Transplacental Zika virus transmission in ex vivo perfused human placentas

Abstract

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.

Comparative Analysis of In Vitro Models to Study Antibody-Dependent Enhancement of Zika Virus Infection

“…These data are in line with data from a study with pregnant non-human primates and indicate that during pregnancy, pre-existing DENV immunity is not likely to be a risk for a more severe ZIKV infection in the mother [64]. A possible facilitating role of DENV immunity on the risk of transplacental ZIKV transmission is not ruled out based on the results of this study and is suggested in multiple experimental studies and should be studied in more detail in human studies [17,18,55,60,65].…”

“…However, as with the cell lines, we did not detect an increase in IL-10 production in monocyte-derived macrophages during ADE of ZIKV infection, which has been suggested to be one of the hallmarks of intrinsic ADE for DENV and seems to contribute to disease severity in severe DENV infections [11,12,[57][58][59]. It is possible that a non-increased IL-10 production during ADE of infection is specific for ZIKV as we and others have not observed increased IL-10 production during ADE of ZIKV infection in fetal macrophages and in primary human cells [35,55,60].…”

Mucosal Responses to Zika Virus Infection in Cynomolgus Macaques

“…Numerous ex vivo models of ZIKV infection have been described using placenta or brain tissue [43][44][45][46][47][48][49][50][51][52][53][54], but there is limited literature describing infection of other mucosal tissues [55] and the impact of viral exposure on the mucosal environment. Our ex vivo mucosal tissue explant models of ZIKV challenge for the colorectum and the FGT were adapted from the models used for HIV [56][57][58][59].…”

Exploring Zika Virus Impact on Endothelial Permeability: Insights into Transcytosis Mechanisms and Vascular Leakage

“…This activation suppresses the innate immune response, facilitating productive infection [ 55 , 56 ]. According to several in vitro and ex vivo studies, ZIKV is known to replicate in a variety of human cells, including endothelial and epithelial cells [ 57 ], peripheral blood mononuclear cells (PBMCs) [ 57 ], astrocyte and microglial cells [ 55 ], trophoblasts [ 58 ], Hofbauer cells in chorionic villi and amniotic epithelial cells [ 58 , 59 ], and fibroblasts [ 60 ] (placental, uterine, and pulmonary) [ 59 ] ( Figure 2 ). Concurrently, these particular cell type's infections are linked to higher AXL protein levels [ 50 ].…”