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Exosomes mediate the cell-to-cell transmission of IFN-α-induced antiviral activity

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Abstract

The cell-to-cell transmission of viral resistance is a potential mechanism for amplifying the interferon-induced antiviral response. In this study, we report that interferon-α (IFN-α) induced the transfer of resistance to hepatitis B virus (HBV) from nonpermissive liver nonparenchymal cells (LNPCs) to permissive hepatocytes via exosomes. Exosomes from IFN-α-treated LNPCs were rich in molecules with antiviral activity. Moreover, exosomes from LNPCs were internalized by hepatocytes, which mediated the intercellular transfer of antiviral molecules. Finally, we found that exosomes also contributed to the antiviral response of IFN-α to mouse hepatitis virus A59 and adenovirus in mice. Thus, we propose an antiviral mechanism of IFN-α activity that involves the induction and intercellular transfer of antiviral molecules via exosomes.

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Figure 1: Transmission of the IFN-α-induced antiviral response from LNPCs to cells in which HBV is replicating, in vitro and in vivo.
Figure 2: Inhibition of exosome biogenesis impairs the cell-to-cell transfer of IFN-α-induced antiviral activity against HBV in vitro.
Figure 3: Exosomes are sufficient to mediate the transfer of an IFN-α-induced antiviral response in vitro.
Figure 4: Inhibition of exosome release from LNPCs impairs the anti-HBV activity of IFN-α in mice.
Figure 5: Treatment with IFN-α changes the cargo content of exosomes.
Figure 6: Exosomal molecules with different expression restrict HBV replication.
Figure 7: IFN-α induces cell-to-cell transfer of antiviral molecules both in vitro and in vivo.
Figure 8: Exosomes contribute to the interferon-induced antiviral response to MHV-A59 and adenovirus in mice.

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Acknowledgements

We thank C. Dong, N. Weng, J. Guo, J. Hu, S. Zhou and Q. Cai for suggestions and critical reading of the manuscript. Supported by the National Key Basic Research Program of China (2012CB519000 to Z.Y.), the National Megaprojects of China for Infectious Diseases (2012ZX10002007-001 to Z.Y.), the German Research Foundation (SFB/Transregio TRR60 to Z.Y.), the National Natural Science Foundation of China (31200129 to J. Li) and the China Postdoctoral Science Foundation (201104232 to J. Li).

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Contributions

J. Li conceived of the study, designed the experiments, did most of the experiments and wrote the manuscript; K.L. isolated, characterized and labeled exosomes; Y.L. did quantitative RT-PCR; Y.X. and T.P. contributed to the HCV-replication assays; F.Z. generated the lentiviral expression vectors; H.Y. and X.Z. assisted in the hydrodynamic injections; J. Liu provided reagents; J.C. and M.W. helped with depletion and reconstitution of macrophages; and Z.Y. supervised all aspects of the study.

Corresponding author

Correspondence to Zhenghong Yuan.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Figures and Text

Supplementary Figures 1–9, Supplementary Table 1 legend, and Supplementary Tables 2 and 3 (PDF 843 kb)

Supplementary Table 1

Differentially expressed mRNAs and miRNA in the exosomes from IFN-α-stimulated and unstimulated LSECs by microarray (XLS 462 kb)

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Li, J., Liu, K., Liu, Y. et al. Exosomes mediate the cell-to-cell transmission of IFN-α-induced antiviral activity. Nat Immunol 14, 793–803 (2013). https://doi.org/10.1038/ni.2647

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