Malaria remains to be the most important vector-borne human disease with an estimated 240 million cases in 2020. In the same year, more than 600.000 cases were fatal, mainly children under the age of five. The most severe form of human malaria is caused by the single-celled eukaryote Plasmodium falciparum, which alone is responsible for over 90 % of all malaria cases. Despite some progress in curbing the disease since the year 2000, the number of cases and the mortality increased again in recent years. In addition, resistance to the first-line treatment, artemisinin, is emerging in all endemic regions.
P. falciparum proliferates inside host erythrocytes, which is responsible for all clinical symptoms of malaria and disease severity is intimately linked to parasite burden. The parasite proliferates via an unusual cell cycle called schizogony, during which the nuclei divide several times, forming a multinucleated stage that can harbor up to 30 nuclei. Multinucleated cells can be found on all branches of the eukaryotic tree of life and when two or more nuclei reside in the same cytoplasm, they usually progress synchronously through the cell cycle. However, P. falciparum nuclei divide asynchronously despite residing in the same cytoplasm.
Within the second funding period, we achieved three key biological breakthroughs in understanding parasite proliferation and disease severity. Firstly, we discovered that during the dry season in endemic countries, when transmitting mosquitoes are absent, P. falciparum circulate longer in the peripheral blood before they adhere to endothelial cells. Although parasite proliferation is not altered during the dry season, this increased circulation leads to persistent and asymptomatic infections. Secondly, we uncovered that the parasites unusual cell cycle with asynchronously multiplying nuclei is tailored to balance limited resources with rapid parasite proliferation. Thirdly, we found that the major S-phase promoter PfCRK4 is also critical for the reorganization of nuclear microtubules, rendering PfCRK4 the key regulator of nuclear-cycle progression. We also developed a nuclear cycle sensor system for long-term live-cell imaging that allows us to follow individual nuclei as they progress through nuclear multiplication.