人类胎肝器官培养中源自肝细胞的疟原虫Plasmodium falciparum肝期形成的研究
Development of Plasmodium falciparum liver-stages in hepatocytes derived from human fetal liver organoid cultures.
发表日期：2023 Aug 02
作者：
Annie S P Yang, Devanjali Dutta, Kai Kretzschmar, Delilah Hendriks, Jens Puschhof, Huili Hu, Kim E Boonekamp, Youri van Waardenburg, Susana M Chuva de Sousa Lopes, Geert-Jan van Gemert, Johannes H W de Wilt, Teun Bousema, Hans Clevers, Robert W Sauerwein
来源：
Parasites & Vectors
摘要：
恶性疟原虫（Pf）在肝内的寄生体发育代表了通过感染Pf的蚊子叮咬进入人体宿主的生命周期的初始阶段。尽管肝细胞与寄生虫的相互作用是寄生虫生命周期干扰的有吸引力的阶段，但由于现有体外模型的限制，我们对此了解仍然不够。我们探索了肝细胞类器官（HepOrgs）对Pf发育的适用性，并表明这些细胞允许不同Pf菌株的寄生虫侵袭、分化和成熟。Pf感染的HepOrg细胞的单细胞信使RNA测序（scRNAseq）鉴定了感染后5天上调的80个Pf转录本。在肝细胞中发现了涉及不同代谢途径的转录谱变化，Scavenger受体B1（SR-B1）转录本高度上调。通过对新鲜原代肝细胞的研究证实了其在裂殖体成熟中的新功能参与。因此，HepOrgs为实现Pf肝阶段的基础生物学研究和快速开发新型疟疾防控工具提供了坚实的体外模型基础。© 2023. 作者。
Plasmodium falciparum (Pf) parasite development in liver represents the initial step of the life-cycle in the human host after a Pf-infected mosquito bite. While an attractive stage for life-cycle interruption, understanding of parasite-hepatocyte interaction is inadequate due to limitations of existing in vitro models. We explore the suitability of hepatocyte organoids (HepOrgs) for Pf-development and show that these cells permitted parasite invasion, differentiation and maturation of different Pf strains. Single-cell messenger RNA sequencing (scRNAseq) of Pf-infected HepOrg cells has identified 80 Pf-transcripts upregulated on day 5 post-infection. Transcriptional profile changes are found involving distinct metabolic pathways in hepatocytes with Scavenger Receptor B1 (SR-B1) transcripts highly upregulated. A novel functional involvement in schizont maturation is confirmed in fresh primary hepatocytes. Thus, HepOrgs provide a strong foundation for a versatile in vitro model for Pf liver-stages accommodating basic biological studies and accelerated clinical development of novel tools for malaria control.© 2023. The Author(s).