Zika virus propagation and release in human fetal astrocytes can be suppressed by neutral sphingomyelinase-2 inhibitor GW4869

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.

Propofol reduces microglia activation and neurotoxicity through inhibition of extracellular vesicle release

“…EVs can be found in interstitial fluid, cerebrospinal fluid (Vella et al, 2008), circulating blood (Suetsugu et al, 2013), and primarily assert biological function through delivering cytokines, nucleic acids, lipids, and proteins to nearby or distant cells, suggesting that they play an important role in cell-to-cell communication (Thery et al, 2006). EV secretion is increased during neuroinflammation; our previous studies, along with others', have suggested that EVs fuel pathogenic processes in the brain during neuroinflammation (Gupta and Pulliam, 2014;Huang et al, 2018;Wang et al, 2017;Wu et al, 2015;Wu et al, 2018).…”

Host-Directed Antivirals: a Realistic Alternative to Fight Zika Virus

“…Likewise, imipramine, an FDA-approved antidepressant, inhibits ZIKV-RNA replication and virion production in human skin fibroblasts, probably by interfering with intracellular cholesterol transport [107]. Regarding sphingolipid metabolism, which has been involved in flavivirus infection [64], treatment with the neutral sphingomyelinase inhibitor GW4869 reduced ZIKV production by affecting viral morphogenesis [108] as described for other flaviviruses [109]. Finally, the activation of adenosine monophosphate-activated protein kinase (AMPK), a master regulator of lipid metabolism, using PF-06409577 or metformin reduced ZIKV infection, being its effect associated to an impairment of viral replication due to the modulation of the host cell lipid metabolism exerted by the compound [110,111].…”

Neutral Sphingomyelinase Inhibition Alleviates LPS-Induced Microglia Activation and Neuroinflammation after Experimental Traumatic Brain Injury

“…A number of studies have also begun to examine the effects of nSMase inhibitors, such as altenusin and GW4869, on brain immune cell function and as potential anti-inflammatory agents (Iguchi et al, 2016;Chua et al, 2017;Dickens et al, 2017;Huang et al, 2018;Sobue et al, 2018). The nSMases are a family of sphingomyelin phosphodiesterase enzymes that catalyze hydrolysis of sphingomyelin, a major component of eukaryotic cell membrane, to produce phosphocholine and ceramide (Wu et al, 2010;Figuera-Losada et al, 2015).…”