The link between Zika virus (ZIKV) infection and microcephaly has raised urgent global alarm. The historical African ZIKV MR766 was recently shown to infect cultured human neural precursor cells (NPCs), but unlike the contemporary ZIKV strains, it is not believed to cause microcephaly. Here we investigated whether the Asian ZIKV strain SZ01 could infect NPCs in vivo and affect brain development. We found that SZ01 replicates efficiently in embryonic mouse brain by directly targeting different neuronal linages. ZIKV infection leads to cell-cycle arrest, apoptosis, and inhibition of NPC differentiation, resulting in cortical thinning and microcephaly. Global gene expression analysis of infected brains reveals upregulation of candidate flavirus entry receptors and dysregulation of genes associated with immune response, apoptosis, and microcephaly. Our model provides evidence for a direct link between Zika virus infection and microcephaly, with potential for further exploration of the underlying mechanisms and management of ZIKV-related pathological effects during brain development.

When this paper was originally published, the accession number for the RNA-seq dataset included in the study was unfortunately omitted. The dataset has now been submitted to the Genome Sequence Archive of the Beijing Institute of Genomics Data Center under the accession number PRJCA000267. The online version of the paper has also been modified to include an Accession Numbers section with this information.

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.