Zonal human hepatocytes are differentially permissive to Plasmodium falciparum malaria parasites

Plasmodium falciparum (Pf) is a major cause of human malaria and is transmitted by infected Anopheles mosquitoes. The initial asymptomatic infection is characterized by parasite invasion of hepatocytes, followed by massive replication generating schizonts with blood-infective merozoites. Hepatocytes can be categorized by their zonal location and metabolic functions within a liver lobule. To understand specific host conditions that affect infectivity, we studied Pf parasite liver stage development in relation to the metabolic heterogeneity of fresh human hepatocytes. We found selective preference of different Pf strains for a minority of hepatocytes, which are characterized by the particular presence of glutamine synthetase (hGS). Schizont growth is significantly enhanced by hGS uptake early in development, showcasing a novel import system. 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.

Automated summary

The development of Plasmodium falciparum in hepatocytes is strongly influenced by the metabolic status of hepatocyte subtypes, with a selective preference for a minority of hepatocytes. Schizont growth is significantly enhanced by the uptake of glutamine synthetase (hGS), showcasing a novel import system. These findings underscore the importance of understanding detailed hepatocyte host-Plasmodium falciparum interactions and may provide new pathways for intervention strategies.