Abstract
Background: Malaria parasites go through major transitions during their complex life cycle, yet the underlying differentiation pathways remain obscure. Here we apply single cell transcriptomics to unravel the program inducing sexual differentiation in Plasmodium falciparum. Parasites have to make this essential life-cycle decision in preparation for human-to-mosquito transmission. Methods: By combining transcriptional profiling with quantitative imaging and genetics, we defined a transcriptional signature in sexually committed cells. Results: We found this transcriptional signature to be distinct from general changes in parasite metabolism that can be observed in response to commitment-inducing conditions. Conclusions: This proof-of-concept study provides a template to capture transcriptional diversity in parasite populations containing complex mixtures of different life-cycle stages and developmental programs, with important implications for our understanding of parasite biology and the ongoing malaria elimination campaign.
Highlights
Malaria remains a major global health issue, with roughly 200 million infections and more than 400,000 fatal cases caused by Plasmodium falciparum each year[1]
Development of a single-cell RNA-sequencing pipeline in P. falciparum To capture the transcriptional profile of sexual commitment, cells were exposed to a pulse of defined medium lacking LysoPC (−SerM), as described previously[16]
Reads representing the 3’ end of transcripts from each cell were aligned to the P. falciparum reference genome (PlasmoDB version 29) and filtered for unique molecular identifier (UMIs) to avoid repeat sampling of the same original RNA molecules, and ribosomal RNA species were removed (Table 1 and Supplementary File 1)
Summary
Malaria remains a major global health issue, with roughly 200 million infections and more than 400,000 fatal cases caused by Plasmodium falciparum each year[1]. Malaria parasites have a complex life cycle, and patient blood samples usually contain a mixture of asexually replicating parasites and a small fraction of terminally differentiated sexual-stage parasites. The latter, so-called mature gametocytes are required for parasite transmission to mosquitos. Our study provides a template for capturing transcriptional diversity in heterogeneous parasite populations, which we hope will springboard future endeavors in single cell transcriptomics of Plasmodium. Conclusions: This proof-of-concept study provides a template to capture transcriptional diversity in parasite populations containing complex mixtures of different life-cycle stages and developmental programs, with important implications for our understanding of parasite biology and the ongoing malaria elimination campaign
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