Modeling Toxoplasma gondii infection in human cerebral organoids.

Pluripotent stem cell-derived cerebral organoids have the potential to recapitulate the pathophysiology ofin vivohuman 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 limitedin vitromodel systems. Here, we developed a newin vitromodel system ofT. gondiiinfection 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 theT. gondiiasexual life cycle is efficiently simulated in the brain organoids. Transcriptomic analysis ofT. gondii-infected organoids revealed the activation of the type I interferon immune response against infection. In addition, in brain organoids,T. gondiiexhibited a changed transcriptome related to protozoan invasion and replication. This study shows cerebral organoids as physiologically relevantin vitromodel systems useful for advancing the understanding ofT. gondiiinfections and host interactions.