Vertical transmission of African-lineage Zika virus through the fetal membranes in a rhesus Macaque (Macaca mulatta) model

Abstract

Zika virus (ZIKV) can be transmitted vertically from mother to fetus during pregnancy, resulting in a range of outcomes, including severe birth defects and fetal/infant death. Potential pathways of vertical transmission in utero have been proposed but remain undefined. Identifying the timing and routes of vertical transmission of ZIKV may help us identify when interventions would be most effective. Furthermore, understanding what barriers ZIKV overcomes to effect vertical transmission may help improve models for evaluating infection by other pathogens during pregnancy. To determine the pathways of vertical transmission, we inoculated 12 pregnant rhesus macaques with an Africanlineage ZIKV at gestational day 30 (term is 165 days). Eight pregnancies were surgically terminated at either seven or 14 days post-maternal infection. Maternal-fetal interface and fetal tissues and fluids were collected and evaluated with RT-qPCR, in situ hybridization for ZIKV RNA, immunohistochemistry, and plaque assays. Four additional pregnant macaques were inoculated and terminally perfused with 4% paraformaldehyde at three, six, nine, or ten days post-maternal inoculation. For these four cases, the entire fixed pregnant uterus was evaluated with in situ hybridization for ZIKV RNA. We determined that ZIKV can reach the MFI by six days post-infection and infect the fetus by ten days. Infection of the chorionic membrane and the extraembryonic coelomic fluid preceded infection of the fetus and the mesenchymal tissue of the placental villi. We did not find evidence to support a transplacental route of ZIKV vertical transmission via infection of syncytiotrophoblasts or villous cytotrophoblasts. The pattern of infection observed in the maternal-fetal interface provides evidence of vertical ZIKV transmission through the fetal membranes.

Zika virus infection histories in brain development

“…The amniotic fluid is in direct contact with these epithelia and can be the source of this fetal blood-independent pathway for ZIKV. Indeed, in a recent preprint, Koenig and collaborators inoculated rhesus monkeys with ZIKV at a late embryonic stage to describe the timing of infection of the tissues in the maternal–fetal interface ( Koenig et al, 2023 preprint). Their results showed that ZIKV possibly reaches the fetus through a route that does not involve the placenta – by infecting the decidua and, later, the fetal membranes ( Koenig et al, 2023 preprint).…”

“…Indeed, in a recent preprint, Koenig and collaborators inoculated rhesus monkeys with ZIKV at a late embryonic stage to describe the timing of infection of the tissues in the maternal–fetal interface ( Koenig et al, 2023 preprint). Their results showed that ZIKV possibly reaches the fetus through a route that does not involve the placenta – by infecting the decidua and, later, the fetal membranes ( Koenig et al, 2023 preprint). It is, therefore, possible that ZIKV can reach the embryo using pathways that do not involve the placenta and fetal blood infection.…”