Knowledge on the cell types and cell-specific gene expression of multicellular pathogens facilitates drug discovery and allows gaining a deeper understanding of pathogen biology. By utilizing single-cell RNA sequencing (scRNA-seq), we analyzed 19,581 cells of a globally prevalent parasitic flatworm, the liver fluke Fasciola hepatica, which affects health of both humans and animals. We identified 15 distinct clusters, including stem cells, gonadal, muscle and intestinal cells. Differentiation lineages within this parasite were identified and characterized by integrating RNA velocity and spatial transcriptomics data. Furthermore, an ELF5- and TRPM(PZQ)-expressing cell cluster was discovered, characterized by high expression of protein kinases, including the p21-activated kinase PAK4. Treatment with a PAK4 inhibitor efficiently killed the parasites. These data provide insight into the cellular composition of a complex multicellular pathogen and demonstrate how gene expression at single-cell resolution can serve as a resource for the identification of new drug targets.
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