Pluripotent stem cell-derived cerebral organoids have the potential to recapitulate the pathophysiology of in vivo human brain tissue, constituting a valuable resource for modelling brain disorders, including infectious diseases. Toxoplasma gondii, an intracellular protozoan parasite, infects most warm-blooded animals, including humans, causing toxoplasmosis. In immunodeficient patients and pregnant women, infection often results in severe central nervous system disease and fetal miscarriage. However, understanding the molecular pathophysiology of the disease has been challenging due to limited in vitro model systems. Here, we developed a new in vitro model system of T. gondii infection using human brain organoids. We observed that tachyzoites can infect human cerebral organoids and are transformed to bradyzoites and replicate in parasitophorous vacuoles to form cysts, indicating that the T. gondii asexual life cycle is efficiently simulated in the brain organoids. Transcriptomic analysis of T. gondii-infected organoids revealed the activation of the type I interferon immune response against infection. In addition, in brain organoids, T. gondii exhibited a changed transcriptome related to protozoan invasion and replication. This study shows cerebral organoids as physiologically relevant in vitro model systems useful for advancing the understanding of T. gondii infections and host interactions.

多能干细胞来源的脑器官有可能重新概括体内人脑组织的病理生理学，从而构成了用于模拟包括传染病在内的脑部疾病的宝贵资源。弓形虫，一种细胞内的原生动物寄生虫，感染包括人类在内的大多数温血动物，引起弓形虫病。在免疫缺陷的患者和孕妇中，感染通常会导致严重的中枢神经系统疾病和胎儿流产。然而，由于有限的体外模型系统，了解该疾病的分子病理生理学一直具有挑战性。在这里，我们开发了新的弓形虫体外模型系统使用人脑类器官感染。我们观察到，速殖子可以感染人类的​​大脑类器官，并转化为缓殖子，并在寄生虫的液泡中复制以形成囊肿，这表明弓形虫的无性生活周期在大脑类器官中得到了有效的模拟。弓形虫感染类器官的转录组学分析揭示了针对感染的I型干扰素免疫反应的激活。此外，在脑类器官中，刚地弓形虫表现出与原生动物入侵和复制相关的转录组。这项研究表明脑类器官作为生理相关的体外模型系统，可用于增进对弓形虫的了解。 感染和宿主互动。