Last Updated: 01/08/2024
Plasmodium liver stage schizogony: high replication and genetic diversity (PASSAGE)
Objectives
By using a combination of molecular, cell biology and genetic approaches, this proposal now sets to characterize the mechanisms, define the molecular players, and reveal the causes and consequences of such a high replication rate in the outcome of infection and progression of disease, by exposing the consequences for parasite genetic diversity and virulence.
A world free of malaria is certainly a desirable goal. However, in spite of the significant incidence reduction achieved globally between 2000-2015, malaria still kills a child every minute. The limited understanding of Plasmodium’s biology hampers the development of novel intervention strategies. Upon transmission by Anopheles mosquitos, Plasmodium parasites must reach the liver and infect hepatocytes. Inside a hepatocyte, each parasite replicates into thousands of new erythrocyte-infectious forms, which lead to disease. The parasite biomass generated during the liver stage (LS) of infection is directly associated with malaria severity, but how the parasite achieves such a high replication rate, and the consequences of that, remain utterly unexplored. Notably, Plasmodium replication is unusual. The parasite divides by schizogony, with divisions occurring without cytokinesis and it cannot salvage pyrimidines from the environment, relying solely on nucleotides synthesized de novo. Using a Plasmodium transgenic line specifically designed to study DNA replication throughout parasite development, it was unveiled for the first time the temporal dynamics of DNA replication throughout parasite LS and show that Plasmodium’s LS high replication rate is accompanied by DNA damage. Thus, the hypothesis is that DNA damage accumulation during LS schizogony is a generator of genetic variability prior to intra-erythrocytic infection. Connecting LS schizogony with parasite genetic diversity and virulence for the first time will be conceptually transformative, and will certainly provide valuable targets and tools for the combat against malaria.
Jun 2023 — May 2028
$2.67M
