Progeny counter mechanism in malaria parasites is linked to extracellular resources

Malaria is caused by the rapid proliferation of Plasmodium parasites in patients and disease severity correlates with the number of infected red blood cells in circulation. Parasite multiplication within red blood cells is called schizogony and occurs through an atypical multinucleated cell division mode. The mechanisms regulating the number of daughter cells produced by a single progenitor are poorly understood. We investigated underlying regulatory principles by quantifying nuclear multiplication dynamics in Plasmodium falciparum and knowlesi using super-resolution time-lapse microscopy. This confirmed that the number of daughter cells was consistent with a model in which a counter mechanism regulates multiplication yet incompatible with a timer mechanism. P. falciparum cell volume at the start of nuclear division correlated with the final number of daughter cells. As schizogony progressed, the nucleocytoplasmic volume ratio, which has been found to be constant in all eukaryotes characterized so far, increased significantly, possibly to accommodate the exponentially multiplying nuclei. Depleting nutrients by dilution of culture medium caused parasites to produce fewer merozoites and reduced proliferation but did not affect cell volume or total nuclear volume at the end of schizogony. Our findings suggest that the counter mechanism implicated in malaria parasite proliferation integrates extracellular resource status to modify progeny number during blood stage infection. Malaria remains a significant burden on global health and has even seen a resurgence over the last years. The disease is caused by a small unicellular eukaryotic parasite of the Plasmodium genus, which proliferates by invading red blood cells and replicating within them. Contrary to most studied model organisms, Plasmodium does not replicate by binary division, but instead undergoes multiple nuclear division cycles without dividing. Only thereafter those nuclei are packaged into up to 30 new invasive daughter cells. The number of daughter cells per parasite affects the speed of proliferation, but it is currently unclear how it is regulated. This study describes nuclear multiplication in individual parasites in unprecedented detail using super-resolving live cell microscopy. Mathematical modelling of the data suggests that the parasite uses a 'counter' mechanism to predetermine the final number of daughter cells. By reducing the amount of available nutrients, we show that the parasite modulates its progeny number in response to external cues. These findings suggest that patients with different nutritional status might have varying susceptibility to malaria parasite proliferation in their blood.

Automated summary

This study provides unprecedented detail about nuclear multiplication in individual malaria parasites using super-resolving live cell microscopy. The results suggest that the parasite uses a 'counter' mechanism to determine the final number of daughter cells, and the progeny number is modulated in response to external cues such as nutrient availability. These findings suggest that patients with different nutritional status may have varying susceptibility to malaria parasite proliferation in their blood.