Host cell maturation modulates parasite invasion and sexual differentiation in Plasmodium.

Malaria remains a global health problem with over 400,000 deaths annually1. Plasmodium parasites, the causative agents of malaria, replicate asexually in red blood cells (RBCs) of their vertebrate host, while a subset differentiates into sexual stages (gametocytes) for mosquito transmission. Parasite replication and gametocyte maturation in the erythropoietic niches of the bone marrow and spleen contribute to pathogenesis and drive transmission2, but the mechanisms underlying this organ enrichment remain unknown. We performed a comprehensive single cell analysis of rodent P. berghei in spleen, bone marrow and blood to define parasite phenotypes specific to those niches. Single cell RNA-seq analysis of host and parasite cells reveals an interferon-driven host response to infection as well as transcriptional adaptations of Plasmodium to RBC maturation status. We show that P. berghei exhibits a bimodal invasion pattern into either normocytes or early reticulocytes and, using functional assays, identify CD71 as a host receptor for reticulocyte invasion. Importantly, we observe an increased rate of gametocyte formation in reticulocytes that is nutrient-dependent and triggered post invasion (i.e., same cycle sexual commitment). Our data provides a thorough characterisation of host-parasite interactions in erythropoietic niches and defines host cell maturation state as the key driver of parasite adaptation.