Abstract
Zika virus (ZIKV) infection is associated with severe neurological defects in fetuses and newborns, such as microcephaly. However, the underlying mechanisms remain to be elucidated. In this study, proteomic analysis on ZIKV-infected primary human fetal neural progenitor cells (NPCs) revealed that virus infection altered levels of cellular proteins involved in NPC proliferation, differentiation and migration. The transcriptional levels of some of the altered targets were also confirmed by qRT-PCR. Among the altered proteins, doublecortin (DCX) plays an important role in NPC differentiation and migration. Results showed that ZIKV infection downregulated DCX, at both mRNA and protein levels, as early as 1 day post infection (1 dpi), and lasted throughout the virus replication cycle (4 days). The downregulation of DCX was also observed in a ZIKV-infected fetal mouse brain model, which displayed decreased body weight, brain size and weight, as well as defective cortex structure. By screening the ten viral proteins of ZIKV, we found that both the expression of NS4A and NS5 were correlated with the downregulation of both mRNA and protein levels of DCX in NPCs. These data suggest that DCX is modulated following infection of the brain by ZIKV. How these observed changes of DCX expression translate in the pathological consequences of ZIKV infection and if other cellular proteins are equally involved remains to be investigated.
Highlights
A Zika virus (ZIKV) outbreak has been ongoing in central and south America for the past 2 years, and has raised global concerns with regards to public health (Gulland, 2016; Lazear and Diamond, 2016)
We found that neural progenitor cells (NPCs) were vulnerable to ZIKV infection, that multiple signaling pathways and cellular functions associated with neurogenesis were impaired by the infection, and that ZIKV infection downregulates DCX expression in NPC and mouse fetal brain, which further related to the decreased thickness of cortex layers
When infected human NPCs were infected with ZIKV at a low multiplicity of infection (MOI) of 0.1, the titer of ZIKV in the supernatant initially reached to 30 PFU/ml at 1 dpi, and increased to 1 × 103 PFU/ml at 5 dpi, indicating that similar yield of infectious viral particles can still be reached when infected at a low MOI (Figure 1A)
Summary
A Zika virus (ZIKV) outbreak has been ongoing in central and south America for the past 2 years, and has raised global concerns with regards to public health (Gulland, 2016; Lazear and Diamond, 2016). It has been shown to be associated with microcephaly in newborns whose mothers were infected with ZIKV during pregnancy (Musso and Gubler, 2016; Rubin et al, 2016). ZIKV was detected in the placenta and amniotic fluids from the infected women during pregnancy, and in the blood and brain of congenitally infected fetuses, suggesting a potential for vertical transmission and an association with microcephaly and other birth defects (Calvet et al, 2016; Rubin et al, 2016). ZIKV has been shown to infect neural progenitor cells (NPCs) and inhibits cell proliferation, growth of neurospheres and brain organoids, suggesting that the neuropathology induced by ZIKV might be associated with NPC cell fate (Garcez et al, 2016; Tang et al, 2016). The molecular mechanism(s) of ZIKV affecting neurogenesis still remains to be elucidated
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