Zika Virus Disrupts Neural Progenitor Development and Leads to Microcephaly in Mice

Abstract

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.

Zika virus disease: a current review of the literature

“…Recently, a few studies [79,80,[82][83][84][85] have evidenced the pathogenic potential of Brazilian strain of ZIKV during the development of fetus in animal models. These studies concluded that ZIKV first infects the placenta and then the brain of fetus, where it preferentially infects neural progenitor cells and decreases their viability and growth as neurospheres through down-regulation of genes that are involved in cell and organ development, and up-regulation of genes that are involved in immune responses.…”

“…This results in inhibited cellular proliferation and differentiation, neuronal apoptosis, thinning of the cortex and macroscopic features similar to microcephaly. Based on the results of the above stated studies [79,80,[82][83][84][85], a causal link between ZIKV infection and microcephaly could be hypothesized.…”

Editorial brain malformation surveillance in the Zika era

“…Both the Brazilian ZIKV strain and the Asian ZIKV strain cause abnormal cortical development in mice (Cugola et al, 2016; Li et al, 2016) that would be consistent with multiple different types of cortical malformations in human infants exposed in utero to ZIKV among both those with congenital microcephaly and those with normal head circumferences at birth. Therefore, it was not surprising when several different types of brain malformations were recently reported among infants exposed in utero to ZIKV, including polymicrogyria with schizencephalic clefts, areas of thickened cortex, areas of thinning cortex, and focal cortical dysplasia, often with asymmetry and with different types of malformations and/or brain injury in the same infant, and occurring among infants with congenital microcephaly as well as among some infants with normal head circumference at birth (de Oliveria‐Szejnfeld et al, 2016).…”

“…ZIKV invades fetal neural progenitor cells and causes brain abnormalities by at least two general mechanisms: (1) direct destruction of neuronal progenitor cells and developing neurons, and (2) disruption of the differentiation, development, and migration of neurons in the developing brain (Garcez et al, 2016; Qian et al, 2016; Sarno et al, 2016; Tang et al, 2016; Cugola et al, 2016; Li et al, 2016). Both the Brazilian ZIKV strain and the Asian ZIKV strain cause abnormal cortical development in mice (Cugola et al, 2016; Li et al, 2016) that would be consistent with multiple different types of cortical malformations in human infants exposed in utero to ZIKV among both those with congenital microcephaly and those with normal head circumferences at birth.…”

Pregnancy, the placenta and Zika virus (ZIKV) infection

“…These are mainly observational data with minimal controls, albeit with autopsy and ultrasound data being consistent with microcephaly resulting from ZIKV infection during pregnancy 15 . ZIKV has been known to be neurotropic in animals for 60 years, with more recent murine experiments demonstrating replication in embryonic brain targeting neural progenitor cells, with consequent cell cycle arrest, apoptosis and inhibited neural progenitor cell differentiation 9,16 . This is presumed to result in the microcephalic phenotype via neuronal cell death 16 .…”