Maternal immunity and antibodies to dengue promote Zika virus-induced microcephaly in fetuses

Zika virus (ZIKV), a recently emerged flaviviral pathogen, has been linked to microcephaly in neonates 1 . Yet, it is not understood why some fetuses develop severe microcephaly due to maternal ZIKV infection while others do not. The risk for ZIKV-induced microcephaly is greatest during the first trimester of pregnancy in humans 2,3 , yet this alone cannot account for the varied presentation of microcephaly observed. Given the antigenic similarity between ZIKV and closely related dengue virus (DENV) 4 , combined with the substantial immunity to DENV in ZIKV target populations in recent outbreaks, we hypothesized that maternal antibodies against DENV could promote ZIKV-induced microcephaly. Here, using immune-competent mice, we show that maternal to fetal transmission of ZIKV occurs, leading to fetal infection and disproportionate microcephaly. DENV-specific antibodies in pregnant female mice enhance vertical transmission of infection and result in a severe microcephaly like-syndrome during ZIKV infection. Furthermore, fetal infection was promoted by the neonatal Fc receptor (FcRN). Our results identify a novel immune-mediated mechanism of vertical transmission of viral infection and raise caution since ZIKV epidemic regions are also endemic to DENV.