Modelling Toxoplasma gondii infection in human cerebral organoids

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类器官（cerebral organoids）具备重现活体人类脑组织病理生理学特征的潜力，是构建包括传染病在内的脑部疾病模型的宝贵研究资源。刚地弓形虫（Toxoplasma gondii）是一种胞内原生动物寄生虫，可感染包括人类在内的多数温血动物，引发弓形虫病。对于免疫缺陷患者与孕妇而言，该感染常导致严重的中枢神经系统疾病与胎儿流产。然而，由于现有体外模型系统存在局限，解析该疾病的分子病理生理学机制一直颇具挑战。本研究借助人类脑类器官，构建了一种新型的刚地弓形虫感染体外模型。研究观察到，速殖子（tachyzoites）可感染人类脑类器官，并转化为缓殖子（bradyzoites），在纳虫空泡（parasitophorous vacuoles）中增殖形成包囊，证实刚地弓形虫的无性生命周期可在脑类器官中得到高效模拟。对刚地弓形虫感染的类器官开展转录组学分析后发现，宿主激活了针对感染的I型干扰素免疫应答。此外，在脑类器官中，刚地弓形虫的转录组发生了与原生动物入侵及增殖相关的显著改变。本研究证实，脑类器官作为具备生理相关性的体外模型系统，可用于深化对刚地弓形虫感染及其宿主相互作用的理解。