Organotypic models of type III interferon-mediated protection from Zika virus infections at the maternal–fetal interface

Abstract

Protecting the fetus from the hematogenous spread of viruses requires multifaceted layers of protection and relies heavily on trophoblasts, the fetal-derived cells that comprise the placental barrier. We showed previously that trophoblasts isolated from full-term placentas resist infection by diverse viruses, including Zika virus (ZIKV), and transfer this resistance to nonplacental cells through the activity of paracrine effectors, including the constitutive release of type III interferons (IFNs). Here, we developed 3D cell-line-based models of human syncytiotrophoblasts, cells that lie in direct contact with maternal blood, and show that these cells recapitulate the antiviral properties of primary trophoblasts through the constitutive release of type III IFNs (IFNλ1 and IFNλ2) and become resistant to ZIKV infection. In addition, using organotypic human midgestation chorionic villous explants, we show that syncytiotrophoblasts isolated from the second trimester of pregnancy also constitutively release type III IFNs and use these IFNs in autocrine and paracrine manners to restrict ZIKV infection. Collectively, these data provide important insights into the defense mechanisms used by syncytiotrophoblasts at various stages of human gestation to resist ZIKV infection and new human models to study the role of type III IFNs in the vertical transmission of ZIKV and other viruses associated with congenital disease.

Gestational Stage and IFN-λ Signaling Regulate ZIKV Infection In Utero

“…A recent report showed that third trimester primary human syncytialized trophoblasts were resistant to ZIKV infection, and conditioned medium from these cells protected against ZIKV infection, a property ascribed to the actions of constitutively released IFN-λ (Bayer et al, 2016). Consistent with this observation, first trimester syncytialized trophoblasts appear resistant to ZIKV infection (Bhatnagar et al, 2017; Ritter et al, 2017), and the syncytium in second trimester human explants constitutively release IFN-λ and do not support ZIKV infection (Corry et al, 2017). In comparison, first- and second-trimester cytotrophoblasts in cell culture are susceptible to ZIKV infection (El Costa et al, 2016; Weisblum et al, 2016).…”

“…Routes of ZIKV vertical transmission could include infection of permissive extravillous trophoblasts (Tabata et al, 2016) and/or the maternal decidua, which would allow ZIKV to circumvent many of the most robust placental barrier functions, including those presented by syncytiotrophoblasts. In addition, primary human umbilical vein endothelial cells (HUVEC), uterine microvascular endothelial cells (hUtMEC), and primary full-term placental fibroblasts all are non-responsive to IFN-λ ((Fig S5) and (Corry et al, 2017)); cells that are non-responsive to IFN-λ could provide portals to facilitate ZIKV transplacental transmission.…”

“…Furthermore, the relative responsiveness of the late gestation placenta to IFN-λ treatment, as contrasted to the lack of inhibitory effect in early gestation, suggests that IFN-λ may contribute to the stage-dependent susceptibility of the placenta and fetus to ZIKV infection observed here and described elsewhere (Honein et al, 2017; Shapiro-Mendoza et al, 2017). However, RNASeq-based transcpritonal profiling of mid- and late-gestation human placental explants or cells did not identify substantive differences in mRNA expression of the type I (IFNAR) or III (IFNLR1 and IL10R-β) IFN receptors with increasing gestational age that would impact the responsiveness of the human placenta to IFNs during gestation (Corry et al, 2017). Although treatment of WT dams with pegIFN-λ2 comfirmed an inhibitory effect aganst ZIKV infection in the placenta at later gestational times, at present, it remains uncertain if its actions were on the maternal decidua or the adjacent junctional layer of the placenta.…”

“…Beyond this, the placenta, which serves as a physical and immunological barrier, changes dramatically during gestation, particularly between the early (first trimester) and later (second and third trimester) stages of human pregnancy when the intervillous space becomes filled with maternal blood and the placental villi have fully developed (Arora et al, 2017). Isolated human fetal-derived chorionic villi or trophoblast cells obtained later during gestation support less ZIKV infection compared to many non-placental cell types, which likely reflects stage-dependent effects of trophoblast differentiation (Bayer et al, 2016; Corry et al, 2017; Sheridan et al, 2017; Weisblum et al, 2016). The reduced susceptibility to ZIKV infection at later stages of gestation could result from distinct innate immune profiles including production of type III interferon (IFN)-λ (Bayer et al, 2016) or differential expression of putative entry receptors (Tabata et al, 2016).…”

Persistent Zika virus infection in porcine conceptuses is associated with elevated in utero cortisol levels

“…Such clinical signs and behavioral abnormalities can be partially associated with altered glucocorticoid levels [7]. Zika virus also replicates in the placenta [8][9][10], a crucial player in cortisol traffic from mother to fetus in humans [11] and pigs [12]. Thus, we hypothesize that congenital ZIKV infection may affect in utero cortisol levels.…”