Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Virus-cell fusion as a trigger of innate immunity dependent on the adaptor STING

Nature Immunology volume 13, pages 737–743 (2012)Cite this article

Subjects

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: VLPs induce a type I interferon response.
Figure 2: VLPs enhance the sensitivity of TLR7 and TLR9 and induce the recruitment and activation of leukocytes in vivo.
Figure 3: Fusion induces the expression of type I interferon and CXCL10.
Figure 4: Fusion induces a STING-dependent innate immune response.
Figure 5: Fusion leads to activation of the PLC-γ–PI(3)K pathway upstream of CXCL10 expression.

Similar content being viewed by others

References

  1. Paludan, S.R., Bowie, A.G., Horan, K.A. & Fitzgerald, K.A. Recognition of herpesviruses by the innate immune system. Nat. Rev. Immunol. 11, 143–154 (2011).

    Article  CAS  Google Scholar 

  2. Brennan, K. & Bowie, A.G. Activation of host pattern recognition receptors by viruses. Curr. Opin. Microbiol. 13, 503–507 (2010).

    Article  CAS  Google Scholar 

  3. Ishikawa, H., Ma, Z. & Barber, G.N. STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity. Nature 461, 788–792 (2009).

    Article  CAS  Google Scholar 

  4. Ishikawa, H. & Barber, G.N. STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling. Nature 455, 674–678 (2008).

    Article  CAS  Google Scholar 

  5. Sadler, A.J. & Williams, B.R. Interferon-inducible antiviral effectors. Nat. Rev. Immunol. 8, 559–568 (2008).

    Article  CAS  Google Scholar 

  6. Orvedahl, A. et al. Autophagy protects against Sindbis virus infection of the central nervous system. Cell Host Microbe 7, 115–127 (2010).

    Article  CAS  Google Scholar 

  7. Ichinohe, T., Lee, H.K., Ogura, Y., Flavell, R. & Iwasaki, A. Inflammasome recognition of influenza virus is essential for adaptive immune responses. J. Exp. Med. 206, 79–87 (2009).

    Article  CAS  Google Scholar 

  8. Noyce, R.S. et al. Membrane perturbation elicits an IRF3-dependent, interferon-independent antiviral response. J. Virol. 85, 10926–10931 (2011).

    Article  CAS  Google Scholar 

  9. Roberts, A.P. et al. Differing roles of inner tegument proteins pUL36 and pUL37 during entry of herpes simplex virus type 1. J. Virol. 83, 105–116 (2009).

    Article  CAS  Google Scholar 

  10. Dargan, D.J., Patel, A.H. & Subak-Sharpe, J.H. PREPs: herpes simplex virus type 1-specific particles produced by infected cells when viral DNA replication is blocked. J. Virol. 69, 4924–4932 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Unterholzner, L. et al. IFI16 is an innate immune sensor for intracellular DNA. Nat. Immunol. 11, 997–1004 (2010).

    Article  CAS  Google Scholar 

  12. Zhang, Z. et al. The helicase DDX41 senses intracellular DNA mediated by the adaptor STING in dendritic cells. Nat. Immunol. 12, 959–965 (2011).

    Article  CAS  Google Scholar 

  13. Hornung, V. et al. AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC. Nature 458, 514–518 (2009).

    Article  CAS  Google Scholar 

  14. Janeway, C.A. Jr. Approaching the asymptote? Evolution and revolution in immunology. Cold Spring Harb. Symp. Quant. Biol. 54, 1–13 (1989).

    Article  CAS  Google Scholar 

  15. Kawai, T. & Akira, S. Toll-like receptors and their crosstalk with other innate receptors in infection and immunity. Immunity 34, 637–650 (2011).

    Article  CAS  Google Scholar 

  16. Szilágyi, J.F. & Cunningham, C. Identification and characterization of a novel non-infectious herpes simplex virus-related particle. J. Gen. Virol. 72, 661–668 (1991).

    Article  Google Scholar 

  17. Roche, M. et al. HIV-1 escape from the CCR5 antagonist maraviroc associated with an altered and less-efficient mechanism of gp120–CCR5 engagement that attenuates macrophage tropism. J. Virol. 85, 4330–4342 (2011).

    Article  CAS  Google Scholar 

  18. Tanaka, T. et al. DiC14-amidine cationic liposomes stimulate myeloid dendritic cells through Toll-like receptor 4. Eur. J. Immunol. 38, 1351–1357 (2008).

    Article  CAS  Google Scholar 

  19. Csiszár, A. et al. Novel Fusogenic liposomes for fluorescent cell labeling and membrane modification. Bioconjug. Chem. 21, 537–543 (2010).

    Article  Google Scholar 

  20. Sun, Y. et al. TLR4 and TLR5 on corneal macrophages regulate Pseudomonas aeruginosa keratitis by signaling through MyD88-dependent and -independent pathways. J. Immunol. 185, 4272–4283 (2010).

