Plasmodium falciparum egress disrupts endothelial junctions and activates JAK-STAT signaling in a microvascular 3D blood-brain barrier model
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 barri...
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Nature Portfolio
2025-08-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-62514-2 |
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| author | Livia Piatti Alina Batzilla Fumio Nakaki Hannah Fleckenstein François Korbmacher Rory K. M. Long Daniel Schraivogel John A. Hawkins Tais Romero-Uruñuela Borja López-Gutiérrez Silvia Sanz Sender Yannick Schwab Lars M. Steinmetz James Sharpe Maria Bernabeu |
| author_facet | Livia Piatti Alina Batzilla Fumio Nakaki Hannah Fleckenstein François Korbmacher Rory K. M. Long Daniel Schraivogel John A. Hawkins Tais Romero-Uruñuela Borja López-Gutiérrez Silvia Sanz Sender Yannick Schwab Lars M. Steinmetz James Sharpe Maria Bernabeu |
| author_sort | Livia Piatti |
| collection | DOAJ |
| description | 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 increases microvascular permeability, likely due to transcriptional downregulation of junctional and vascular development genes in endothelial cells. In addition, it increases the expression of ferroptosis markers, antigen presentation and type I interferon genes and upregulates the JAK-STAT pathway across all BBB cell types. Incubation with cytoadherent schizont-stage P. falciparum-infected erythrocytes induces a similar, but highly localized transcriptional shift, along with inter-endothelial gaps at sites of parasite egress, leading to enhanced permeability. Treatment with the JAK-STAT inhibitor Ruxolitinib prevents the increase in permeability induced by P. falciparum egress products. These findings provide key insights into the parasite-mediated mechanisms driving brain microvascular pathogenesis in cerebral malaria and suggest potential avenues for adjunctive therapies. |
| format | Article |
| id | doaj-art-e041b1b78b514e29b433c8179b317947 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-e041b1b78b514e29b433c8179b3179472025-08-20T04:03:01ZengNature PortfolioNature Communications2041-17232025-08-0116111910.1038/s41467-025-62514-2Plasmodium falciparum egress disrupts endothelial junctions and activates JAK-STAT signaling in a microvascular 3D blood-brain barrier modelLivia Piatti0Alina Batzilla1Fumio Nakaki2Hannah Fleckenstein3François Korbmacher4Rory K. M. Long5Daniel Schraivogel6John A. Hawkins7Tais Romero-Uruñuela8Borja López-Gutiérrez9Silvia Sanz Sender10Yannick Schwab11Lars M. Steinmetz12James Sharpe13Maria Bernabeu14European Molecular Biology Laboratory (EMBL) BarcelonaEuropean Molecular Biology Laboratory (EMBL) BarcelonaEuropean Molecular Biology Laboratory (EMBL) BarcelonaEuropean Molecular Biology Laboratory (EMBL) BarcelonaEuropean Molecular Biology Laboratory (EMBL) BarcelonaEuropean Molecular Biology Laboratory (EMBL) BarcelonaEuropean Molecular Biology Laboratory (EMBL), Genome Biology UnitEuropean Molecular Biology Laboratory (EMBL), Genome Biology UnitEuropean Molecular Biology Laboratory (EMBL) BarcelonaEuropean Molecular Biology Laboratory (EMBL) BarcelonaEuropean Molecular Biology Laboratory (EMBL) BarcelonaEuropean Molecular Biology Laboratory (EMBL), Cell Biology and Biophysics UnitEuropean Molecular Biology Laboratory (EMBL), Genome Biology UnitEuropean Molecular Biology Laboratory (EMBL) BarcelonaEuropean Molecular Biology Laboratory (EMBL) BarcelonaAbstract 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 increases microvascular permeability, likely due to transcriptional downregulation of junctional and vascular development genes in endothelial cells. In addition, it increases the expression of ferroptosis markers, antigen presentation and type I interferon genes and upregulates the JAK-STAT pathway across all BBB cell types. Incubation with cytoadherent schizont-stage P. falciparum-infected erythrocytes induces a similar, but highly localized transcriptional shift, along with inter-endothelial gaps at sites of parasite egress, leading to enhanced permeability. Treatment with the JAK-STAT inhibitor Ruxolitinib prevents the increase in permeability induced by P. falciparum egress products. These findings provide key insights into the parasite-mediated mechanisms driving brain microvascular pathogenesis in cerebral malaria and suggest potential avenues for adjunctive therapies.https://doi.org/10.1038/s41467-025-62514-2 |
| spellingShingle | Livia Piatti Alina Batzilla Fumio Nakaki Hannah Fleckenstein François Korbmacher Rory K. M. Long Daniel Schraivogel John A. Hawkins Tais Romero-Uruñuela Borja López-Gutiérrez Silvia Sanz Sender Yannick Schwab Lars M. Steinmetz James Sharpe Maria Bernabeu Plasmodium falciparum egress disrupts endothelial junctions and activates JAK-STAT signaling in a microvascular 3D blood-brain barrier model Nature Communications |
| title | Plasmodium falciparum egress disrupts endothelial junctions and activates JAK-STAT signaling in a microvascular 3D blood-brain barrier model |
| title_full | Plasmodium falciparum egress disrupts endothelial junctions and activates JAK-STAT signaling in a microvascular 3D blood-brain barrier model |
| title_fullStr | Plasmodium falciparum egress disrupts endothelial junctions and activates JAK-STAT signaling in a microvascular 3D blood-brain barrier model |
| title_full_unstemmed | Plasmodium falciparum egress disrupts endothelial junctions and activates JAK-STAT signaling in a microvascular 3D blood-brain barrier model |
| title_short | Plasmodium falciparum egress disrupts endothelial junctions and activates JAK-STAT signaling in a microvascular 3D blood-brain barrier model |
| title_sort | plasmodium falciparum egress disrupts endothelial junctions and activates jak stat signaling in a microvascular 3d blood brain barrier model |
| url | https://doi.org/10.1038/s41467-025-62514-2 |
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