In vitro models for human malaria: targeting the liver stage

The Plasmodium liver stage represents a vulnerable therapeutic target to prevent disease progression as the parasite resides in the liver before clinical representation caused by intraerythrocytic development. However, most antimalarial drugs target the blood stage of the parasite's life cycle, and the few drugs that target the liver stage are lethal to patients with a glucose-6-phosphate dehydrogenase deficiency. Furthermore, implementation of in vitro liver models to study and develop novel therapeutics against the liver stage of human Plasmodium species remains challenging. In this review, we focus on the progression of in vitro liver models developed for human Plasmodium spp. parasites, provide a brief review on important assay requirements, and lastly present recommendations to improve models to enhance the discovery process of novel preclinical therapeutics.