Human liver organoids are susceptible to Plasmodium vivax infection

Abstract The eradication of Plasmodium vivax malaria iscomplicated due to the presence of hypnozoites, the hidden dormant form of the parasite that is present in the liver. Currently available drug regimens are effective at killing hypnozoites but cause side effects and are difficult to administer. Studies testing drugs for liver-stage malaria remain rare and mainly relyon the use of cancerous or immortalized hepatic cells and primary hepatocytes. Here, we examined the feasibility of using an emerging organoid platform to model liver-stage vivax malaria. Hepatic endoderm cells, endothelial progenitor cells and mesenchymal cells were generated from human induced pluripotent stem cells and self-assembled intoliver organoids. These liver organoids resemble mature hepatocytes in terms of albumin secretion, fat and glycogen storage and cytochrome activity. Following the invasion of P. vivaxsporozoites, the expression levels of Plasmodium 18S RNA transcripts were upregulated. Changes in the transcript levels of genes involved in cholesterol synthesis were also observed. Thus, stem cell-derived liver organoids are susceptible to infection with P. vivax sporozoites, paving the way for studies on the mechanism of hypnozoite formation and testing of possible hypnozoitocidal drugs.