Zonal human hepatocytes are differentially permissive toPlasmodium falciparummalaria parasites

Abstract

<jats:title>Abstract</jats:title><jats:p><jats:italic>Plasmodium falciparum (Pf)</jats:italic> 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 <jats:italic>Pf</jats:italic> parasite liver stage development in relation to the metabolic heterogeneity of fresh human hepatocytes. We show selective preference of different <jats:italic>Pf</jats:italic> 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, <jats:italic>Pf</jats:italic> development is strongly determined by the differential metabolic status in hepatocyte subtypes. These findings underscore the importance of detailed understanding of hepatocyte host-<jats:italic>Pf</jats:italic> interactions and may delineate novel pathways for intervention strategies.</jats:p>

A spatiotemporally resolved single cell atlas of the Plasmodium liver stage

“…Periportal hepatocytes engage in protein secretion, ureagenesis and gluconeogenesis, whereas pericentral hepatocytes specialize in processes such as bile acid production, xenobiotic metabolism and glutamine biosynthesis 3 . Previous ex-vivo studies suggested that the pace of Plasmodium infection could differ between pericentral and periportal hepatocytes 9,10 . Studies using bulk RNA measurements characterized the transcriptomes of host and parasite during the liver stage of infection 11,12 , and a malaria single cell atlas was generated using an ex-vivo platform 13 .…”

A Portfolio of Geographically Distinct Laboratory-adapted Plasmodium Falciparum Clones With Consistent Infection Rates in Anopheles Mosquitoes

“…An additional limitation is that the current study stopped when oocysts were detected in the mosquito midgut. For a number of isolates data on sporozoite production are also available [13,14] but comparing sporozoite production or infectivity between individual isolates was beyond the scope of this manuscript.…”

“…Given the importance of genetic variation for vaccine and drug e cacy, reliance on a single parasite isolate fails to give a comprehensive insight into intervention potency in natural infections [10]. Similarly, relevant inter-strain variation in parasite growth rates [11], gametocyte production [12] and sporozoite invasion capacity [13,14] warrant further examination. The current portfolio of laboratory isolates for studies on sexual and sporogonic stages is very limited.…”

Liver stage fate determination in Plasmodium vivax parasites: characterization of schizont growth and hypnozoite fating from patient isolates

“…Alternatively, the process for manufacturing cryo-plateable lots of primary hepatocytes could affect cell phenotypes, including the aforementioned surface receptors, and alter hepatocyte permissiveness [18,19]. Host cell permissiveness is likely also modulated by host cell environment as sufficient glycolytic and respiratory activities are needed to sustain the energy demands of an intracellular parasite [20][21][22]. As such, liver lobules perform different metabolic functions and have recently been shown to influence P. falciparum parasite preferences and growth in the host cell [22].…”