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

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.

The role of miR‐146a in viral infection

“…Besides, Hurwit and colleagues demonstrated that EBV LMP1 protein upregulated exosome secretion in the various cellular models related to EBV pathogenesis . Fu and colleagues showed that the EV71 infection results in an increased exosome release in THP‐1 and HT‐29 cells, as well as differential packaging of miR‐146a and the viral genomic RNA into exosomes. The exosomal EV71‐RNA genome can be transferred to a new target cell and replicates in these cells, while exosomal miR‐146a inhibits IFN‐I response in target cells, thereby facilitating the EV71 replication.…”

“…Since nonpermissive L929 cells do not express PSGL‐1 and SCARB2, it is suggested that exosomal EV71 RNA can overcome the limitation of the receptor for cellular entry, and mediate replication of the virus in a receptor‐independent manner. Of note, exosomal miR‐146a contributes to replicate exosomal EV71 RNA by suppressing IFN‐I response . In other viral infections or virus‐induced cancers, the role of exosomal miR‐146a in the modulation of the host immune system has not been studied, and further researches are needed.…”

“…In some studies, it has been indicated that miR‐146a is selectively packaged into exosomes. Also, overexpressed exosomal miR‐146a has been detected in exosomes released from enterovirus‐infected cells . Thus, immune response modulation by miR‐146a in the recipient cells can possibly make them more susceptible to the virus infection.…”

“…Also, overexpressed exosomal miR-146a has been detected in exosomes released from enterovirus-infected cells. 9 Thus, immune response modulation by miR-146a in the recipient cells can possibly make them more susceptible to the virus infection. In this review, we discuss recent reports regarding miR-146a expression levels, related target genes, functions, and mechanistic roles during the pathogenesis of viral infection, and provide a clue to progress new therapeutic and controlling strategy of viral infections in the future.…”

Extracellular RNA in viral–host interactions: Thinking outside the cell

“…EVs derived from EV71‐infected cells, for example, were preferentially enriched for miR‐146a, the miRNA that has been well‐documented to inhibit type I IFN responses (as described above). It was shown that the transfer of this miRNA in EVs resulted in suppression of type I IFN responses in recipient cells (Fu et al, ). In this report, the EVs were also found to contain the RISC proteins Argonaute 2 (AGO2) and GW182 and the authors suggest the transfer of the miRNA‐RISC complex might enable suppression of targets immediately after cell entry.…”