293tExosome-mediated miR-146a transfer suppresses type I #interferon response and facilitates #EV71 #infection (PLoS Pathogens, abstract)

[Source: PLoS Pathogens, full page: (LINK). Abstract, edited.]

OPEN ACCESS /  PEER-REVIEWED / RESEARCH ARTICLE

293tExosome-mediated miR-146a transfer suppresses type I interferon response and facilitates EV71 infection

Yuxuan Fu, Li Zhang, Fang Zhang, Ting Tang, Qi Zhou, Chunhong Feng, Yu Jin, Zhiwei Wu

Published: September 14, 2017 / DOI: https://doi.org/10.1371/journal.ppat.1006611 /  This is an uncorrected proof.

 

Abstract

Exosomes can transfer genetic materials between cells. Their roles in viral infections are beginning to be appreciated. Researches have shown that exosomes released from virus-infected cells contain a variety of viral and host cellular factors that are able to modulate recipient’s cellular response and result in productive infection of the recipient host. Here, we showed that EV71 infection resulted in upregulated exosome secretion and differential packaging of the viral genomic RNA and miR-146a into exosomes. We provided evidence showing that miR-146a was preferentially enriched in exosomes while the viral RNA was not in infected cells. Moreover, the exosomes contained replication-competent EV71 RNA in complex with miR-146a, Ago2, and GW182 and could mediate EV71 transmission independent of virus-specific receptor. The exosomal viral RNA could be transferred to and replicate in a new target cell while the exosomal miR-146a suppressed type I interferon response in the target cell, thus facilitating the viral replication. Additionally, we found that the IFN-stimulated gene factors (ISGs), BST-2/tetherin, were involved in regulating EV71-induced upregulation of exosome secretion. Importantly, in vivo study showed that exosomal viral RNA exhibited differential tissue accumulation as compared to the free virus particles. Together, our findings provide evidence that exosomes secreted by EV71-infected cells selectively packaged high level miR-146a that can be functionally transferred to and facilitate exosomal EV71 RNA to replicate in the recipient cells by suppressing type I interferon response.

 

Author summary

Exosomes are small membrane-encapsulated vesicles that secrete into the extracellular environment. Various proteins and RNA molecules have been identified in exosomes whose content reflects the physiological or pathological state of the host cells. Researches have shown that exosomes released from virus-infected cells contain a variety of viral and host cellular factors that are able to modulate recipient’s cellular responses and result in productive infection of the recipient host. Here, we showed that Enterovirus 71 (EV71), a non-enveloped, single-strand positive sense RNA virus that belongs to the family Picornaviridae and is a major etiologic agent of hand-foot and-mouth disease (HFMD), could stimulate exosome secretion and differential packaging of the viral genomic RNA and miR-146a into exosomes. The exosomal viral RNA could be transferred to and replicate in a new target cell while the exosomal miR-146a suppressed type I interferon response in the target cell, thus facilitating the viral replication. Importantly, in vivo study showed that exosomal viral RNA exhibited differential tissue accumulation as compared to the free virus particles. We postulate that the preferential packaging of miRNA-146a into exosome is a viral strategy of suppressing host innate immunity upon infection and the exosomal EV 71 RNA may play an important pathogenic role in the infection.

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Citation: Fu Y, Zhang L, Zhang F, Tang T, Zhou Q, Feng C, et al. (2017) 293tExosome-mediated miR-146a transfer suppresses type I interferon response and facilitates EV71 infection. PLoS Pathog 13(9): e1006611. https://doi.org/10.1371/journal.ppat.1006611

Editor: Carolyn B. Coyne, University of Pittsburgh, UNITED STATES

Received: May 4, 2017; Accepted: August 28, 2017; Published: September 14, 2017

Copyright: © 2017 Fu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All relevant data are within the paper and its Supporting Information files.

Funding: This study was supported by The National Key Research and Development Program of China (2016YFC1201000), Nature Science Foundation of Jiangsu Province (BY2015069-02) and National Nature Science Foundation of China (81672020). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

Keywords: EV-71; Interferons.

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Giuseppe Michieli

I am an Italian blogger, active since 2005 with main focus on emerging infectious diseases such as avian influenza, SARS, antibiotics resistance, and many other global Health issues. Other fields of interest are: climate change, global warming, geological and biological sciences. My activity consists mainly in collection and analysis of news, public services updates, confronting sources and making decision about what are the 'signals' of an impending crisis (an outbreak, for example). When a signal is detected, I follow traces during the entire course of an event. I started in 2005 my blog ''A TIME'S MEMORY'', now with more than 40,000 posts and 3 millions of web interactions. Subsequently I added an Italian Language blog, then discontinued because of very low traffic and interest. I contributed for seven years to a public forum (FluTrackers.com) in the midst of the Ebola epidemic in West Africa in 2014, I left the site to continue alone my data tracking job.