Dr Olivier Silvie

Molecular mechanisms of malaria liver infection.

Plasmodium parasites, the causative agents of malaria, are transmitted by Anopheles mosquitoes, which inject motile forms termed sporozoites in the skin. In the first hours of infection, sporozoites migrate in the skin, enter the blood circulation and travel to the liver. There, sporozoites invade hepatocytes inside a specialized compartment, the parasitophorous vacuole. Inside the vacuole, the parasite replicates and differentiates into thousands of merozoites. Once released in the blood circulation, merozoites infect erythrocytes and initiate the clinical phase of infection, associated with the symptoms and complications of malaria.

Infection of hepatocytes by Plasmodium sporozoites is an essential and clinically silent phase of the parasite life cycle, and therefore constitutes an ideal target for anti-malarial prophylactic approaches, notably vaccines. Our group study the molecular mechanisms involved during infection of the liver by Plasmodium. Our projects focus on two aspects: host cell invasion and regulation of gene expression in Plasmodium sporozoites.

The molecular mechanisms of host cell invasion by Plasmodium sporozoites remain unknown. According to the current model, entry into host cells occurs through a tight junction formed by parasite ligands bound to host receptors, which have not been identified yet. The parasite propels itself actively through the junction to enter the cell inside a vacuole. Our objective is to identify parasite and host molecules involved during sporozoite invasion of hepatocytes. In particular, we study the role of CD81, a transmembrane protein expressed at the surface of hepatocytes that is required for Plasmodium sporozoite invasion.

We are also interested in regulation of gene expression during Plasmodium transmission from the mosquito vector to the mammalian host. We investigate transcriptional and post-transcriptional regulatory mechanisms controlling expression of parasite factors that are required during Plasmodium liver stage development. In particular, we study the role of SLARP, a key regulator of sporozoite gene expression, and the post-transcriptional regulation of UIS4, an essential protein of the parasitophorous vacuole membrane.

Our long-term goal is to improve our understanding of the mechanisms of Plasmodium sporozoite invasion and differentiation, in order to develop novel prophylactic approaches against malaria liver infection.