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Malaria Cell Atlas Tracks Parasite Activity With Single-Cell Transcriptomes

NEW YORK (GenomeWeb) – A Wellcome Trust Sanger Institute- and University of Cambridge-led team has presented the first iteration of the Malaria Cell Atlas that includes single-cell RNA sequence data on hundreds of Plasmodium isolates.

"We have established an optimized protocol for generating single-cell transcriptome sequences of Plasmodium parasites with power to identify not only different cell types, but also to explore potential functional variation from one cell to another," the researchers wrote in a study published online today in the journal eLife.

The researchers used this approach to start putting together a collection of high-throughput single-cell transcriptomes for more than 500 Plasmodium individual parasites, representing the human parasite P. falciparum or the rodent-infecting parasite P. berghei. The growing resource is expected to help in unraveling the genes that are active during different stages of the parasite's life cycle.

"We can now begin to truly understand diversity between individual parasites, even within the same human infection," senior author Mara Lawniczak, an evolutionary genetics and malaria program researcher at the Sanger Institute, said in a statement.

"This is the first step towards creating the Malaria Cell Atlas," Lawniczak explained, "a data resource that we hope will be valuable to the important global community of malaria researchers working to eliminate this devastating disease."

The team's initial analyses of the individual parasite sequences provided insights into the processes at play during Plasmodium's life cycle — from sexual forms of the parasite that get sucked up when mosquitoes bite infected hosts to the asexual malaria tucked away in infected red blood cells following mosquito-borne transmission.

"We uncover previously hidden discrete transcriptional signatures during the pathogenic part of the life cycle, suggesting that expression over development is not as continuous as commonly thought," Lawniczak and her co-authors wrote. "In transmission stages, we find novel, sex-specific roles for differential expression of contingency gene families that are usually associated with immune evasion and pathogenesis."

The researchers used fluorescence-activated cell sorting, a modified version of the SmartSeq2 protocol, and Illumina HiSeq 4000 or HiSeq 2500 instruments to sequence 188 individual P. berghei parasite from mixed blood samples, 174 asexual P. falciparum representatives, and 237 sexual representatives from the P. falciparum species.

After tossing out cells with relatively few reads, the team compared the single-cell RNA sequence reads to a combined reference genome for the human- and rodent parasites, identifying species- and life cycle stage-specific expression patterns in Plasmodium. The results were validated with additional comparisons to available RNA sequence and microarray-based expression data.

By continuing to analyze and expand the single-cell RNA-seq set for Plasmodium parasites, the researchers explained, it may ultimately be possible to uncover parasite vulnerabilities by tracing transcriptional programs switched on and off over time.

"Knowing how the parasite's lifecycle is controlled by particular genes, we have a stronger chance of interfering with it using drugs," co-first author Arthur Talman, a post-doctoral researcher in Lawniczak's Sanger Institute lab, said in a statement.