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Activation of innate immune antiviral responses by Nod2

A Corrigendum to this article was published on 01 October 2010

This article has been updated

Abstract

Pattern-recognition receptors (PRRs), including Toll-like receptors (TLRs) and RIG-like helicase (RLH) receptors, are involved in innate immune antiviral responses. Here we show that nucleotide-binding oligomerization domain 2 (Nod2) can also function as a cytoplasmic viral PRR by triggering activation of interferon-regulatory factor 3 (IRF3) and production of interferon-β (IFN-β). After recognition of a viral ssRNA genome, Nod2 used the adaptor protein MAVS to activate IRF3. Nod2-deficient mice failed to produce interferon efficiently and showed enhanced susceptibility to virus-induced pathogenesis. Thus, the function of Nod2 as a viral PRR highlights the important function of Nod2 in host antiviral defense mechanisms.

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Figure 1: Activation of Nod2 by ssRNA.
Figure 2: Activation of antiviral response by Nod2 in virus infected cells.
Figure 3: Nod2 is required for interferon production.
Figure 4: Activation of Nod2 by viral ssRNA.
Figure 5: Function of MAVS during Nod2-mediated activation of the antiviral pathway.
Figure 6: Interaction of MAVS with Nod2.
Figure 7: The NBD and LRR domains of Nod2 are essential for interaction with MAVS.
Figure 8: Nod2 is essential for host defense against viral infection.

Change history

  • 25 June 2010

    In the version of this article initially published, some panels in Figure 8e were incorrect. The error has been corrected in the HTML and PDF versions of the article.

References

  1. Kawai, T. & Akira, S. Innate immune recognition of viral infection. Nat. Immunol. 7, 131–137 (2006).

    CAS  Article  Google Scholar 

  2. Bose, S. & Banerjee, A.K. Innate immune response against nonsegmented negative strand RNA viruses. J. Interferon Cytokine Res. 23, 401–412 (2003).

    CAS  Article  Google Scholar 

  3. Stark, G.R., Kerr, I.M., Williams, B.R.G., Silverman, R.H. & Schreiber, R.D. How cells respond to interferons. Annu. Rev. Biochem. 67, 227–264 (1998).

    CAS  Article  Google Scholar 

  4. Uematsu, S. & Akira, S. Toll-like receptors and type I interferons. J. Biol. Chem. 282, 15319–15323 (2007).

    CAS  PubMed  Google Scholar 

  5. O'Neill, L.A. How Toll-like receptors signal: what we know and what we don't know. Curr. Opin. Immunol. 18, 3–9 (2006).

    CAS  Article  Google Scholar 

  6. Basler, C.F. & Garcia-Sastre, A. Sensing RNA virus infections. Nat. Chem. Biol. 3, 20–21 (2007).

    CAS  Article  Google Scholar 

  7. Martinon, F. & Tschopp, J. NLRs join TLRs as innate sensors of pathogens. Trends Immunol. 26, 447–454 (2005).

    CAS  Article  Google Scholar 

  8. Fritz, J.H., Ferrero, R.L., Philpott, D.J. & Girardin, S.E. Nod-like proteins in immunity, inflammation and disease. Nat. Immunol. 7, 1250–1257 (2006).

    CAS  Article  Google Scholar 

  9. Kanneganti, T.D., Lamkanfi, M. & Núñez, G. Intracellular NOD-like receptors in host defense and disease. Immunity 27, 549–559 (2007).

    CAS  Article  Google Scholar 

  10. Franchi, L., Warner, N., Viani, K. & Nuñez, G. Function of Nod-like receptors in microbial recognition and host defense. Immunol. Rev. 227, 106–128 (2009).

    CAS  Article  Google Scholar 

  11. Moore, C.B. et al. NLRX1 is a regulator of mitochondrial antiviral immunity. Nature 451, 573–577 (2008).

    CAS  Article  Google Scholar 

  12. Tattoli, I. et al. NLRX1 is a mitochondrial NOD-like receptor that amplifies NF-κB and JNK pathways by inducing reactive oxygen species production. EMBO Rep. 9, 293–300 (2008).

    CAS  Article  Google Scholar 

  13. Kota, S. et al. Role of human β defensin-2 during tumor necrosis factor-α/NF-κB mediated innate anti-viral response against human respiratory syncytial virus. J. Biol. Chem. 283, 22417–22429 (2008).

    CAS  Article  Google Scholar 

  14. Voss, E. et al. NOD2/CARD15 mediates induction of the antimicrobial peptide human β-defensin-2. J. Biol. Chem. 281, 2005–2011 (2006).

    CAS  Article  Google Scholar 

  15. Hall, C.B. Respiratory syncytial virus and parainfluenza virus. N. Engl. J. Med. 344, 1917–1928 (2001).

    CAS  Article  Google Scholar 

  16. Falsey, A.R., Hennessey, P.A., Formica, M.A., Cox, C. & Walsh, E.E. Respiratory syncytial virus infection in elderly and high-risk adults. N. Engl. J. Med. 352, 1749–1759 (2005).

