Differentiation enhances Zika virus infection of neuronal brain cells

Abstract

Zika virus (ZIKV) is an emerging, mosquito-borne pathogen associated with a widespread 2015–2016 epidemic in the Western Hemisphere and a proven cause of microcephaly and other fetal brain defects in infants born to infected mothers. ZIKV infections have been also linked to other neurological illnesses in infected adults and children, including Guillain-Barré syndrome (GBS), acute flaccid paralysis (AFP) and meningoencephalitis, but the viral pathophysiology behind those conditions remains poorly understood. Here we investigated ZIKV infectivity in neuroblastoma SH-SY5Y cells, both undifferentiated and following differentiation with retinoic acid. We found that multiple ZIKV strains, representing both the prototype African and contemporary Asian epidemic lineages, were able to replicate in SH-SY5Y cells. Differentiation with resultant expression of mature neuron markers increased infectivity in these cells, and the extent of infectivity correlated with degree of differentiation. New viral particles in infected cells were visualized by electron microscopy and found to be primarily situated inside vesicles; overt damage to the Golgi apparatus was also observed. Enhanced ZIKV infectivity in a neural cell line following differentiation may contribute to viral neuropathogenesis in the developing or mature central nervous system.

Asian Zika Virus Isolate Significantly Changes the Transcriptional Profile and Alternative RNA Splicing Events in a Neuroblastoma Cell Line

“…These studies used different ZIKV strains, multiplicities of infection, and lengths of infection, and thus the extent of ZIKV infection ranged from 2.5% to 90% [27,[29][30][31][32][33][34][35]. Consistent with earlier reports of ZIKV infection in SH-SY5Y cells [80,81], immunofluorescence analyses revealed that 40% of cells were infected (Figure 1a,b). While we recognized that the differential gene expression and alternative splicing analyses collected would be on a modest number of infected cells, we reasoned that this level of infection would be comparable to the previous transcriptome-wide studies [27,[29][30][31][32][33][34][35] and that, thus, changes in the alternative splicing landscape would model such changes in ZIKV-infected neurons.…”

Filoviruses Can Efficiently Infect Human Neuron-Like Cells Without Genetic Adaptation

“…The human neuroblastoma cell lines SH-SY5Y and BE(2)-M17 are two of the best-characterised cell lines for studies into human neurological disease, such as Alzheimer’s and Parkinson’s diseases (30–35), and neurovirology (39–46, 49, 52). Previous studies have confirmed their suitability as in vitro models of human neurons due to their expression of human neuron-specific markers, and the fact that their neuron-like phenotypes can be further improved through the use of chemical differentiation agents, such as RA and staurosporine (36–38, 43).…”

Zika Virus Infects Trabecular Meshwork and Causes Trabeculitis and Glaucomatous Pathology in Mouse Eyes

“…Studies from our lab and others have shown that ZIKV infects a variety of retinal (6, 12, 17, 22–24), corneal (25), and other cell types, including neuronal cells (26, 27); placental cells (28, 29); skin fibroblasts, keratinocytes, and dendritic cells (30); and endometrial stromal cells (31). In vivo studies using local as well systemic infection in mouse models have demonstrated that ZIKV causes a variety of ocular pathologies and infects various parts of the eye including ciliary body, iris, conjunctiva, retina, and optic nerve head (6, 12, 17).…”