Oropouche virus causes 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 discover that injection of a low inoculum of the epidemic OROVIRCCS-SCDC_1/2024 strain into the placenta of Swiss mice results in viral replication across embryonic organs, in particular the brain. Infected embryos present with multi-organ pathology, pneumonitis, myocarditis, steatohepatitis and severe neuropathology, including microcephaly, ventriculomegaly and neural loss. Neural cell populations are drastically altered due to massive cell death. OROV-induced neuroinflammation is marked by cytokine upregulation, microglial activation and neutrophil infiltration. When we compare to Zika virus (ZIKV) infection in the same model, a much lower inoculum of OROV than of ZIKV results in embryonic malformations, with markedly distinct neurological developmental and immune responses. Our findings establish a link between congenital OROV infection and neurodevelopmental disease, underscoring its teratogenic potential.