Abstract
ABSTRACT The harmful effects of ZIKA virus (ZIKV) infection are reflected by severe neurological manifestations such as microcephaly in neonates and other complications associated with Guillain-Barré syndrome in adults. The transmission dynamics of ZIKV in or between neurons, or within the developing brains of the foetuses are not fully understood. Using primary cultures of murine cortical neurons, we show that ZIKV uses exosomes as mediators of viral transmission between neurons. Cryo-electron microscopy showed heterogeneous population of neuronal exosomes with a size range of 30–200 nm. Increased production of exosomes from neuronal cells was noted upon ZIKV infection. Neuronal exosomes contained both ZIKV viral RNA and protein(s) that were highly infectious to naïve cells. RNaseA and neutralizing antibodies treatment studies suggest the presence of viral RNA/proteins inside exosomes. Exosomes derived from time- and dose-dependent incubations showed increasing viral loads suggesting higher packaging and delivery of ZIKV RNA and proteins. Furthermore, we noted that ZIKV induced both activity and gene expression of neutral Sphingomyelinase (nSMase)-2/SMPD3, an important molecule that regulates production and release of exosomes. Silencing of SMPD3 in neurons resulted in reduced viral burden and transmission through exosomes. Treatment with SMPD3 specific inhibitor GW4869, significantly reduced ZIKV loads in both cortical neurons and in exosomes derived from these neuronal cells. Taken together, our results suggest that ZIKV modulates SMPD3 activity in cortical neurons for its infection and transmission through exosomes perhaps leading to severe neuronal death that may result in neurological manifestations such as microcephaly in the developing embryonic brains.
Highlights
Mosquito-borne Zika virus (ZIKV) is a positive sense single-stranded RNA virus that belongs to the flavivirus genus of the family Flaviviridae [1]
Our work suggests that neutral Sphingomyelinase SMPD3, an enzyme sphingomyelin phosphodiesterase is involved in ZIKA virus (ZIKV) infection, replication, and mediates infectious viral RNA and protein transmission via neuronal exosomes
Due to the occurrence of RNA in the exosomes, we hypothesized whether exosomes are carriers of viral RNA from the latest emerging ZIKV
Summary
Mosquito-borne Zika virus (ZIKV) is a positive sense single-stranded RNA virus that belongs to the flavivirus genus of the family Flaviviridae [1]. Since more than 60 years, ZIKV existed in the Zika forest of Uganda and recently has become an International prominence and Public Health Emergency of International Concern (PHEIC) [1,2,3]. ZIKV belongs to the Spondweni serocomplex and is closely related to dengue (DENV) and West Nile virus (WNV) [1]. The sexual transmission of ZIKV, with replicative viral particles being detectable in semen for at least two months, proposes it to be a significant global threat and a pathogen of high priority concern to the public health [4,5]
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