Summary
Apicomplexan are obligatory intracellular parasites. The ability of these parasites (Plasmodium, Toxoplasma) to cause disease depends on the coordinated secretion of specialized secretory organelles. The rhoptries are particularly important, because they act as the apicomplexan equivalent of bacterial secretion systems. They inject parasite proteins directly in the cytoplasm of host cells not only for invasion but also to hijack host functions crucial to establish and maintain infection. However, in contrast to bacteria where the secretion machinery has been resolved to atomic detail, how eukaryotic parasites secrete and inject rhoptry effectors into cells is an enigma. This proposal aims to dissect the mechanistic steps and the molecular components that assemble the rhoptry secretion machine.
Our aims are:
1- To explore the mechanisms that trigger rhoptry exocytosis upon binding of the parasite to the host cell.
2- To provide insights into fusion machinery of rhoptry with the parasite plasma membrane. Our model is based on the discovery that free-living Ciliates and intracellular Apicomplexa share an evolutionarily conserved blueprint for their fusion mechanism.
3- To test and expand our hypothesis that rhoptries deliver their content through a transient pore formed into the host cell membrane.
We will employ powerful experimental systems in Toxoplasma, Plasmodium and the Ciliate Tetrahymena, taking full advantage of the relative strength of each model. This comprehensive project will bring together comparative genomics, targeted and global genetics, biochemistry, high resolution imaging and electrophysiology.
This project answers a question of fundamental biological importance. How can a parasite sense the host cell and inject virulence factors to attain control? Understanding this mechanism will guide future efforts to disrupt parasite infection and will contribute to broader understanding of fascinating questions of membrane fusion and export processes.
Our aims are:
1- To explore the mechanisms that trigger rhoptry exocytosis upon binding of the parasite to the host cell.
2- To provide insights into fusion machinery of rhoptry with the parasite plasma membrane. Our model is based on the discovery that free-living Ciliates and intracellular Apicomplexa share an evolutionarily conserved blueprint for their fusion mechanism.
3- To test and expand our hypothesis that rhoptries deliver their content through a transient pore formed into the host cell membrane.
We will employ powerful experimental systems in Toxoplasma, Plasmodium and the Ciliate Tetrahymena, taking full advantage of the relative strength of each model. This comprehensive project will bring together comparative genomics, targeted and global genetics, biochemistry, high resolution imaging and electrophysiology.
This project answers a question of fundamental biological importance. How can a parasite sense the host cell and inject virulence factors to attain control? Understanding this mechanism will guide future efforts to disrupt parasite infection and will contribute to broader understanding of fascinating questions of membrane fusion and export processes.
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More information & hyperlinks
| Web resources: | https://cordis.europa.eu/project/id/833309 |
| Start date: | 01-10-2020 |
| End date: | 30-09-2025 |
| Total budget - Public funding: | 2 496 210,00 Euro - 2 496 210,00 Euro |
Cordis data
Original description
Apicomplexan are obligatory intracellular parasites. The ability of these parasites (Plasmodium, Toxoplasma) to cause disease depends on the coordinated secretion of specialized secretory organelles. The rhoptries are particularly important, because they act as the apicomplexan equivalent of bacterial secretion systems. They inject parasite proteins directly in the cytoplasm of host cells not only for invasion but also to hijack host functions crucial to establish and maintain infection. However, in contrast to bacteria where the secretion machinery has been resolved to atomic detail, how eukaryotic parasites secrete and inject rhoptry effectors into cells is an enigma. This proposal aims to dissect the mechanistic steps and the molecular components that assemble the rhoptry secretion machine.Our aims are:
1- To explore the mechanisms that trigger rhoptry exocytosis upon binding of the parasite to the host cell.
2- To provide insights into fusion machinery of rhoptry with the parasite plasma membrane. Our model is based on the discovery that free-living Ciliates and intracellular Apicomplexa share an evolutionarily conserved blueprint for their fusion mechanism.
3- To test and expand our hypothesis that rhoptries deliver their content through a transient pore formed into the host cell membrane.
We will employ powerful experimental systems in Toxoplasma, Plasmodium and the Ciliate Tetrahymena, taking full advantage of the relative strength of each model. This comprehensive project will bring together comparative genomics, targeted and global genetics, biochemistry, high resolution imaging and electrophysiology.
This project answers a question of fundamental biological importance. How can a parasite sense the host cell and inject virulence factors to attain control? Understanding this mechanism will guide future efforts to disrupt parasite infection and will contribute to broader understanding of fascinating questions of membrane fusion and export processes.
Status
SIGNEDCall topic
ERC-2018-ADGUpdate Date
27-04-2024
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