Zika Virus-Induced Neuronal Apoptosis via Increased Mitochondrial Fragmentation.

Shu Yang,Natalia De Val,Hongjun Song,Guoli Ming,Hengli Tang,Ferri Soheilian,Nuo Sun,Emily M Lee,Yu-Shan Cheng,Wei Zheng,Miao Xu,Kirill Gorshkov

doi:10.3389/fmicb.2020.598203

Abstract

The 2015 to 2016 outbreak of Zika virus (ZIKV) infections in the Americas coincided with a dramatic increase in neurodevelopmental abnormalities, including fetal microcephaly, in newborns born to infected women. In this study, we observed mitochondrial fragmentation and disrupted mitochondrial membrane potential after 24 h of ZIKV infection in human neural stem cells and the SNB-19 glioblastoma cell line. The severity of these changes correlated with the amount of ZIKV proteins expressed in infected cells. ZIKV infection also decreased the levels of mitofusin 2, which modulates mitochondria fusion. Mitochondrial division inhibitor 1 (Mdivi-1), a small molecule inhibiting mitochondria fission, ameliorated mitochondria disruptions and reduced cell death in ZIKV-infected cells. Collectively, this study suggests that abnormal mitochondrial fragmentation contributes to ZIKV-induced neuronal cell death; rebalancing mitochondrial dynamics of fission-fusion could be a therapeutic strategy for drug development to treat ZIKV-mediated neuronal apoptosis.

Highlights

Zika virus (ZIKV) belongs to the Flavivirus genus in the Flaviviridae family of RNA viruses (Ming et al, 2016)
We found that ZIKV infection disrupted mitochondrial dynamics, mitochondrial network structure, and function by decreasing mitofusin 2 (MFN2) protein levels
To further investigate the cellular pathology of ZIKV infection, each set of Differentially expressed genes (DEGs) was submitted to gene ontology (GO) pathway analysis

Summary

Introduction

Zika virus (ZIKV) belongs to the Flavivirus genus in the Flaviviridae family of RNA viruses (Ming et al, 2016). ZIKV is most commonly transmitted through the bites of infected Aedes mosquitoes. Unlike other flaviviruses, ZIKV can be sexually and vertically transmitted (Musso et al, 2015; Venturi et al, 2016; Mesci et al, 2018). The single-strand, positive-sense RNA genome in ZIKV encodes a large polyprotein. It is posttranslationally cleaved by both viral and host proteases to form many proteins. The three structural proteins are the capsid (C), the precursor membrane (prM) that is further cleaved in the maturing virion to form the membrane (M) protein, and the envelope (ENV) (Ye et al, 2016). The structural proteins, together with the single-strand RNA genome, form the enveloped ZIKV spherical particle with a diameter of approximately 40 nm (Chambers et al, 1990). 80% of ZIKV-infected individuals are asymptomatic or exhibit mild

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