Disruption of glial cell development by Zika virus contributes to severe microcephalic newborn mice

Cui Li,Jesse W Xu,Qing Ye,Zhiheng Xu,Xingliang Zhu,Dan Xu,Weixiang Guo,Yisheng Jiang,Linqi Zhang,Qin Wang,Fuchun Zhang,Lei Shi,Lei Yu,Cheng-Feng Qin,Ruoke Wang,Fei Gao

doi:10.1038/s41421-018-0042-1

Abstract

The causal link between Zika virus (ZIKV) infection and microcephaly has raised alarm worldwide. Microglial hyperplasia, reactive gliosis, and myelination delay have been reported in ZIKV-infected microcephalic fetuses. However, whether and how ZIKV infection affects glial cell development remain unclear. Here we show that ZIKV infection of embryos at the later stage of development causes severe microcephaly after birth. ZIKV infects the glial progenitors during brain development. Specifically, ZIKV infection disturbs the proliferation and differentiation of the oligodendrocyte progenitor cells and leads to the abolishment of oligodendrocyte development. More importantly, a single intraperitoneal injection of pregnant mice with a human monoclonal neutralizing antibody provides full protection against ZIKV infection and its associated damages in the developing fetuses. Our results not only provide more insights into the pathogenesis of ZIKV infection, but also present a new model for the preclinical test of prophylactic and therapeutic agents against ZIKV infection.

Highlights

The world’s attention has been drawn to a global Zika virus (ZIKV) outbreak and its link with devastating cases of microcephaly
Infected brains were substantially smaller in size, thinner in cortex, and larger in lateral ventricle compared to that of uninfected mice inspected at postnatal day 3 (P3) and P5 (Fig. 1a, b and Supplementary Fig.1c–d)
With this standardized new mouse model of microcephaly, we have discovered the progressive activation of microglia, astrogliosis, and the disruption of oligodendrocyte development by ZIKV infection, mimicking the symptoms of congenital ZIKV syndrome

Summary

Introduction

The world’s attention has been drawn to a global Zika virus (ZIKV) outbreak and its link with devastating cases of microcephaly. The Brazilian Ministry of Health reported a 20-fold increase in cases of neonatal microcephaly, which corresponds geographically and temporally to the ZIKV outbreak in November 20151. A causal link between ZIKV infection and microcephaly or fetal death was confirmed recently by the presence of microcephaly and other brain abnormalities in the pups of mice infected with ZIKV2–5. Disturbance of the proper proliferation/self-renewal and differentiation of neural progenitor cells (NPCs), as well as neuronal migration and maturation, may lead to developmental brain disorders including microcephaly[6,7,8,9]. The infection results in dysregulation of NPC proliferation, differentiation, and neuronal cell death.

Methods

Results

Conclusion