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 pla-centa. Furthermore, results from studies in pregnant mice and non-human primates are con-flicting 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.
Bibliographical noteFunding Information:
This work was supported in part by the European Union?s Horizon 2020 Research and Innovation Programme under ZIKAlliance Grant Agreement no. 734548. This grant was received by EvG, MK and BR. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We would like to thank the study participants for donating their placenta for this study. Furthermore, we would like to thank Peter van de Run for assistance with tissue preparation for immunohistochemistry and Rugina Neuman and Zhongli Chen for assistance with patient recruitment and ex vivo placental perfusions.
© 2022 Langerak et al.