Cells usually multiply by duplicating their genome and divide themselves into two daughter cells. Yet, in some organisms, cellular multiplication follows distinct, somewhat bizarre routes. One of these rather unusual ways can be seen in Plasmodium spp., the causative agent of malaria, which remains a major scourge of humanity.
An unusual feature of Plasmodium replication inside erythrocytes, known as schizogony, is the number of nuclei and, hence, daughter cells they produce during one round of intracellular replication. Parasites with odd numbers of nuclei can be readily seen (Fig. 1). Divergence from a geometric expansion, which would lead to 2, 4, 8, 16, or 32 daughter cells, is caused by asynchronous replication.
This suggests that individual nuclei replicate autonomously until a global mechanism takes over and co-ordinates daughter cell formation. This is in striking contrast with nuclear division in other multinucleated cells, such as the early Drosophila embryo, where nuclei follow a geometric expansion, as their division is relatively synchronous.
To gain insight into the regulation of Plasmodium falciparum replication, we conducted a forward genetic screen for the conditional protein expression of protein kinases and identified a kinase as essential for proliferation (Fig. 2)
This kinase is Plasmodium-specific and a crucial regulator of the continuous rounds of DNA replication, histone modification, and regulation of gene expression. We also found that this kinase is required for transmission to the mosquito. This work serves as a starting point to gain a better understanding of Plasmodium replication biology.
We are currently using the human pathogen Plasmodium falciparum to uncover the signalling cascade that orchestrates parasite multiplication in the blood stage of infection. Furthermore, our previous work suggests that a set of unknown genes is involved in parasite replication. We are using classical reverse genetic tools and inducible gene-depletion approaches to characterize the function of these unknown genes. Additionally, we are analyzing the spatiotemporal organization of schizogony using live-cell microscopy.
Our overall aim is to elucidate the regulatory mechanisms that govern Plasmodium replication and understand a process that seemingly cannot be explained by current models of cell cycle regulation.
Currently our interests include:
- Investigating the genes involved in the regulation of replication and nuclear division
- Defining the interactome of the Plasmodium-specific kinase CRK4
- Deciphering the spatiotemporal organization of schizogony
- In collaboration with Zendia GmbH - developing a rapid diagnostics test for Malaria