Oropouche virus results in severe congenital disease in embryonic mice

The recent outbreak of Oropouche virus (OROV) in Latin-America with unprecedented reports of vertical transmission resulting in congenital malformations and fetal death, redefines the threat posed by this arbovirus. We here explore the teratogenic potential of an epidemic strain of the virus in a mouse model, whereby a low inoculum of OROV is injected into the placenta. The virus replicates efficiently in multiple embryonic organs, with high titers in the brain, and causes intrauterine growth restriction. Infected embryos display multi-organ pathology, including pneumonitis, myocarditis, steatohepatitis and severe neuropathology. Embryonic brains exhibit microcephaly, ventriculomegaly and extensive neural loss, mirroring findings in human fetal cases. A dramatic alteration of the neural cell population correlates with massive cell death, demonstrating the extreme cytotoxicity of OROV for the developing brain. The infection also triggers neuroinflammation characterized by cytokine upregulation, microglial activation and neutrophil infiltration. Altogether, our findings establish a link between congenital OROV infection and neurodevelopmental disease, highlighting its teratogenic potential.