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Malaria Cell Atlas Encompasses Transcriptomic Profiles Throughout Parasite's Life Cycle

NEW YORK – Researchers have generated a cell atlas for malaria parasites that stretches across its life cycle.

This atlas, the researchers said, could help spur the development of new ways of both preventing and treating malaria. Single-celled malaria parasites infect some 219 million people worldwide and lead to half a million deaths each year, according to the World Health Organization.

A Wellcome Sanger Institute-led team of researchers generated single-cell transcriptomic profiles for more than 1,700 Plasmodium berghei from throughout its various life stages. As they reported in Science this week, the researchers could tease out gene expression patterns associated with its parasite stage, cellular strategy, and host environment.

They supplemented those transcriptomes with droplet sequencing of nearly 16,000 blood-stage malaria parasites cells from not only Plasmodium berghei, but also other malaria-causing Plasmodium species like P. falciparum, P. malariae, and P. knowlesi.

"We've created an atlas of gene activity that spans the complete life cycle of the malaria parasite. This is the first atlas of its kind for a single-cell organism," co-first author Virginia Howick, a postdoctoral fellow at the Wellcome Sanger Institute, said in a statement. "The malaria parasite's life cycle is key to research into this disease and the Malaria Cell Atlas will help us truly understand the parasite in order to effectively control malaria."

The researchers isolated and purified P. berghei cells from across its life cycle, which begins when infected mosquitos inject malaria sporozoites into the bloodstream off its mammalian hosts. The parasites then accumulate in the host liver and develop and replicate before infecting red blood cells. They replicate there asexually, then burst to reinfect red blood cells, and, possibly, get taken up by mosquitos where they then infect the midgut and salivary glands.

Using a modified Smart-seq2 approach, the researchers profiled parasite cells from each of these stages. After quality control, they reported uncovering a mean 1,527 genes per cell, though that number varied by parasite stage.

Through visualization and clustering analysis, the researchers found that the parasite cells' transcriptomes largely clustered by life cycle stage and host. In particular, they noted that merozoites, rings, trophozoites, and schizonts — which encompass aspects of its aesxual blood stage — form a circle, reflecting its cyclical nature.

The researchers also uncovered gene expression clusters, and while two clusters housed mainly housekeeping genes and were expressed across the life cycle, most clusters were expressed during a particular stage. For instance, they noted cluster 16 includes the genes that encode the CelTOS and circumsporozoite proteins, which are important in parasite invasion as well as nearly 80 other genes that are expressed during the invasive period. Other genes expressed by this cluster, though, have unclear functions, but the researchers noted that their association here with invasion could inform future functional studies. These gene expression clusters could also help identify potential treatment targets by identifying ones that are integral to particular key life cycle stages.

The researchers also used 10X Genomics' droplet-based Chromium platform to capture additional Plasmodium parasites from the asexual blood stage for analysis. Across these different malaria-inducing parasite species, the researchers broadly found similar gene transcription patterns, though they noted some differences by life cycle stage and genes. In particular, they noted that parasites that infect different mammalian hosts tend to have asexual blood stages that last different lengths of time.

This atlas, the researchers added, could be used to peg data generated through bulk transcriptomic studies to particular parasitic life cycle stages, which they illustrated using published P. berghei and P. falciparum RNA-seq data. Additionally, using a set of clinical samples, the researchers found that the transcriptomes again clustered by life cycle stage, rather than by donor. This, the researchers said, suggest that this approach can be used to study parasites isolated from their natural habitat.

"This rich dataset can be used to find new therapeutic candidates as well as to better understand transcriptional control networks," the University of California, San Diego's Elizabeth Winzeler wrote in an accompanying editorial in Science.

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