The host cell drives Plasmodium developmental decisions

The intra-erythrocytic cycle of P. falciparum is responsible for malaria pathology. During this cycle, parasites replicate asexually and can also bifurcate to a sexual fate which will lead to their eventual transmission to mosquitoes. Although P. falciparum can invade all red blood cell types including maturing ones, it is unclear whether the host cell environment influences the intracellular life of the parasites and its developmental decisions. Here we mapped the host cell environment using flow cytometry to demonstrate that P. falciparum preferentially invades and resides in reticulocytes. We next used single cell RNAseq of parasites from naturally-infected carriers to understand how the host cell affects parasite decision making and transcriptional response. We find that commitment to sex can occur in both reticulocytes and normocytes but commitment is much more likely in reticulocytes, indicating a link between host cell and parasite fate. We further find commitment to sex in reticulocytes is a same cycle decision made post-invasion. Altogether our data highlight the host cell as a pivotal determinant of the parasite's developmental decisions, and establishes the first single cell intrahost dynamic map of natural P. falciparum infections.