Abstract
The innate immune system senses infection by detecting either evolutionarily conserved molecules essential for the survival of microbes or the abnormal location of molecules. Here we demonstrate the existence of a previously unknown innate detection mechanism induced by fusion between viral envelopes and target cells. Virus-cell fusion specifically stimulated a type I interferon response with expression of interferon-stimulated genes, in vivo recruitment of leukocytes and potentiation of signaling via Toll-like receptor 7 (TLR7) and TLR9. The fusion-dependent response was dependent on the stimulator of interferon genes STING but was independent of DNA, RNA and viral capsid. We suggest that membrane fusion is sensed as a danger signal with potential implications for defense against enveloped viruses and various conditions of giant-cell formation.
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Acknowledgements
We thank A.R. Thomsen (Copenhagen University) for mice deficient in the receptor for type I interferon (Ifnar1−/− mice); J. Sodroski (Dana Farber Cancer Institute) for the pSVIII-ADA Env plasmid (obtained via P. Gorry); and P. Gorry (Burnet Institute) for the fusion-deficient construct pSVIII-ADA Y552F. Supported by The Danish Medical Research Council (09-072636 and 10-081986), The Novo Nordisk Foundation, The Velux Foundation, Christian d. Tiendes Fond, Aase og Ejnar Danielsens Fond, Fhv. Direktør Leo Nielsen og hustru Karen Margrethe Nielsen's legat for Lægevidenskabelig Grundforskning, The Lundbeck Foundation (R17-A1526 and R34-3855), Elvira og Rasmus Riisforts almenvelgørende Fond, Aarhus University Research Foundation, Kathrine og Vigo Skovgaards Fond, the US National Institutes of Health (AI061679 to B.C.H., and AI083713 and AI067497 to K.A.F.), the Faculty of Health Sciences of Aarhus Univeristy (S.B.J. and S.B.R.), the European Union Seventh Framework Programme Marie Curie Action (K.A.H.) and the UK Medical Research Council (F.J.R.).
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C.K.H., K.A.F. and S.R.P. conceived of the project; C.K.H. designed the experimental setup, organized the project, did most of the experiments, drafted the manuscript and, together with S.R.P. and K.A.F. edited and finalized the manuscript; S.B.J., M.R.J., K.A.H., M.H.C., R.G.-D., S.B.R., H.B.M. and N.C. did experiments; S.R.P., K.A.F. and B.C.H. supervised experiments; and F.J.R. and T.O.Y. provided reagents.
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Holm, C., Jensen, S., Jakobsen, M. et al. Virus-cell fusion as a trigger of innate immunity dependent on the adaptor STING. Nat Immunol 13, 737–743 (2012). https://doi.org/10.1038/ni.2350
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DOI: https://doi.org/10.1038/ni.2350
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