A spatiotemporally resolved single cell atlas of the Plasmodium liver stage

Abstract Malaria infection involves an obligatory, yet clinically silent liver stage 1,2 . Hepatocytes operate in repeating units termed lobules, exhibiting heterogeneous gene expression patterns along the lobule axis 3 , but the effects of hepatocyte zonation on parasite development have not been molecularly explored. Here, we combine single-cell RNA sequencing 4 and single-molecule transcript imaging 5 to characterize the host’s and parasite’s temporal expression programs in a zonally-controlled manner for the rodent malaria parasite Plasmodium berghei ANKA. We identify differences in parasite gene expression in distinct zones, and a sub-population of periportally-biased hepatocytes that harbor abortive infections associated with parasitophorous vacuole breakdown. These ‘abortive hepatocytes’ up-regulate immune recruitment and key signaling programs. They exhibit reduced levels of Plasmodium transcripts, perturbed parasite mRNA localization, and may give rise to progressively lower abundance of periportal infections. Our study provides a resource for understanding the liver stage of Plasmodium infection at high spatial resolution and highlights heterogeneous behavior of both the parasite and the host hepatocyte.