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.
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