Project: Mechanisms of Plasmodium departure from the liver infection stage
While replication of Plasmodium parasites in the blood of infected individuals causes the symptoms of malaria, the preceding liver stage of Plasmodium infection is crucial for establishing infection. The transition from the liver into the blood is likely a vulnerable time for malaria parasites. The number of Plasmodium parasites transmitted by a mosquito bite are limited, and the opportunity for parasite expansion in hepatic cells is restricted to one round of replication. At the end of their development in the liver, Plasmodium take advantage of their host cells to facilitate their release. Packages of merozoites, the Plasmodium form infectious to erythrocytes, are extruded from the host hepatocytes and surrounded by hepatocyte plasma membrane. Within these so called merosomes, parasites hide from the host immune system as they transit into the blood circulation. The exit process is actively orchestrated by the parasite to ensure successful transition to the new environment.
A family of cysteine proteases is conserved across Plasmodium species and members of this family are known to be involved in parasite egress. We have found that one member of this family, PbSERA4, is important for efficient egress of Plasmodium berghei from host cells following liver-stage development.
The overall goals of this study are to characterize how parasite cysteine proteases contribute to the exit of Plasmodium parasites from the liver and to identify additional factors from the parasite or host that contribute to this egress process. We will investigate the specific step in liver-stage egress at which PbSERA4 is functioning and search for substrates of this enzyme. Since late-stage infected liver cells are crucial for establishing the blood infection stage and could contain a potential arsenal of merozoite antigens beneficial to the immune response, we will also explore the fate of cells from which egress of PbSERA4-deficient Plasmodium is unproductive. In parallel, we will evaluate how host lipids influence the formation of P. berghei-containing merosomes from infected cells. This project will take a collaborative multi-disciplinary approach to better understand the molecular mechanisms governing exit of Plasmodium from the liver.