Single cell RNA-sequencing of malaria merozoites reveals that the parasite prepares for life within the red blood cell by activating a gene network
Abstract
The intraerythrocytic developmental cycle (IDC) during which the malaria parasitePlasmodium falciparummultiplies asexually within the human host red blood cell is the symptomatic stage of the life cycle. The IDC initiates when parasite stages called merozoites are released into the bloodstream, following schizont rupture, and invade the host red blood cells. The merozoite is the less studied stage of the IDC, despite its importance for the establishment of infection. We did the first transcriptional profiling of merozoites throughout development inside the schizont and after egress. Merozoites within the schizont, activate a series of tightly regulated gene expression programs, each encoding for proteins implicated in a specific process required for invasion and life within the host. After schizont egress, free merozoites still express some of these programs. Upon invasion, ring cells have a distinct transcriptional profile. The gene expression programs are regulated by specific transcription factors and chromatin accessibility as well as post-transcriptional mechanisms. Our work gains unprecedent insight into gene expression prior to and during host cell invasion and identifies potential new antimalarial targets.
Author Summary
The malaria parasitePlasmodium falciparum, which causes the death of over half a million people each year, has a complex life cycle but symptoms only arise when the parasite invades and develops inside the host red blood cells. The merozoites are responsible for invading the human red blood cells but because they are only briefly extracellular, their gene expression profile had yet to be determined. Here we used single cell RNA-sequencing to establish the gene expression program of merozoites throughout development inside schizonts and once free, prior to host cell invasion. We found that, in order to prepare for invasion and life within the host cell, merozoites activate a series of gene expression programs, each encoding for proteins implicated in a specific process. While some of the genes expressed by merozoites during maturation are still expressed in free merozoites, these transcripts are no longer detected after host cell invasion. This implicates tight regulation of gene expression. We suggest that regulation implicates binding of specific transcription factors, epigenetics as well as post-transcriptional mechanisms.
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