Mechanisms of Plasmodium departure from the liver infection stage

Although replication of Plasmodium parasites in red blood cells causes malaria, the blood is not the first site of infection in the vertebrate hosts: Plasmodium initially develop in cells of the liver after mosquito transmission. 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. It has been found that one member of this family, PbSERA4, is important for efficient egress of Plasmodium berghei from host cells following liver-stage development. In the absence of PbSERA4, liver-stage P. berghei infection produces fewer merosomes, and the period before parasites are detected in the blood of infected animals is prolonged. P. berghei will be egineered to express biosensors and reporters to characterize the specific involvement of PbSERA4 in egress, and the exit of these parasites will be visualized by advanced electron microscopy. In addition, this study will explore the contribution of a related cysteine protease, which is also expressed late during the liver infection stage and may also contribute to Plasmodium exit from the liver. The analyses will include investigating the fate of the cells infected with SERA-deficient parasite lines from which egress is unproductive. Since late-stage infected cells are crucial for establishing the blood infection stage and could contain a potential arsenal of merozoite antigens beneficial to the immune response, the fate of these cells is critical for infection outcome. Additionally, the aim is to better understand the contribution of protease activity on merosome release from host cells by identifying substrates of cleavage. Egress of liver-stage Plasmodium requires intimate interaction between parasite and host, and targets of cleavage could be from either of these organisms. In parallel, evaluation of manipulating metabolism and transport of prominent plasma membrane lipid species influences the formation of P. berghei-containing merosomes from infected cells will be done.

Project details

Basic Science

Jan 2021

Germany