Abstract Plasmodium falciparum (Pf) is a major cause of malaria. The mosquito-borne parasite asymptomatically infects hepatocytes in the liver. The resulting schizonts undergo massive replication to generate blood-infective merozoites. Liver lobules are zonated: hepatocytes in different zones perform differential metabolic functions. In search for specific host conditions that affect infectability, we studied the Pf parasite liver stage development in relation to the metabolic heterogeneity of fresh human hepatocytes. We show selective preference of different Pf strains for a minority of zone 3 hepatocytes characterized by the particular presence of glutamine synthetase (hGS). Parasite schizont growth is significantly enhanced by hGS uptake early in development, which showcases an import system at this stage of the parasite life-cycle. In conclusion, Pf development is strongly determined by the differential metabolic status in hepatocyte subtypes. These findings underscore the importance of detailed understanding of hepatocyte host- Pf interactions and may delineate novel pathways for intervention strategies.

Zonal human hepatocytes are differentially permissive to Plasmodium falciparum malaria parasites