FcγRI is the key determinant of antibody-mediated Zika virus infection of human placental macrophages

Zika virus (ZIKV) can be vertically transmitted from a pregnant mother to the developing fetus, resulting in microcephaly and/or other congenital malformations. Dengue virus (DENV) cross-reactive antibodies can facilitate ZIKV placental transcytosis and enhance ZIKV infection of placenta macrophage-Hofbauer cells through binding to Fc-γ receptors (FcγRs). To understand the role of individual FcγR in antibody-mediated ZIKV placental infection, we generated a comprehensive panel of Fc-variants spanning a wide range of binding affinities to different FcγRs. We found that mutations with increased affinity to FcγRI strongly correlated with an increased frequency of infected pro-monocytic U937 and Hofbauer cells. Next, we genetically deleted individual FcγR in U937 cells, and found that the knockout of FCGR1A gene completely abolished ZIKV infection. In contrast, the deletion of FCGR2B gene showed no effect on ZIKV infection, and the deletion of FCGR2A gene had only a moderate impact on ZIKV infection. We further observed that FcγRI was involved in both increased ZIKV internalization and replication. Collectively, our results establish FcγRI as the key Fc receptor responsible for antibody-mediated ZIKV infection in both U937 and primary placental macrophages. These mechanistic findings not only provide insight into the importance of FcγRI in ZIKV vertical transmission but also highlight FcγRI as a potential therapeutic target, with significant implications for the development of strategies to prevent ZIKV transmission from mother to fetus.