Vertical Transmission of Past and Present Oropouche Virus Isolates: Comparing Tropism and Pathogenesis using Human Ex Vivo and Rodent in Vivo Models

PROJECT SUMMARY: Vertical transmission of past and present Oropouche virus isolates: Comparing tropism and pathogenesis using human ex vivo and rodent in vivo models. Oropouche virus (OROV) is an emerging bunyavirus with epidemic potential. The 2024 OROV outbreak has revealed a previously unrecognized diversity of clinical outcomes including adult fatalities, cases of vertical transmission, and adverse outcomes in newborns including microcephaly, still-birth and neonatal deaths. There are major gaps in our understanding of OROV pathogenesis and there are no vaccines or therapeutics to mitigate disease. Given the recent first reports of vertical transmission, we seek to understand how OROV is transmitted from mother to offspring and to define its potential impact on maternal and fetal health. Here, we propose to leverage our experience studying vertical transmission of a related bunyavirus, Rift Valley fever virus, and re-establish ex vivo and in vivo models to study OROV vertical transmission. Genomic reassortment may be associated with this perceived change in tropism and virulence, therefore we aim to investigate differences in vertical transmission between four strains (BeAn19991, BeH759021, LET2083, AM0088) representing four genetically distinct lineages of OROV (OROVBR/TT 1955-2003, OROVBR 2009-2018, OROVPE/CO/EC 2008-2021, OROVBR 2015-2024, respectively). This work will be performed by highly productive and collaborative investigators with expertise in every aspect of the proposed studies, including bunyavirus pathogenesis, immunology, virology, histopathology, and the use of models of the maternal-fetal interface. Completion of these studies will provide valuable information regarding OROV vertical transmission and lay the groundwork for future studies identifying genetic and molecular changes to OROV that contribute to vertical transmission or fetal demise. We expect to identify strain-specific tropisms, pathologies, and host responses at the maternal-fetal interface that is validated across multiple models, providing well-characterized models to test therapeutics and vaccines.