Abstract
Zika virus (ZIKV) infection during pregnancy can lead to fetal brain infection and developmental anomalies collectively known as congenital Zika syndrome (CZS). To define the molecular features underlying CZS in a relevant human cell model, we evaluate ZIKV infection in primary human fetal brain explants and human induced pluripotent stem cell-derived mixed neural cultures at single-cell resolution. We identify astrocytes as important innate immune sentinel cells detecting ZIKV and producing interferon-beta (IFN-β). In contrast, neural stem cells display impaired innate immunity and support high levels of viral replication. ZIKV infection of neurons suppresses differentiation and synaptic signaling gene networks and programs a molecular switch from neurogenesis to astrogliogenesis. We identify a universal ZIKV-driven cellular stress response linked to intrinsic apoptosis and regulated by IFN-β. These findings reveal innate immune signaling intersecting with ZIKV-driven perturbations in cellular function to influence CZS outcomes including neuron developmental dysfunction and apoptotic cell death.