Zika virus-induced fetal demise is triggered by strain- and dose-specific RLR-driven activation of the interferon response in the decidua, placenta, and fetus in <i>Ifnar1</i> ^−/− mice

Congenital Zika syndrome is a constellation of fetal abnormalities ranging from fetal demise and microcephaly to infants that are born apparently healthy only to develop neurocognitive impacts later. ZIKV is now endemic in many regions worldwide, but how ZIKV harms the developing fetus remains an outstanding question. Previously, we used a mouse model of ZIKV infection during pregnancy to assess the pathogenic potential to the fetus of a panel of five low-passage ZIKV strains representing the viral genetic diversity in the Americas. We found that phenotypic heterogeneity existed between these closely related ZIKV strains. Here, we show that this heterogeneity is driven by RIG-I-like receptor-mediated activation of the interferon response at the maternal-fetal interface. We used chemical inhibition of the RIG-I pathway and measured the transcriptional activity of interferon-stimulated genes in fetuses to demonstrate that the fetal immune response may contribute to fetal demise.