MALISTA · Malaria liver stages: characterization of essential genes for novel intervention strategies
FP6 — Marie Curie Actions (Human Resources and Mobility)
- Duration
- 2007-01-01 → 2008-12-31
- EU contribution
- €156,496
- Participants
- 1
- Scheme
- EIF
Lines connect the coordinator with its partners.
Results in brief
Final Activity Report Summary - MALISTA (Malaria liver stages: characterization of essential genes for novel intervention strategies.)
Plasmodium parasites, the causative agents of malaria, have a complex life cycle that alternates between a mosquito vector and a vertebrate host. Infected mosquitoes transmit plasmodium forms called sporozoites, which rapidly migrate to the host liver, invade hepatocytes and differentiate into replicative liver stages (LS). After intensive multiplication, LS release merozoites that invade erythrocytes and cause malaria symptoms. Plasmodium LS are clinically silent and represent ideal targets for prophylactic antimalarial drug and vaccine interventions. However, the molecular mechanisms underlying LS development remain poorly characterised. The aim of this project was to characterise genes involved during LS development. We identified a plasmodium protein, termed SLARP, which was specifically expressed in sporozoites and LS. In the absence of SLARP, sporozoites invaded host cells normally but were then completely arrested at a very early stage of LS development. Our results indicated that SLARP functioned as a specific regulator of the expression of genes involved in LS replication. Interestingly, early arrested SLARP-deficient parasites conferred only limited protection in immunised mice, suggesting a requirement of parasite maturation to induce optimal protective immune responses against LS. Our study provided new insights into gene expression regulation during the complex life cycle of the malaria parasite and had important implications for the design of vaccines targeting plasmodium liver stages.
Data: CORDIS, © European Union
Project objective
During malaria transmission Plasmodium sporozoites actively enter the liver and transform into clinically silent liver stages (LS). Each individual LS undergoes multiple rounds of nuclear divisions and eventually produces thousands of first-generation merozoites that initiate the erythrocytic cycle causing malaria pathology.Liver stages are ideal targets for causal prophylactic drugs and vaccine strategies. Immunization with radiation- or genetically-attenuated parasites confers protective immunity against live sporozoite challenge. This protection relies primarily on CD8+ T cell responses against parasite antigens expressed by early LS, but the nature of these antigens still remains unknown.Recent advances in the identification of Plasmodium genes which a re specifically expressed during LS development opened new opportunities to study these stages. Here, I propose to employ a reverse genetic approach to identify parasite genes that perform essential functions during LS development. Using gene targeting in the Plasmodium berghei rodent malaria model, I will produce parasite knockout mutants for genes specifically expressed throughout LS development.Importantly, I expect to generate attenuated parasites blocked at different stages (early, intermediate, and l ate) during LS development. I will include gene products with potential roles in selective protein processing and degradation, since they may constitute potential targets for causal prophylactic anti-malarial drugs. Mutants that attenuate during LS development will be tested for their ability to induce protective immune responses in mice.Ultimately, the characterization of the antigenic repertoire of protective versus non-protective mutants will help defining parasite gene products specifically associated with protection against Plasmodium liver stages. This fellowship will provide me with an excellent training in reverse genetics, and will be critical for the continuation of my career as a researcher.
Original text from CORDIS.
Participants
- UNIVERSITÄTSKLINIKUM HEIDELBERG · HEIDELBERGCoordinatorGermany
Links
Data: CORDIS, © European Union