Competitive resource allocation drives asynchronous and rapid nuclear multiplication in the malaria parasite

The unicellular malaria parasite Plasmodium falciparum proliferates within red blood cells of its human host, where it generates approximately 20 new parasites within a two-day developmental cycle. Before cellularization and release of the daughter cells, the nuclei multiply in a shared cytoplasm. In stark contrast to highly synchronized nuclear division cycles seen in other developing eukaryotes, Plasmodium nuclear cycles desynchronize rapidly. Combining live-cell imaging with biophysical modeling, we elucidate the mechanism of desynchronization and study its impact on parasite proliferation. We find that standard models of autonomous nuclear cycles cannot account for the experimental data, and therefore desynchronization requires nuclear coupling. Competition for a limiting pool of proteins needed for DNA replication explains the data, provided that they are allocated sequentially to individual nuclei. Sequential allocation can be achieved by reversible but stable association of the resources with DNA. Remarkably, the resultant asynchronous nuclear cycles accelerate parasite proliferation by minimizing idling times of the resource. This mechanism may be a general strategy to maximize proliferation in suboptimal growth conditions. Together, our findings identify nuclear cycle asynchrony as a resource-efficient means to achieve rapid proliferation.