Pathogenic mechanisms of Plasmodium falciparum egress unveiled by a microvascular 3D blood-brain barrier model

Piatti, L.; Batzilla, A.; Nakaki, F.; Fleckenstein, H.; Korbmacher, F.; Long, R. K. M.; Schraivogel, D.; Hawkins, J. A.; Romero-Urunuela, T.; Lopez-Gutierrez, B.; Sanz, S.; Schwab, Y.; Steinmetz, L. M.; Sharpe, J.; Bernabeu, M.

doi:10.1101/2024.10.15.618439

bioRxiv · 10.1101/2024.10.15.618439

Pathogenic mechanisms of Plasmodium falciparum egress unveiled by a microvascular 3D blood-brain barrier model

Piatti, L.·Batzilla, A.·Nakaki, F.·Fleckenstein, H.·Korbmacher, F.·Long, R. K. M.·Schraivogel, D.·Hawkins, J. A.·Romero-Urunuela, T.·Lopez-Gutierrez, B.·Sanz, S.·Schwab, Y.·Steinmetz, L. M.·Sharpe, J.·Bernabeu, M.

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Abstract

Cerebral malaria is a severe neurovascular complication of Plasmodium falciparum infection, with high mortality rates even after treatment with effective antimalarials. Limitations in current experimental models have hindered our knowledge of the disease. We developed a 3D blood-brain barrier (BBB) model with enhanced barrier properties using primary brain endothelial cells, astrocytes and pericytes. Exposure to parasite egress products increased microvascular permeability, likely due to transcriptional downregulation of junctional and vascular development genes in endothelial cells. In addition, it increased the expression of ferroptosis markers, antigen presentation and type I interferon genes and upregulated the JAK-STAT pathway across all BBB cell types. Incubation with cytoadherent schizont-stage P. falciparum-infected erythrocytes induced a similar, but highly localized transcriptional shift, along with inter-endothelial gaps at sites of parasite egress, significantly increasing permeability. The co-administration of egress products with the JAK-STAT inhibitor Ruxolitinib prevented junctional disruption and BBB breakdown. These findings provide key insights into the parasite-mediated mechanisms driving brain microvascular pathogenesis in cerebral malaria and suggest potential avenues for adjunctive therapies.

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Piatti, L., Batzilla, A., Nakaki, F., Fleckenstein, H., Korbmacher, F., Long, R. K. M., Schraivogel, D., Hawkins, J. A., Romero-Urunuela, T., Lopez-Gutierrez, B., Sanz, S., Schwab, Y., Steinmetz, L. M., Sharpe, J., Bernabeu, M.. 2024-10-16. Pathogenic mechanisms of Plasmodium falciparum egress unveiled by a microvascular 3D blood-brain barrier model. https://doi.org/10.1101/2024.10.15.618439

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