Preventive effects of folic acid on Zika virus-associated poor pregnancy outcomes in immunocompromised mice

PLoS Pathog. 2020 May 11;16(5):e1008521. doi: 10.1371/journal.ppat.1008521. eCollection 2020 May.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Disease Models, Animal
  • Female
  • Folic Acid / pharmacology*
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Mice
  • Microcephaly / metabolism
  • Microcephaly / pathology
  • Microcephaly / prevention & control
  • Microcephaly / virology
  • Placenta* / metabolism
  • Placenta* / pathology
  • Placenta* / virology
  • Pregnancy
  • Pregnancy Complications, Infectious* / metabolism
  • Pregnancy Complications, Infectious* / pathology
  • Pregnancy Complications, Infectious* / prevention & control
  • Zika Virus / metabolism*
  • Zika Virus Infection / metabolism
  • Zika Virus Infection / pathology
  • Zika Virus Infection / prevention & control*

Substances

  • Folic Acid

Grants and funding

This work was supported by Academia Sinica (AS-Summit-109, 109-2101-01-19-20 to YLLIN) and the Ministry of Science and Technology, Taiwan (MOST 108-3114-Y-001-002, MOST 108-2321-B-001-011, MOST 108-2320-B-001-030-MY3 to YLLIN).The funders had no role in study design, data collection and analysis, decision to publish, or preparation to the manuscript.