Malaria parasites multiply inside red blood cells by first copying their nucleus up to 24 times before finally splitting into daughter cells, and this project aims to find the molecular switches that control that unusual form of division. This matters because malaria cases and deaths are rising again, and the parasite is evolving resistance to the most effective drugs. The blood-stage infection—when parasites burst out of red blood cells in waves, causing fever and anaemia—is the phase that makes people sick. Yet the fundamental biology of how the parasite decides to start multiplying, and how it times each step, remains poorly understood. The researcher has developed a new technique that allows them to knock out several genes at once in the same experiment, something that was previously extremely difficult in malaria parasites. They will use this to identify which DNA-binding proteins are essential for schizogony, then use single-cell RNA sequencing to see how each gene disruption alters the parasite’s gene expression. This is fundamental science. It will not produce a new drug or vaccine tomorrow. But understanding how an early-diverging eukaryotic cell controls its unusual cell cycle could reveal entirely new targets for antimalarial drugs—targets that the parasite cannot easily mutate around. Similar fundamental work on parasite biology has previously uncovered vulnerabilities that led to artemisinin-based therapies, the current frontline treatment.
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Malaria remains a significant threat to global health. Malaria cases and deaths have continued to rise in recent years despite concerted efforts to curb the disease, and the situation is exacerbated by emerging resistance to the most potent class of antimalarial drugs. During the critical blood stage infection, each malaria parasite multiplies extensively within host red blood cells to produce up to 24 daughter parasites. The parasite achieves this remarkable feat through an unusual form of cell division called schizogony in which it first multiplies its nucleus several times before finally dividing its cell. Several aspects of this fascinating process remain enigmatic, including how the parasite enters into and controls the timing of this proliferative phase. Such key decisions during the parasite lifecycle are usually taken by at least two classes of DNA binding proteins (DBPs), viz. transcription factors and reader proteins, many of them likely essential for the parasite but with unknown functions. Here, I will disrupt the function of several candidate DBPs to identify those important in schizogony and I will work out their mechanism of action. For this, I will employ an exciting new technology that I have recently developed which enables the study of several knockout mutant parasites at the same time, an endeavour previously notoriously difficult in the malaria parasite. I will then capture the effect each gene disruption has on the global gene expression in the parasite using single-cell RNA sequencing, again targeting several mutants at once. This, combined with further in-depth characterisation of schizogony-regulating DBPs, will generate important new fundamental knowledge about how cell division in this early-diverging parasitic eukaryote is regulated, and hopefully aid the development of new intervention strategies against this devastating disease.
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