    Article  CAS  Google Scholar 

  21. Cheshenko, N. et al. Herpes simplex virus triggers activation of calcium-signaling pathways. J. Cell Biol. 163, 283–293 (2003).

    Article  CAS  Google Scholar 

  22. Gonzalez-Dosal, R. et al. HSV infection induces production of ROS, which potentiate signaling from pattern recognition receptors: role of S-glutathionylation of TRAF3 and 6. PloS Pathogen 7, e1002250 (2011).

    Article  CAS  Google Scholar 

  23. Murthy, M., Teodoro, R.O., Miller, T.P. & Schwarz, T.L. Sec5, a member of the exocyst complex, mediates Drosophila embryo cellularization. Development 137, 2773–2783 (2010).

    Article  CAS  Google Scholar 

  24. Dong, B. et al. Phospholipid scramblase 1 potentiates the antiviral activity of interferon. J. Virol. 78, 8983–8993 (2004).

    Article  CAS  Google Scholar 

  25. Smith-Garvin, J.E., Koretzky, G.A. & Jordan, M.S. T cell activation. Annu. Rev. Immunol. 27, 591–619 (2009).

    Article  CAS  Google Scholar 

  26. Alon, R. & Shulman, Z. Chemokine triggered integrin activation and actin remodeling events guiding lymphocyte migration across vascular barriers. Exp. Cell Res. 317, 632–641 (2011).

    Article  CAS  Google Scholar 

  27. Tiwari, V. & Shukla, D. Phosphoinositide 3 kinase signalling may affect multiple steps during herpes simplex virus type-1 entry. J. Gen. Virol. 91, 3002–3009 (2010).

    Article  CAS  Google Scholar 

  28. Li, E., Stupack, D., Klemke, R., Cheresh, D.A. & Nemerow, G.R. Adenovirus endocytosis via αv integrins requires phosphoinositide-3-OH kinase. J. Virol. 72, 2055–2061 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Saeed, M.F., Kolokoltsov, A.A., Freiberg, A.N., Holbrook, M.R. & Davey, R.A. Phosphoinositide-3 kinase-Akt pathway controls cellular entry of Ebola virus. PLoS Pathog. 4, e1000141 (2008).

    Article  Google Scholar 

  30. Herschke, F. et al. Cell-cell fusion induced by measles virus amplifies the type I interferon response. J. Virol. 81, 12859–12871 (2007).

    Article  CAS  Google Scholar 

  31. Nordborg, C., Larsson, K., Aman, P. & Nordborg, E. Expression of the class I interferon-related MxA protein in temporal arteries in polymyalgia rheumatica and temporal arteritis. Scand. J. Rheumatol. 38, 144–148 (2009).

    Article  CAS  Google Scholar 

  32. Sharma, S. et al. Innate immune recognition of an AT-rich stem-loop DNA motif in the Plasmodium falciparum genome. Immunity 35, 194–207 (2011).

    Article  CAS  Google Scholar 

Download references

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.).

Author information

Author notes

  1. Katherine A Fitzgerald and Søren R Paludan: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biomedicine, Aarhus University, Aarhus, Denmark

    Christian K Holm, Søren B Jensen, Martin R Jakobsen, Kristy A Horan, Hanne B Moeller, Regina Gonzalez-Dosal, Simon B Rasmussen, Maria H Christensen & Søren R Paludan

  2. Aarhus Research Center for Innate Immunology, Aarhus University, Aarhus, Denmark

    Christian K Holm, Martin R Jakobsen & Søren R Paludan

  3. Department of Medicine, Division of Infectious Diseases and Immunology, University of Massachusetts, Worcester, Massachusetts, USA

    Søren B Jensen & Katherine A Fitzgerald

  4. Department of Pediatrics, Albert Einstein College of Medicine, Bronx, New York, USA

    Natalia Cheshenko & Betsy C Herold

  5. Department of Internal Medicine, Section of Cardiovascular Medicine, Yale University School of Medicine, New Haven, Connecticut, USA

    Timur O Yarovinsky

  6. Medical Research Council–University of Glasgow Center for Virus Research, Glasgow, UK

    Frazer J Rixon

Authors
  1. Christian K Holm
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Søren B Jensen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Martin R Jakobsen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Natalia Cheshenko
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kristy A Horan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hanne B Moeller
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Regina Gonzalez-Dosal
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Simon B Rasmussen
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Maria H Christensen
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Timur O Yarovinsky
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Frazer J Rixon
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Betsy C Herold
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Katherine A Fitzgerald
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Søren R Paludan
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

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.

Corresponding author

Correspondence to Søren R Paludan.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–8 (PDF 930 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni.2350

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing