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bioRxiv · 10.1101/2025.02.12.637947

Zika virus-induced fetal demise is driven by strain- and dose-specific RLR-driven activation of the interferon response in the decidua, placenta, and fetus in Ifnar1-/- mice.

Bohm, E. K.·Castaneda, D.·Lu, Q.·Cameron, M. D.·Aliota, M. T.
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Abstract

Congenital Zika syndrome (CZS), the set of fetal and neonatal complications associated with Zika virus (ZIKV) infection in pregnancy, was first noted during the outbreak in the Americas in 2015-16. However, there was an unequal distribution of ZIKV cases and severe outcomes in all areas where ZIKV emerged in the Americas, demonstrating that the risk of CZS varied over space and time. Recently, we demonstrated that phenotypic heterogeneity existed between closely-related ZIKV strains. All ZIKV strains tested infected the placenta but varied in their capacity to cause overt fetal harm. Here, we further characterized the relative contributions of virus genotype and infecting dose of two phenotypically distinct ZIKV strains across multiple timepoints in gestation in pregnant mice that lack type-I interferon receptor function (Ifnar1-/-). To better understand the underlying causes of adverse fetal outcomes, we used RNA sequencing to compare ZIKV-infected and uninfected tissues. We found that ZIKV infection triggers retinoic acid-inducible gene I (RIG-I)-like receptor-mediated activation of the interferon response at the maternal-fetal interface. However, modest chemical inhibition of RIG-I activation in the decidua and placenta did not protect against fetal demise. Instead, the fetal interferon response was significantly associated with fetal demise. Together, these findings suggest that the response to ZIKV at the maternal-fetal interface can vary depending on the infecting ZIKV genotype and dose, and that the fetal immune response is an important mediator of fetal harm. IMPORTANCEPreviously, 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 retinoic acid-inducible gene I (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.

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Bohm, E. K., Castaneda, D., Lu, Q., Cameron, M. D., Aliota, M. T.. 2025-02-13. Zika virus-induced fetal demise is driven by strain- and dose-specific RLR-driven activation of the interferon response in the decidua, placenta, and fetus in Ifnar1-/- mice.. https://doi.org/10.1101/2025.02.12.637947

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