    CAS  Article  Google Scholar 

  17. Bose, S., Malur, A. & Banerjee, A.K. Polarity of human parainfluenza virus type 3 infection in polarized human lung epithelial A549 cells: Role of microfilament and microtubule. J. Virol. 75, 1984–1989 (2001).

    CAS  Article  Google Scholar 

  18. Bose, S., Kar, N., Maitra, R., DiDonato, J.A. & Banerjee, A.K. Temporal activation of NF-κB regulates an interferon-independent innate antiviral response against cytoplasmic RNA viruses. Proc. Natl. Acad. Sci. USA 100, 10890–10895 (2003).

    CAS  Article  Google Scholar 

  19. Jamaluddin, M. et al. IFN-β mediates coordinate expression of antigen-processing genes in RSV-infected pulmonary epithelial cells. Am. J. Physiol. Lung Cell. Mol. Physiol. 280, L248–L257 (2001).

    CAS  Article  Google Scholar 

  20. Liu, P. et al. Retinoic acid-inducible gene I mediates early antiviral response and Toll-like receptor 3 expression in respiratory syncytial virus-infected airway epithelial cells. J. Virol. 81, 1401–1411 (2007).

    CAS  Article  Google Scholar 

  21. Inohara, N., Ogura, Y. & Nuñez, G. Nods: a family of cytosolic proteins that regulate the host response to pathogens. Curr. Opin. Microbiol. 5, 76–80 (2002).

    CAS  Article  Google Scholar 

  22. Franchi, L. et al. Intracellular NOD-like receptors in innate immunity, infection and disease. Cell. Microbiol. 10, 1–8 (2008).

    CAS  PubMed  Google Scholar 

  23. Wathelet, M.G. et al. Virus infection induces the assembly of coordinately activated transcription factors on the IFN-β enhancer in vivo. Mol. Cell 1, 507–518 (1998).

    CAS  Article  Google Scholar 

  24. Jafri, H.S. et al. Respiratory syncytial virus induces pneumonia, cytokine response, airway obstruction, and chronic inflammatory infiltrates associated with long-term airway hyperresponsiveness in mice. J. Infect. Dis. 189, 1856–1865 (2004).

    Article  Google Scholar 

  25. Bolger, G. et al. Primary infection of mice with high titer inoculum respiratory syncytial virus: characterization and response to antiviral therapy. Can. J. Physiol. Pharmacol. 83, 198–213 (2005).

    CAS  Article  Google Scholar 

  26. Guerrero-Plata, A. et al. Activity and regulation of α interferon in respiratory syncytial virus and human metapneumovirus experimental infections. J. Virol. 79, 10190–10199 (2005).

    CAS  Article  Google Scholar 

  27. Guerrero-Plata, A., Casola, A. & Garofalo, R.P. Human metapneumovirus induces a profile of lung cytokines distinct from that of respiratory syncytial virus. J. Virol. 79, 14992–14997 (2005).

    CAS  Article  Google Scholar 

  28. Pletneva, L.M., Haller, O., Porter, D.D., Prince, G.A. & Blanco, J.C. Induction of type I interferons and interferon-inducible Mx genes during respiratory syncytial virus infection and reinfection in cotton rats. J. Gen. Virol. 89, 261–270 (2008).

    CAS  Article  Google Scholar 

  29. Chávez-Bueno, S. et al. Respiratory syncytial virus-induced acute and chronic airway disease is independent of genetic background: an experimental murine model. Virol. J. 2, 46 (2005).

    Article  Google Scholar 

  30. Castro, S.M. et al. Antioxidant treatment ameliorates respiratory syncytial virus-induced disease and lung inflammation. Am. J. Respir. Crit. Care Med. 174, 1361–1369 (2006).

    CAS  Article  Google Scholar 

  31. Hippenstiel, S., Opitz, B., Schmeck, B. & Suttorp, N. Lung epithelium as a sentinel and effector system in pneumonia--molecular mechanisms of pathogen recognition and signal transduction. Respir. Res. 7, 97 (2006).

    Article  Google Scholar 

  32. Yasui, K. et al. Neutrophil-mediated inflammation in respiratory syncytial viral bronchiolitis. Pediatr. Int. 47, 190–195 (2005).

    Article  Google Scholar 

  33. Wang, S.Z. & Forsyth, K.D. The interaction of neutrophils with respiratory epithelial cells in viral infection. Respirology 5, 1–10 (2000).

    CAS  Article  Google Scholar 

  34. Wang, S.Z. et al. Neutrophils induce damage to respiratory epithelial cells infected with respiratory syncytial virus. Eur. Respir. J. 12, 612–618 (1998).

    CAS  Article  Google Scholar 

  35. Bubeck, S.S., Cantwell, A.M. & Dube, P.H. Delayed inflammatory response to primary pneumonic plague occurs in both outbred and inbred mice. Infect. Immun. 75, 697–705 (2007).

