Abstract
Zika virus (ZIKV) infection during pregnancy leads to an increased risk of fetal growth restriction and fetal central nervous system malformations, which are outcomes broadly referred to as the Congenital Zika Syndrome (CZS). Here we infect pregnant rhesus macaques and investigate the impact of persistent ZIKV infection on uteroplacental pathology, blood flow, and fetal growth and development. Despite seemingly normal fetal growth and persistent fetal-placenta-maternal infection, advanced non-invasive in vivo imaging studies reveal dramatic effects on placental oxygen reserve accompanied by significantly decreased oxygen permeability of the placental villi. The observation of abnormal oxygen transport within the placenta appears to be a consequence of uterine vasculitis and placental villous damage in ZIKV cases. In addition, we demonstrate a robust maternal-placental-fetal inflammatory response following ZIKV infection. This animal model reveals a potential relationship between ZIKV infection and uteroplacental pathology that appears to affect oxygen delivery to the fetus during development.
Highlights
Zika virus (ZIKV) infection during pregnancy leads to an increased risk of fetal growth restriction and fetal central nervous system malformations, which are outcomes broadly referred to as the Congenital Zika Syndrome (CZS)
When comparing DCE-magnetic resonance imaging (MRI) results for the five ZIKV-infected animals to a group of six pregnant rhesus macaque controls matched at 135dGA, we found modest, but not statistically significant, decreases in both total placental blood flow (139 ml/min vs. 161 ml/min, respectively) and normalized placental blood flow (1.14 ml/ml/min vs. 1.25 ml/ml/min, respectively)
Combined with our observation of nearly normal maternal blood flow and increased levels of oxygenated blood within the placenta, these results strongly suggest that ZIKV infection impairs transplacental transport of oxygen, potentially resulting in long-term fetal oxygen deprivation during gestation, likely secondary to placental damage occurring at the level of the fetal villi
Summary
Zika virus (ZIKV) infection during pregnancy leads to an increased risk of fetal growth restriction and fetal central nervous system malformations, which are outcomes broadly referred to as the Congenital Zika Syndrome (CZS). We demonstrate a robust maternal-placental-fetal inflammatory response following ZIKV infection This animal model reveals a potential relationship between ZIKV infection and uteroplacental pathology that appears to affect oxygen delivery to the fetus during development. Infection with other flaviviruses such as dengue virus are rarely associated with fetal infection or severe birth defects[10], suggesting that ZIKV is quite unique in this regard These observations strongly suggest a component of placental dysfunction in ZIKV cases, which has not previously been extensively investigated in vivo. The available data from nonhuman primate studies and human cohorts suggest some underlying inflammation contributing to the placental dysfunction in ZIKV-infected pregnancies, but prior to such assessments have not been linked to an in vivo functional correlate
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