Abstract
The human diploid cell line Medical Research Council -5 (MRC-5) is commonly utilized for vaccine development. Although a rabies vaccine developed in cultured MRC-5 cells exists, the poor susceptibility of MRC-5 cells to the rabies virus (RABV) infection limits the potential yield of this vaccine. The underlying mechanism of MRC-5 cell resistance to RABV infection remains unknown. In this study, we demonstrate that viral infection increased exosomal release from MRC-5 cells; conversely, blocking exosome release promoted RABV infection in MRC-5 cells. Additionally, RABV infection up-regulated microRNA (miR)-423-5p expression in exosomes, resulting in feedback inhibition of RABV replication by abrogating the inhibitory effect of suppressor of cytokine signaling 3 (SOCS3) on type I interferon (IFN) signaling. Furthermore, intercellular delivery of miR-423-5p by exosomes inhibited RABV replication in MRC-5 cells. We also show that RABV infection increased IFN-β production in MRC-5 cells and that blocking the type I IFN receptor promoted RABV infection. In conclusion, MRC-5 cells were protected from RABV infection by the intercellular delivery of exosomal miR-423-5p and the up-regulation of IFN-β. These findings reveal novel antiviral mechanisms in MRC-5 cells against RABV infection. miR-423-5p, exosomes, and IFN signaling pathways may therefore be potential targets for improving MRC-5 cell-based rabies vaccine production.
Highlights
Rabies virus (RABV) is a negative-sense, non-segmented, single-stranded RNA virus that attacks the nervous systems of humans and other animals, causing rabies [1]
We investigated whether exosomes participate in the resistance of Medical Research Council -5 (MRC-5) cells against RABV infection and attempted to identify the antiviral molecule involved in this process
We showed that RABV infection increased IFN-β expression and induced the transfer of antiviral miRNAs from RABV-infected MRC-5 cells to neighboring cells via exosomes
Summary
Rabies virus (RABV) is a negative-sense, non-segmented, single-stranded RNA virus that attacks the nervous systems of humans and other animals, causing rabies [1]. Giugliano et al [30] showed that hepatitis C virus (HCV) infection can induce autocrine interferon signaling and exosomal release by human liver endothelial cells, thereby inhibiting viral replication. We investigated whether exosomes participate in the resistance of MRC-5 cells against RABV infection and attempted to identify the antiviral molecule involved in this process. 2g01, 9t,h2e0, cxoFnOfRoPcEaElRmREicVrIoEWscopy data indicate that MRC-5 cells treated with si-IFN8 oAf 1R51 or anti-IFNAR1 monoclonal antibody were susceptible to RABV infection (Figure 5E). These data indicate that sIiF-NIFN-βApRl1ayosraanntiim-IFpNorAtaRn1tmroolneoicnloMnaRlCa-n5ticbeoldl ydewfeenresesuasgcaeipntsibt lienfteocRtiAonB.V infection (Figure 5E). VScNalepbroarte=in50anμtmib.ody (greeTnh)refeorin2dehp,eannddentheexpceerlilmneunctslewi ewreerpeersftoarimnedd. *w, *i*th, an4d,6*-*d* ianmdicidatienpo-
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