Deciphering the molecular mechanisms that underly heterogenous nuclear protein accumulation in multinucleated Plasmodium falciparum cells

• Applicant: Dr. Markus Ganter
• Subject Area: Parasitology and Biology of Tropical Infectious Disease Pathogens
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 572009475

Malaria remains a major public health burden with an estimated 263 million cases and nearly 600.000 deaths in 2023. Malaria is caused by unicellular eukaryotes of the genus Plasmodium, with P. falciparum causing the most virulent form of human malaria. After an infectious mosquito bite, the parasite migrates through the skin and via the blood to the liver, where it proliferates inside hepatocytes before entering the blood again. This blood stage of infection is responsible for all clinical symptoms of malaria and disease severity correlates with the parasite burden in the blood of patients. To curb malaria, a better understanding of the basic biology of P. falciparum is urgently needed and the parasite’s unique mode of proliferation likely offers targets for novel interventions. Thus, this project aims at generating a molecular understanding of P. falciparum proliferation inside erythrocytes, focussing in particular on elucidating how asynchronous nuclear multiplication cycles are established. P. falciparum proliferates inside erythrocytes through a unique cell cycle called schizogony: after an initial growth phase in the ring and trophozoite stages, the parasite begins to multiply its nuclei in the schizont stage. In marked contrast to other multinucleated cells, such as the early Drosophila embryo, P. falciparum nuclei multiply asynchronously despite sharing a common cytoplasm, and cells with odd numbers of nuclei can be readily seen. A hallmark of this apparent autonomy of P. falciparum nuclei is the heterogeneous accumulation of the proliferating cell nuclear antigen (PfPCNA1) among individual nuclei of a given cell. However, the underlying molecular mechanisms that allow PfPCNA1 to accumulate heterogeneously among nuclei that share a common cytoplasm are unknown. Thus, this project aims at generating a molecular understanding of heterogeneous nuclear protein accumulation, which will inform on how the apparent nuclear autonomy can be established.

• DFG Programme: Research Grants