocytes correlated with transcriptional changes in BMECs indicative of reduced {beta}-catenin activity. Incubation of the human astrocyte-like glioma cell-line CCF-STTG1 with interferon-{gamma} (IFN-{gamma}) decreased the general production of Wnt7a in response to P. falciparum iRBCs. However astrocyte conditioned medium incubated with IFN-{gamma} strengthened the barrier function in vitro when added onto monolayers the human cerebral microvascular endothelial cell line D3 (hCMEC/D3). This data suggests that the response of astrocytes during Plasmodium infection may be protective but unable to overcome dysfunctional responses of BMECs to Plasmodium iRBCs. To test this hypothesis we overexpressed Wnt7a in the brain tissue of mice using an AAV construct but this did not impart increased survival to the neurological effects of PbA infection. Therefore astrocyte responses during Plasmodium infection may not underlie the downregulation of junction proteins on BMECs leading to edema in cerebral malaria.

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Roedel, M., Brooks, N., Andersen, J. N., Cornwall, D. H., Doddavaram, R., Chastang, K., Rubner, L., Liu, T., Lamb, T.. 2026-10-23. Brain microvascular endothelial cell dysfunction during Plasmodium infection does not result from astrocyte-derived wingless-related integration site (Wnt)7a deficiency. https://doi.org/10.64898/2026.10.18.760006

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