The innate immune system limits viral replication via type I interferon and also induces the presentation of viral antigens to cells of the adaptive immune response. Using infection of mice with vesicular stomatitis virus, we analyzed how the innate immune system inhibits viral propagation but still allows the presentation of antigen to cells of the adaptive immune response. We found that expression of the gene encoding the inhibitory protein Usp18 in metallophilic macrophages led to lower type I interferon responsiveness, thereby allowing locally restricted replication of virus. This was essential for the induction of adaptive antiviral immune responses and, therefore, for preventing the fatal outcome of infection. In conclusion, we found that enforced viral replication in marginal zone macrophages was an immunological mechanism that ensured the production of sufficient antigen for effective activation of the adaptive immune response.
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We thank D. Kolakofsky (University of Geneva) for VSV; and K. Schättel for technical support. Supported by the Alexander von Humboldt Foundation (SKA-2008 to K.S.L. and SKA-2010 to P.A.L.), Collaborative Research Center SFB575, Experimental Hepatology (coordinator, D.H.; Deutsche Forschungsgemeinschaft grant LA1419/3-1 to K.S.L. and SFB-TR19 to K.K. and R.K.; FOR729 to K.P.; SFB/Transregio 60 (coordinator, M. Roggendorf), the MOI Manchot Graduate School (Jürgen Manchot Foundation), the Swiss National Science Foundation (PASMP3-127678/1 to M.R.) and the US National Institutes of Health (R01 HL091549 for Usp18-related work in the D.-E.Z. laboratory).
The authors declare no competing financial interests.
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Honke, N., Shaabani, N., Cadeddu, G. et al. Enforced viral replication activates adaptive immunity and is essential for the control of a cytopathic virus. Nat Immunol 13, 51–57 (2012). https://doi.org/10.1038/ni.2169
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