Abstract
Zika virus (ZIKV) is a neurotrophic flavivirus that is capable of infecting humans, leading to brain abnormalities during fetal development. The ZIKV infectivity in neural target cells remains poorly understood. Here, we found that ZIKV specifically infected glial fibrillary acidic protein- and S100B-positive primary human astrocytes derived from fetal brains. In contrast, neuron-specific Class III β-tubulin (TuJ1)-positive neurons in the astrocyte cultures and SOX2-positive neural progenitor cells derived from the fetal brains were less susceptible to ZIKV infection compared with astrocytes. The infected astrocytes released competent viral particles and manifested programmed cell death with a progressive cytopathic effect. Interestingly, ZIKV infection in human fetal astrocytes induced a significant increase of extracellular vesicles (EVs). Treatment with GW4869, a specific inhibitor of neutral sphingomyelinase-2, decreased EV levels, suppressed ZIKV propagation, and reduced the release of infectious virions in astrocytes. Therefore, ZIKV infects primary human fetal astrocytes and the infection can be suppressed by neutral sphingomyelinase-2 inhibitor GW4869. Further investigation into sphingomyelin metabolism and EVs may provide insights to the therapeutic treatment of ZIKV infection.
Highlights
Zika virus (ZIKV) is a single-stranded RNA virus of the Flaviviridae family[1]
We demonstrated that primary human fetal astrocytes are more susceptible to ZIKV compared with neurons in the cultures or neural progenitor cells (NPCs) derived from the same fetal tissues
To prepare primary human fetal astrocytes for ZIKV infection, we obtained single-cell suspensions dissociated from fetal (12–16 weeks) brain tissues, which consisted of mostly progenitor cells
Summary
Zika virus (ZIKV) is a single-stranded RNA virus of the Flaviviridae family[1]. It is transmitted to humans primarily through the bites of infected Aedes mosquitoes, though both perinatal/in utero and sexual transmission have been reported[2,3,4]. Discovered in 1947, ZIKV infection has been reported in Americans since 2014, with a major outbreak in Brazil starting in 2015. Genetic studies have revealed that the ZIKV has three distinct genotypes: West. It has been postulated that the virus evolved from the Asian genotype and spread to French Polynesia (2013) to Brazil (2015)[5]. Infection of ZIKV has been suggested to cause neuropathologies such as microcephalic fetuses[6, 7]. ZIKV infection might be associated with an increased incidence of Guillain–Barre Syndrome in adults[8]. The mechanisms for those neuropathologies are not clear. In the case of microcephaly, recent studies in humans have shown that
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