Oropouche virus disrupts neurodevelopment and exhibits congenital infection potential.

Oropouche virus (OROV) historically caused a self-limiting disease, yet recent strains have been clinically linked to congenital infection and neurodevelopmental disease. These observations highlight the need to study OROV as a congenital pathogen. Here, using both a historical and currently circulating strain, we show OROV infects neurons across differentiation states in human forebrain organoids. Compared with the neurotropic congenital pathogen Zika virus (ZIKV), OROV exhibits a heightened capacity for neuroinfection and pathology in both forebrain organoids and neonatal mice. The increased permissiveness of OROV is driven, in part, by a broader neuronal tropism and a relative insensitivity to neuronal type I interferon-mediated antiviral responses. Consistent with clinical observations, neonatal neuroinfection results in rapid and severe neuropathology marked by cerebral hemorrhage. Finally, using a transient type I interferon-blockade model, we demonstrate that OROV can productively infect the murine placenta and cause fetal growth restriction. Together, our complementary models support a unified framework in which placental and fetal barriers limit productive fetal brain infection, yet OROV exhibits marked neurotropism and neuropathogenic potential upon gaining access to developing neural tissues. These findings reinforce the need for vigilant monitoring of OROV as an emerging pathogen associated with adverse pregnancy outcomes and congenital disease.