Transplacental Zika virus transmission in ex vivo perfused human placentas

Author summaryZika virus is a mosquito-transmitted virus that can cause severe birth defects such as microcephaly when the infection occurs during pregnancy. Understanding how Zika virus crosses the placenta during pregnancy is important for future prevention strategies for vertical Zika virus transmission. Despite significant efforts to study this, to date it remains incompletely understood how Zika virus can cross the placenta and which risk factors contribute to this form of transmission. In this study we use an ex vivo placental perfusion model to study transplacental Zika virus transmission. The ex vivo placental perfusion model is a highly physiological and animal friendly model that mimics the in vivo conditions during pregnancy. We found that antibodies against the closely related dengue virus can significantly enhance placental uptake of Zika virus and Zika virus infection of human placental explants and fetal macrophages. These findings indicate that presence of cross-reactive dengue virus antibodies could contribute to transplacental Zika virus transmission. A Zika virus (ZIKV) infection during pregnancy can result in severe birth defects such as microcephaly. To date, it is incompletely understood how ZIKV can cross the human placenta. Furthermore, results from studies in pregnant mice and non-human primates are conflicting regarding the role of cross-reactive dengue virus (DENV) antibodies on transplacental ZIKV transmission. Elucidating how ZIKV can cross the placenta and which risk factors contribute to this is important for risk assessment and for potential intervention strategies for transplacental ZIKV transmission. In this study we use an ex vivo human placental perfusion model to study transplacental ZIKV transmission and the effect that cross-reactive DENV antibodies have on this transmission. By using this model, we demonstrate that DENV antibodies significantly increase ZIKV uptake in perfused human placentas and that this increased uptake is neonatal Fc-receptor-dependent. Furthermore, we show that cross-reactive DENV antibodies enhance ZIKV infection in term human placental explants and in primary fetal macrophages but not in primary trophoblasts. Our data supports the hypothesis that presence of cross-reactive DENV antibodies could be an important risk factor for transplacental ZIKV transmission. Furthermore, we demonstrate that the ex vivo placental perfusion model is a relevant and animal friendly model to study transplacental pathogen transmission.