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Updated: Sep 12, 2025
Selection of Plasmodium falciparum Parasites for Cytoadhesion to Human Brain Endothelial Cells
Published on: January 3, 2012
Plasmodium falciparum egress disrupts endothelial junctions and activates JAK-STAT signaling in a microvascular 3D
Livia Piatti1, Alina Batzilla1,2, Fumio Nakaki1
1European Molecular Biology Laboratory (EMBL) Barcelona, Barcelona, Spain.
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.
Insights
A new 3D blood-brain barrier model reveals how Plasmodium falciparum infection damages brain vessels. Targeting the JAK-STAT pathway may offer new treatments for cerebral malaria.
Area of Science:
- Neuroscience
- Infectious Diseases
- Vascular Biology
Background:
- Cerebral malaria, a severe complication of Plasmodium falciparum infection, has high mortality despite antimalarial treatments.
- Current experimental models inadequately represent the disease's complexity, limiting understanding.
- The blood-brain barrier (BBB) is crucial in cerebral malaria pathogenesis.
Purpose of the Study:
- To develop an advanced 3D blood-brain barrier model.
- To investigate parasite-induced mechanisms of brain microvascular injury.
- To identify potential therapeutic targets for cerebral malaria.
Main Methods:
- Developed a 3D BBB model using primary brain endothelial cells, astrocytes, and pericytes.
- Exposed the model to Plasmodium falciparum egress products and infected erythrocytes.
- Analyzed transcriptional changes, gene expression (ferroptosis, antigen presentation, interferon), and JAK-STAT pathway activation.
- Evaluated the effect of Ruxolitinib, a JAK-STAT inhibitor, on BBB permeability.
Main Results:
- Parasite egress products increased BBB permeability by downregulating junctional and vascular genes in endothelial cells.
- Exposure upregulated ferroptosis, antigen presentation, and type I interferon genes, activating the JAK-STAT pathway.
- Infected erythrocytes induced localized transcriptional shifts and inter-endothelial gaps, enhancing permeability.
- Ruxolitinib treatment inhibited the permeability increase caused by parasite egress products.
Conclusions:
- Parasite-mediated mechanisms significantly contribute to brain microvascular damage in cerebral malaria.
- The JAK-STAT pathway is a key mediator of BBB dysfunction in this condition.
- Targeting the JAK-STAT pathway presents a promising strategy for adjunctive therapy in cerebral malaria.