    CAS  Article  Google Scholar 

  36. Wilmott, R.W., Kitzmiller, J.A., Fiedler, M.A. & Stark, J.M. Generation of a transgenic mouse with lung-specific overexpression of the human interleukin-1 receptor antagonist protein. Am. J. Respir. Cell Mol. Biol. 18, 429–434 (1998).

    CAS  Article  Google Scholar 

  37. Welliver, T.P. et al. Severe human lower respiratory tract illness caused by respiratory syncytial virus and influenza virus is characterized by the absence of pulmonary cytotoxic lymphocyte responses. J. Infect. Dis. 195, 1126–1136 (2007).

    CAS  Article  Google Scholar 

  38. Kato, H. et al. Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses. Nature 441, 101–105 (2006).

    CAS  Article  Google Scholar 

  39. Opitz, B. et al. Nucleotide-binding oligomerization domain proteins are innate immune receptors for internalized Streptococcus pneumoniae. J. Biol. Chem. 279, 36426–36432 (2004).

    CAS  Article  Google Scholar 

  40. Matikainen, S. et al. Tumor necrosis factor alpha enhances influenza A virus-induced expression of antiviral cytokines by activating RIG-I gene expression. J. Virol. 80, 3515–3522 (2006).

    CAS  Article  Google Scholar 

  41. Le Goffic, R., Pothlichet, J., Vitour, D., Fujita, T., Meurs, E., Chignard, M. & Si-Tahar, M. Influenza A virus activates TLR3-dependent inflammatory and RIG-I-dependent antiviral responses in human lung epithelial cells. J. Immunol. 178, 3368–3372 (2007).

    CAS  Article  Google Scholar 

  42. Abbott, D.W. et al. Coordinated regulation of Toll-like receptor and NOD2 signaling by K63-linked polyubiquitin chains. Mol. Cell. Biol. 27, 6012–6025 (2007).

    CAS  Article  Google Scholar 

  43. Wang, J. et al. Retinoic acid-inducible gene-I mediates late phase induction of TNF-α by lipopolysaccharide. J. Immunol. 180, 8011–8019 (2008).

    CAS  Article  Google Scholar 

  44. Hornung, V. et al. 5′-Triphosphate RNA is the ligand for RIG-I. Science 314, 994–997 (2006).

    Article  Google Scholar 

  45. Pichlmair, A. et al. RIG-I-mediated antiviral responses to single-stranded RNA bearing 5′-phosphates. Science 314, 997–1001 (2006).

    CAS  Article  Google Scholar 

  46. Kanneganti, T.D. et al. Bacterial RNA and small antiviral compounds activate caspase-1 through cryopyrin/Nalp3. Nature 440, 233–236 (2006).

    CAS  Article  Google Scholar 

  47. Kanneganti, T.D. et al. Critical role for Cryopyrin/Nalp3 in activation of caspase-1 in response to viral infection and double-stranded RNA. J. Biol. Chem. 281, 36560–36568 (2006).

    CAS  Article  Google Scholar 

  48. 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).

    CAS  Article  Google Scholar 

  49. Kobayashi, K. et al. RICK/Rip2/CARDIAK mediates signalling for receptors of the innate and adaptive immune systems. Nature 416, 194–199 (2002).

    CAS  Article  Google Scholar 

  50. Tominaga, K. et al. MRG15 regulates embryonic development and cell proliferation. Mol. Cell. Biol. 25, 2924–2937 (2005).

    CAS  Article  Google Scholar 

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Acknowledgements

We thank K. Li (University of Tennessee Health Science Center) for reagents; A. Garcia-Sastre (Mount Sinai School of Medicine) for influenza A virus; Z.J. Chen (University of Texas Southwestern Medical Center) for MAVS-deficient MEFs; the Core Optical Imaging Facility (University of Texas Health Science Center at San Antonio) for confocal images; and K. Moncada Gorena and C. Thomas in the Flow Cytometry Core Facility (supported by the National Institutes of Health (P30 CA54174 to the San Antonio Cancer Institute; P30 AG013319 to the Nathan Shock Center; and P01AG19316)) for flow cytometry. Supported by National Institutes of Health (AI069062 to S.B., CA129246 to S.B. and T32-DE14318 to A.S. and AI067716 to P.H.D.) and the American Lung Association (RG-49629-N to S.B. and AI067716 to P.H.D.).

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A.S. and S.B. designed the experiments and prepared the manuscript; A.S. and T.H.C. did the experiments; R.H. provided technical assistance and did several experiments; Y.X. did the experiments with vaccinia virus; V.F. did the immunofluorescence analysis; K.T. did the studies with mouse embryo fibroblasts; and P.H.D. did the MPO assay.

Corresponding author

Correspondence to Santanu Bose.

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Sabbah, A., Chang, T., Harnack, R. et al. Activation of innate immune antiviral responses by Nod2. Nat Immunol 10, 1073–1080 (2009). https://doi.org/10.1038/ni.1782

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