Asymptomatic and obligatory liver stage (LS) infection of Plasmodium parasites presents an attractive target for antimalarial vaccine and drug development. Lack of robust cellular models to study LS infection has hindered the discovery and validation of host genes essential for intrahepatic parasite development. Here, we present a chemically differentiated mouse embryonic stem cell (ESC)-based LS model, which supports complete development of Plasmodium berghei exoerythrocytic forms (EEFs) and can be used to define new host-parasite interactions. Using our model, we established that host Pnpla2, coding for adipose triglyceride lipase, is dispensable for P. berghei EEF development. In addition, we also evaluated in-vitro-differentiated human hepatocyte-like cells (iHLCs) to study LS of P. berghei and found it to be a sub-optimal infection model. Overall, our results present a new mouse ESC-based P. berghei LS infection model that can be utilized to study the impact of host genetic variation on parasite development.

疟原虫寄生虫的无症状和强制性肝期（LS）感染为抗疟疫苗和药物开发提供了一个有吸引力的目标。缺乏稳健的细胞模型来研究 LS 感染，阻碍了肝内寄生虫发育所必需的宿主基因的发现和验证。在这里，我们提出了一种基于化学分化的小鼠胚胎干细胞（ESC）的LS模型，该模型支持伯氏疟原虫外红细胞形式（EEF）的完整发育，并可用于定义新的宿主-寄生虫相互作用。使用我们的模型，我们确定编码脂肪甘油三酯脂肪酶的宿主Pnpla2对于伯氏疟原虫EEF 发育是必不可少的。此外，我们还评估了体外分化的人肝细胞样细胞（iHLC）来研究伯氏疟原虫的LS，发现它是一个次优的感染模型。总体而言，我们的结果提出了一种新的基于小鼠 ESC 的伯氏疟原虫LS 感染模型，可用于研究宿主遗传变异对寄生虫发育的影响。