Abstract
The World Health Organization has declared ZIKA virus (ZIKV) a global public health emergency, prompted by the association of ZIKV infections with severe brain abnormalities in the human fetus. ZIKV preferentially targets human neuronal precursor cells (NPCs) in both monolayer and cortical brain organoid culture systems and stunts their growth. Although ZIKV is well recognized to cause microcephaly, there is no systematic analysis to demonstrate the effect of ZIKV on central nervous system (CNS) development, including brain malformations and spinal cord dysfunction. Here, we conducted a longitudinal analysis to show that a novel mouse model (infected in utero and monitored after birth until adulthood) recapitulates the effects of ZIKV infection affecting neural stem cells fate and leads to a thinner cortex and a smaller brain. Furthermore, we demonstrate the effect of ZIKV on spinal cord function. Specifically, we found significant reductions in neuron numbers in the anterior horn of grey matter of the spinal cord and muscle dystrophy with a significant decrease in forepaw grip strength in the ZIKV group. Thus, the established mouse model of ZIKV infection leading to abnormal CNS development will help to further advance our understanding of the disease pathogenesis.
Highlights
ZIKA, its name came from the ZIKA Forest of Uganda, where the virus was first isolated in 1947 from a rhesus macaque monkey[1]
Given that neurogenes is occurs in the adult brain, in which there are two neurogenic niche areas at subventricular zone (SVZ) and hippocampal dentate gyrus[13,14], we examined the effect of ZIKA virus (ZIKV) infection on neurogenesis
Congenital Zika syndrome is a serious birth defect caused by Zika virus infection during pregnancy in humans[3,4,5]
Summary
ZIKA, its name came from the ZIKA Forest of Uganda, where the virus was first isolated in 1947 from a rhesus macaque monkey[1]. The human progenitors in vitro, recent studies showed that cerebral organoids can recapitulate key features of human cortical development, including neurogenesis and notably, a distinct human specific outer radial glial cell layer-derived from human iPSCs. ZIKV infection leads to increased cell death and reduced proliferation, resulting in decreased neuronal cell-layer volume resembling microcephaly[6]. Li et al.[11] established a ZIKV infection model in mice via in utero injection during embryonic development and found ZIKV infection causes microcephaly They found that ZIKV infection leads to cell-cycle arrest, apoptosis, and inhibits NPCs differentiation, resulting in thinner cortex during embryonic cortical development. They failed to develop the mouse model that infects ZIKV at the embryonic stage which can allow the mice to survive postnatal till adult stage. Most microcephaly cases indicate that the infection by Zika virus is at the pregnancy stage
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