Modeling Human Cytomegalovirus-Induced Microcephaly in Human iPSC-derived Brain Organoids

We show that HCMV infection of human induced pluripotent stem cell (hiPSC)-derived brain organoids can recapitulate severe clinical manifestations such as microcephaly. We demonstrate that infection of hiPSC-derived brain organoids by the “clinical-like” HCMV strain TB40/E results in substantially reduced brain organoid growth, impaired formation of cortical layers, abnormal calcium signaling, and disrupted neural network. Accordingly, RNA-seq analysis revealed that genes down-regulated in TB40/E-infected brain organoids include those involved in neural development and calcium signaling. Moreover, we show that the impeded brain organoid development and abnormal neural network caused by TB40/E infection can be prevented by neutralizing antibodies (NAbs) that recognize different epitopes of the HCMV envelope pentamer complex (PC), a major target of HCMV-specific humoral immunity. These results demonstrate in a three-dimensional human cellular biosystem that HCMV can cause severe brain malformation and disrupt calcium signaling and neural network activity. This study also provides insights into the potential capacity of NAbs to mitigate brain defects resulted from congenital HCMV infection.