Abstract
Zika virus (ZIKV) is a mosquito-borne virus, which can cause brain abnormalities in newborns, including microcephaly. MicroRNAs (miRNAs) are small non-coding RNAs, which post- transcriptionally regulate gene expression. They are involved in various processes including neurological development and host responses to viral infection, but their potential role in ZIKV pathogenesis remains poorly understood. MiRNAs can be incorporated into extracellular vesicles (EVs) and mediate cell-to-cell communication. While it is well known that in viral infections EVs carrying miRNAs can play a crucial role in disease pathogenesis, ZIKV effects on EV-delivered miRNAs and their contribution to ZIKV pathogenesis have not been elucidated. In the present study, we profiled intracellular and EV-derived miRNAs by next generation sequencing and analyzed the host mRNA transcriptome of neural stem cells during infection with ZIKV Uganda and French Polynesia strains. We identified numerous miRNAs, including miR-4792, which were dysregulated at the intracellular level and had altered levels in EVs during ZIKV infection. Integrated analyses of differentially expressed genes and miRNAs showed that ZIKV infection had an impact on processes associated with neurodevelopment and oxidative stress. Our results provide insights into the roles of intracellular and EV-associated host miRNAs in ZIKV pathogenesis.
Highlights
Zika virus (ZIKV), a mosquito-borne virus and member of the Flaviviridae family, was initially isolated in 1947 from a rhesus monkey in the Zika forest in Uganda [1]
Our results show that ZIKV Uganda and Polynesia modulate the gene expression pattern in lt-NES® cells by causing a dysregulation of genes mainly involved in interferon signaling and cell cycle, which may contribute to ZIKV pathogenesis
ZIKV infection induces severe neurodevelopmental damage with microcephaly observed in children of women infected during pregnancy
Summary
Zika virus (ZIKV), a mosquito-borne virus and member of the Flaviviridae family, was initially isolated in 1947 from a rhesus monkey in the Zika forest in Uganda [1]. In the course of this outbreak, ZIKV infection was for the first time linked to Guillain-Barré Syndrome and severe. ZIKV has circulated for decades in Africa without any documented clinical relevance. It is unclear whether genetic change might have resulted in a greater capacity of neurovirulence or whether ZIKV has always been teratogenic and severe cases have not been documented before 2013 [11,12]. Due to the rapid spread of the virus and its severe effects on infants, on 1st February 2016, the World Health Organization (WHO) declared a Public Health Emergency of International Concern (PHEIC) [13]. Previous studies have shown that ZIKV can infect human neural stem cells (hNSCs) and human neural progenitor cells (hNPCs), disrupting pathways involved in differentiation, apoptosis and cell cycle control [14,15,16,17]
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