Downregulation of Transcriptional Activity, Increased Inflammation, and Damage in the Placenta Following in utero Zika Virus Infection Is Associated With Adverse Pregnancy Outcomes

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 h 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 h 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.

Susceptibility and resilience to maternal immune activation are associated with differential expression of endogenous retroviral elements

“…Again, these effects emerged similarly in placental tissue of male and female offspring and correlated inversely with placental IL-6 transcripts. Previous work in animal models suggested that post-acute pathological consequences of MIA involve abnormal placental development (Hsiao and Patterson, 2011;Fatemi et al, 2012;Wu et al, 2017;Núñez Estevez et al, 2020;Creisher et al, 2022), which in turn may induce placental insufficiency and disrupt normal fetal development. In keeping with the pivotal role of syncytins in placental development (Mi et al, 2000;Dupressoir et al, 2011), the MIA-induced decrease in SynA and SynB expression may highlight a novel pathological mechanism by which this early-life adversity can affect normal placental development and functions.…”

Adverse outcomes in SARS-CoV-2 infected pregnant mice are gestational age-dependent and resolve with antiviral treatment

“…The adverse maternal and fetal outcomes of SARS-CoV-2 infection during pregnancy are like those observed in other mouse models of viral pathogenesis during pregnancy including Zika virus (ZIKV) and influenza A virus (IAV) infection. Mouse models of ZIKV infection during pregnancy have shown that adverse fetal and neonatal outcomes including congenital abnormalities, reduced cortical thickness, and neurobehavioral deficits (35, 38), are mediated in part by transplacental virus transmission and acute placental inflammation (35, 37). While vertical transmission during ZIKV infection contributes to adverse outcomes, we and others have shown that the maternal immune response, including elevated production of IL-1β, also plays a key role in pathogenesis (35, 59).…”

“…Nissl staining was performed, and images were taken under × 5 magnification using a Canon EOS Rebel (Tokyo, Japan). Coronal cortical thickness was measured from five random sections at the striatum level of each neonatal brain, as previously described (38). Cortical thickness was measured from both brain hemispheres in each section using ImageJ software, and the average of 10 measurements per specimen presented.…”

“…Quantification shown represents the average measurement from a single randomly chosen pup for each dam. (38)…”

Sex-specific effect of antenatal Zika virus infection on murine fetal growth, placental nutrient transporters, and nutrient sensor signaling pathways

“…Similar to other flaviviruses, ZIKV requires a variety of intricate interactions with host factors for successful infection, such as reprogramming of cellular metabolism underpinning ZIKV pathogenesis (Thaker et al, 2019;Chen et al, 2020;Yau et al, 2021). In the placenta, ZIKV is able to cause lipid reprogramming, mitochondrial dysfunction, and inflammatory immune imbalance, contributing to placental damage (Chen et al, 2020;Andrade et al, 2021;Creisher et al, 2022).…”