Zika virus infect cortical neurons by exosomes carrying virus RNA and proteins through sphingomyelinase mediation

Wenshuo Zhou, Michael Woodson, Michael B Sherman, Girish Neelakanta, Hameeda Sultana

Overview

ZIKV uses exosomes that contains virus RNA and proteins as mediators of viral transmission between neurons. Exosomes derived from neuronal cells infect naïve cells in a time- and dose-dependent manna. Furthermore, ZIKV infection 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, 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.

Summary

Investigated a new mechanism of how ZIKV could infect naive cells through exosomes and provided a new insight of protection and inhibition of viral infection. Sphingomyelinase could also be a targeted molecule to prevent viral infection and a strategy of viral drug.

Author Comments

Dr wenshuo-zhou, Ph.D
Dr wenshuo-zhou, Ph.D
U.S Food and Drug Administration
Ph.D
Exosomes, virus
Silver Spring, Maryland | United States
For more viral exosome references, please check PLOS pathogens and PNAS papers of Wenshuo ZhouDr wenshuo-zhou, Ph.D

Resources

Exosomes mediate Zika virus transmission through SMPD3 neutral Sphingomyelinase in cortical neurons
https://www.tandfonline.com/doi/full/10.1080/22221751.2019.1578188

Exosomes mediate Zika virus transmission through SMPD3 neutral Sphingomyelinase in cortical neurons.

Authors:
Dr wenshuo-zhou, Ph.D
Dr wenshuo-zhou, Ph.D
U.S Food and Drug Administration
Ph.D
Exosomes, virus
Silver Spring, Maryland | United States

Emerg Microbes Infect 2019 ;8(1):307-326

a Department of Biological Sciences, Center for Molecular Medicine , Old Dominion University , Norfolk , VA , USA.

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.

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Source
http://dx.doi.org/10.1080/22221751.2019.1578188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6455149PMC
July 2019
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References

(Supplied by CrossRef)

Lagunas-Rangel FA et al.
J Virus Erad 2017

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