Modeling Mpox virus infection during pregnancy in vivo and ex vivo

PROJECT SUMMARY: Monkeypox virus (MPXV) poses an escalating global health threat, with recent outbreaks extending beyond endemic regions. Current treatments and vaccines offer limited protection, and a new clade I resurgence in 2024 highlights the urgent need to understand MPXV pathogenesis. Maternal mpox infections have been linked to fetal loss and neonatal death, yet mechanisms of vertical transmission remain unclear due to the lack of suitable small animal models. We developed a pregnancy model to study MPXV in mice and established a human placental tissue model that supports MPXV infection. In this application, we will study pregnant mice as well as a human villous explant system, both of which support MPXV infection to understand how gestational age and viral clade influence infection outcomes in mice and humans. We will then test the extent to which current and next-generation therapeutics, alone and in combination, can alter infection and pathogenesis caused by MPXV. Finally, we will map MPXV-infected cells and the timing of infection at the maternal-fetal interface in mice and human villous explants. Together, this work will provide critical insights into MPXV pathogenesis in pregnancy and guide development of targeted therapies for congenital mpox.