Summary
Plasmodium falciparum cerebral malaria (CM) is the most severe complication during malaria infections. CM is associated with patient coma and blood-brain barrier (BBB) disruption resulting in brain swelling and patient death. In the zoonotic malaria parasite P. knowlesi, CM is described in rhesus macaques but occurs neither in human infections nor in the natural long-tail macaque reservoir. Infected red blood cell cytoadhesion to endothelial cells and the release of parasite toxins have been described as pathogenic mechanisms of falciparum CM. Both factors are present in P. knowlesi in all three primate hosts, albeit at different levels and result in different clinical outcomes. Therefore, I hypothesize that the pathogenic mechanisms of CM in primates are host and parasite-specific. As in vivo studies are limited to post mortem samples, I aim to develop in MAL-ZOO novel microvascular 3D in vitro models of the human, rhesus macaque and long tail macaque BBB. I will adapt existing differentiation protocols for human induced pluripotent stem cells (iPSC) to generate macaque endothelial cells, astrocytes and pericytes, that will be introduced in a 3D microvascular model. Taking advantage of the microfluidic properties of the devices, I will characterize the dynamics of P. knowlesi cytoadhesion to the endothelium of the three hosts. Afterwards, I will measure the BBB pathogenicity of these two parasites by confocal microscopy, functional permeability assays and RNAseq transcriptional analysis and correlate it to the parasite cytoadhesion levels. The cross-species comparison will be used to highlight species-specific virulence factors during P. falciparum and P. knowlesi infections. This will improve our understanding of the mechanisms leading to P. falciparum CM in humans and the pathogenic potential of zoonotic P. knowlesi malaria.
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| Web resources: | https://cordis.europa.eu/project/id/101068552 |
| Start date: | 01-04-2023 |
| End date: | 31-03-2025 |
| Total budget - Public funding: | - 165 312,00 Euro |
Cordis data
Original description
Plasmodium falciparum cerebral malaria (CM) is the most severe complication during malaria infections. CM is associated with patient coma and blood-brain barrier (BBB) disruption resulting in brain swelling and patient death. In the zoonotic malaria parasite P. knowlesi, CM is described in rhesus macaques but occurs neither in human infections nor in the natural long-tail macaque reservoir. Infected red blood cell cytoadhesion to endothelial cells and the release of parasite toxins have been described as pathogenic mechanisms of falciparum CM. Both factors are present in P. knowlesi in all three primate hosts, albeit at different levels and result in different clinical outcomes. Therefore, I hypothesize that the pathogenic mechanisms of CM in primates are host and parasite-specific. As in vivo studies are limited to post mortem samples, I aim to develop in MAL-ZOO novel microvascular 3D in vitro models of the human, rhesus macaque and long tail macaque BBB. I will adapt existing differentiation protocols for human induced pluripotent stem cells (iPSC) to generate macaque endothelial cells, astrocytes and pericytes, that will be introduced in a 3D microvascular model. Taking advantage of the microfluidic properties of the devices, I will characterize the dynamics of P. knowlesi cytoadhesion to the endothelium of the three hosts. Afterwards, I will measure the BBB pathogenicity of these two parasites by confocal microscopy, functional permeability assays and RNAseq transcriptional analysis and correlate it to the parasite cytoadhesion levels. The cross-species comparison will be used to highlight species-specific virulence factors during P. falciparum and P. knowlesi infections. This will improve our understanding of the mechanisms leading to P. falciparum CM in humans and the pathogenic potential of zoonotic P. knowlesi malaria.Status
SIGNEDCall topic
HORIZON-MSCA-2021-PF-01-01Update Date
09-02-2023
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