Defining molecular determinants of Plasmodium falciparum hematopoietic infection using single cell profiling and genetics

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Plasmodium falciparum (Pf) malaria remains a leading cause of death in many low- and middle-income countries, particularly in Sub-Saharan Africa. Further exploration into uncharacterized areas of parasite biology within the human host is essential for identifying novel avenues for antimalarial therapies, transmission-blocking strategies, and/or diagnostics aimed at reducing the global disease burden. Recent work has identified the hematopoietic niches of the bone and spleen as major sites of Pf parasite replication and development. Importantly, these organs serve both as extravascular reservoirs for asexual blood-stage parasites that cause clinical symptoms of malaria, and as sites for development of gametocytes, sexual stages that are required for transmission between human hosts. Nonetheless, the relative inaccessibility of these organs in humans and their highly heterogenous composition has impeded our understanding of the mechanisms underlying parasite replication and differentiation within these niches. Blood-stage parasites also have the capacity to invade erythrocytes of various maturation states, further contributing to the heterogeneity of infection within the hematopoietic niche. Single cell methods provide unprecedented opportunities to investigate these complex processes at exceptionally high resolution. Here, I propose to leverage these technologies, in combination with reverse genetics, to dissect the respective contributions of host cell-intrinsic and -extrinsic factors to parasite development in the hematopoietic niche. I hypothesize that Pf blood-stage parasites transcriptionally adapt both to their external organ environment and to their specific host cell, leading to major changes in parasite biology that can drive pathology, impact transmission, and affect antimalarial drug responses.