Abstract
Zika virus (ZIKV) infection may lead to congenital microcephaly and pregnancy loss in pregnant women. In the context of pregnancy, folic acid (FA) supplementation may reduce the risk of abnormal pregnancy outcomes. Intriguingly, FA may have a beneficial effect on the adverse pregnancy outcomes associated with ZIKV infection. Here, we show that FA inhibits ZIKV replication in human umbilical vein endothelial cells (HUVECs) and a cell culture model of blood-placental barrier (BPB). The inhibitory effect of FA against ZIKV infection is associated with FRα-AMPK signaling. Furthermore, treatment with FA reduces pathological features in the placenta, number of fetal resorptions, and stillbirths in two mouse models of in utero ZIKV transmission. Mice with FA treatment showed lower viral burden and better prognostic profiles in the placenta including reduced inflammatory response, and enhanced integrity of BPB. Overall, our findings suggest the preventive role of FA supplementation in ZIKV-associated abnormal pregnancy and warrant nutritional surveillance to evaluate maternal FA status in areas with active ZIKV transmission.
Highlights
Zika virus (ZIKV), a mosquito-borne flavivirus, is a clinically important pathogen
Zika virus (ZIKV) infection in pregnant women may cause a broad spectrum of abnormal pregnancy outcomes
We observe that folic acid (FA) treatment increases the level of maternal serum FA and improves fetoplacental outcomes in two mouse models of in utero transmission of ZIKV
Summary
Zika virus (ZIKV), a mosquito-borne flavivirus, is a clinically important pathogen. The outbreak of ZIKV in Brazil has created public health of international concern in 2015–2016 [1]. ZIKV infection in pregnant women may cause a broad spectrum of abnormal pregnancy outcomes including intrauterine growth restriction (IUGR), microcephaly, miscarriage, and stillbirth [1,2,3]. Placental insufficiency or dysfunction, a clinical presentation of poor blood flow in the placenta, may lead to IUGR and pregnancy loss [9]. The placenta is a transient organ that facilitates the maternal-fetal exchange of gases, nutrients, hormones, and waste products through the blood-placental barrier (BPB). It provides a physical and immunological barrier against pathogen transmission from the mother to embryo [10]. Maintaining the placental function is critical for normal fetal development and preventing disease transmission
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