Downregulation of transcriptional activity, increased inflammation, and damage in the placenta following in utero Zika virus infection is associated with adverse pregnancy outcomes.

Patrick S Creisher,Anne E Jedlicka,Harish Narasimhan,Anna Chudnovets,Andrew Pekosz,Anguo Liu,Morgan L Sherer,Amanda Dziedzic,Jun Lei,Irina Burd,Ariana D Campbell,Sabra L Klein

doi:10.3389/fviro.2022.782906

Patrick S Creisher, Anne E Jedlicka + Show 10 more

Open Access

https://doi.org/10.3389/fviro.2022.782906

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Abstract

Zika virus (ZIKV) infection during pregnancy causes serious adverse outcomes to the developing fetus, including fetal loss and birth defects known as congenital Zika syndrome (CZS). The mechanism by which ZIKV infection causes these adverse outcomes and specifically, the interplay between the maternal immune response and ZIKV replication has yet to be fully elucidated. Using an immunocompetent mouse model of transplacental ZIKV transmission and adverse pregnancy outcomes, we have previously shown that Asian lineage ZIKV disrupts placental morphology and induces elevated secretion of IL-1β. In the current manuscript, we characterized placental damage and inflammation during in utero African lineage ZIKV infection. Within 48 hours after ZIKV infection at embryonic day 10, viral RNA was detected in placentas and fetuses from ZIKA infected dams, which corresponded with placental damage and reduced fetal viability as compared with mock infected dams. Dams infected with ZIKV had reduced proportions of trophoblasts and endothelial cells and disrupted placental morphology compared to mock infected dams. While placental IL-1β was increased in the placenta, but not the spleen, within 3 hours post infection, this was not caused by activation of the NLRP3 inflammasome. Using bulk mRNAseq from placentas of ZIKV and mock infected dams, ZIKV infection caused profound downregulation of the transcriptional activity of genes that may underly tissue morphology, neurological development, metabolism, cell signaling and inflammation, illustrating that in utero ZIKV infections causes disruption of pathways associated with CZS in our model.

Highlights

Pregnant women and their developing fetuses are at high risk for severe outcomes from a variety of viral, bacterial, and parasitic infections including the “TORCH” pathogens (Toxoplasma gondii, other, rubella virus, cytomegalovirus, herpes simplex virus), which are grouped because of their propensity to induce congenital disease [1, 2]
The causal connection between Zika virus (ZIKV) infection during pregnancy and subsequent birth defects, which are collectively referred to as Congenital Zika Syndrome (CZS), was confirmed with the detection of ZIKV RNA in amniotic fluid of pregnant women carrying children with microcephaly and the isolation of ZIKV from the brain of an infant who died after birth [6, 8]
Since the 2016 ZIKV epidemic, we have investigated the pathogenesis of ZIKV infection during pregnancy after intrauterine infection in immunocompetent mice

Summary

Introduction

Pregnant women and their developing fetuses are at high risk for severe outcomes from a variety of viral, bacterial, and parasitic infections including the “TORCH” pathogens (Toxoplasma gondii, other, rubella virus, cytomegalovirus, herpes simplex virus), which are grouped because of their propensity to induce congenital disease [1, 2]. Often cause adverse consequences during pregnancy for the mother, fetus, or both. Viruses can infect the placenta, fetus, or both to cause adverse consequences, such as loss of pregnancy, preterm birth, birth defects, and growth and neurodevelopmental delays in the fetus and newborn [2, 4]. The causal connection between ZIKV infection during pregnancy and subsequent birth defects, which are collectively referred to as Congenital Zika Syndrome (CZS), was confirmed with the detection of ZIKV RNA in amniotic fluid of pregnant women carrying children with microcephaly and the isolation of ZIKV from the brain of an infant who died after birth [6, 8]. Multiple systematic reviews and meta-analyses performed after the end of the epidemic confirmed the association between ZIKV infection during pregnancy and CZS [9,10,11,12]

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