Liver Stage Malaria Parasite Biology and Therapeutics

Malaria infection begins when sporozoites, the motile form of the Plasmodium parasite, traverse the dermis and invade hepatocytes in the liver. Within these cells the parasite undergoes a silent yet critical phase of development known as the pre‐erythrocytic stage. For Plasmodium falciparum, sporozoites mature into schizonts, releasing thousands of merozoites that seed the bloodstream and cause clinical symptoms. In relapsing species such as P. vivax, a subset of parasites differentiates into dormant hypnozoites that can reactivate weeks or months later, complicating eradication efforts. Advanced in vitro and in vivo models have revolutionised our understanding of parasite–host interactions, unveiling key molecular pathways that sustain parasite maturation, dormancy and reactivation. Organotypic hepatocyte cultures, humanised mouse systems and stem cell–derived liver frameworks now underpin a new generation of drug and vaccine screening platforms. These innovations are enabling the discovery of causal prophylactics to block initial infection, radical curative agents to eliminate hypnozoites and targeted immunogens for pre‐erythrocytic vaccines. The refinement of host–parasite models and the integration of high‐resolution transcriptomic, proteomic and metabolic analyses promise to accelerate the global fight against malaria by focusing intervention strategies on the bottleneck liver stage.

Research from Nature Portfolio

Recent studies have demonstrated the utility of human hepatocyte organoids for modelling Plasmodium falciparum liver stages. In this system organoids support sporozoite invasion, schizont differentiation and full maturation across diverse parasite strains. Single‐cell RNA sequencing of infected hepatocytes revealed transcriptional remodelling of host lipid and scavenger receptor pathways, notably upregulation of Scavenger Receptor B1, which was shown to be functionally essential for schizont development. Another landmark advance is the establishment of a 384‐well culture platform using cryopreserved primary human hepatocytes that sustains both P. vivax hypnozoites and P. falciparum schizonts for extended periods. This multimodal system maintains hepatocyte physiology for over a month and has identified key inhibitory mechanisms, including antibody‐mediated interference with sporozoite surface proteins and the importance of ion homeostasis for parasite viability. Together these models provide scalable, accessible tools for antimalarial drug discovery and pre‐erythrocytic vaccine evaluation.

Liver Stage Malaria Parasite Biology and Therapeutics publication trend

The graph below shows the total number of articles in liver stage malaria parasite biology and therapeutics across all publications each year (not limited to Nature Index journals).

Technical terms

Sporozoite: The motile, liver‐infective stage of Plasmodium transmitted by a mosquito bite.

Hepatocyte organoid: A three‐dimensional culture of liver cells that mimics in vivo hepatic architecture and function.

Schizont: A liver stage characterised by nuclear division leading to the production of merozoites.

Hypnozoite: A dormant liver stage of relapsing Plasmodium species capable of reactivating to cause relapse.

Pre-erythrocytic stage: The phase of parasite development in the liver before entry into the bloodstream.

References

1. Development of Plasmodium falciparum liver-stages in hepatocytes derived from human fetal liver organoid cultures. Nature Communications (2023).
2. Induced pluripotent stem cell–based tissue models to study malaria: a new player in the research game. Current Opinion in Microbiology (2025).
3. Using Cryopreserved Plasmodium falciparum Sporozoites in a Humanized Mouse Model to Study Early Malaria Infection Processes and Test Prophylactic Treatments. Microorganisms (2023).
4. A 3D organoid platform that supports liver-stage P.falciparum infection can be used to identify intrahepatic antimalarial drugs. Heliyon (2024).
5. A comprehensive model for assessment of liver stage therapies targeting Plasmodium vivax and Plasmodium falciparum. Nature Communications (2018).