Researchers have gained a deeper understanding of the complex cell division process of the malaria parasite.

Health

When malaria infects humans, the parasite Plasmodium falciparum first grows in liver cells and then red blood cells. The parasite multiplies, successive cycles destroy red blood cells and the process of cell multiplication continues. Remarkably little is known about the complex DNA dynamics behind the cell cycles of this parasite, however it was something that was explored in depth in the PlasmoCycle project, which was funded by the European Research Council. “The Plasmodium cell cycle is fundamentally unusual, so we didn’t have good precedents to start from,” explains Catherine Merrick, associate professor in the Department of Pathology at Cambridge University and principal investigator of the PlasmoCycle project. Unlike almost all eukaryotic cells, Plasmodium doesn’t divide by binary fission. It also has multiple life-cycle stages, and what is true of one stage might not be true in another. In PlasmoCycle, Merrick and her team investigated how DNA replication in Plasmodium is organised, and how the environment within a human host and exposure to antimalarial drugs impact it.

Studying a strange and complex replication that drives malaria

The PlasmoCycle team first developed new technologies, based on an innovation of Merrick’s – adding a gene to the parasites called thymidine kinase – which let them label replicating DNA in a way that is sensitive, trackable and quantifiable. The researchers then followed all the basic parameters of how the cell cycle works, both in asexual blood stages and in very fast-replicating sexual stages, by observing it in many individual cells. They did this in two different species of human-infective malaria, because the two species take different overall times to rupture their host cell. Then they moved from the level of single cell to single DNA molecule, exploring various questions including the origin and speed of replication. With all this knowledge, they asked a variety of research questions to examine the effects of antimalarial drugs on the DNA, and the impacts of nutrient starvation.

Gaining unprecedented knowledge of the malarial cell cycle

One of the main results of the project was defining all the parameters of replication in blood-stage malaria parasites with unprecedented detail in space and time. “We found that the parameters were somewhat different in two different species,” notes Merrick. In the speedy sexual stage of the life cycle, the team saw a high rate of error and a complete lack of ‘checkpoints’ (which monitor and control the cycle), suggesting this stage trades off speed for accuracy. The researchers did find some of the first evidence of ‘checkpoints’ in the slower asexual stages. When they sustain DNA damage, they can slow down their DNA replication, for example. More investigation is needed into how exactly these work. “These parasites are such odd, early-diverging eukaryotes that a lot of their biology is highly divergent,” says Merrick. The project also started to uncover how stressors such as potentially DNA-damaging antimalarial drugs or nutrient starvation can affect the basic process of replication. “This is important because how fast these parasites replicate is crucial for malarial disease,” Merrick adds.

Feeding into future antimalarial interventions

While the primary aim of the project was a better understanding of the very unusual biology of the malarial parasite, the results could help in future medical developments to counter this pathogen. “The more we understand about the replication process, the smarter we can be in the future about designing interventions,” says Merrick.

Keywords

PlasmoCycle, malaria, parasite, cell cycles, DNA, replication, antimalarial interventions, cell