Article | Published:

Activation of innate immune antiviral responses by Nod2

Nature Immunology volume 10, pages 10731080 (2009) | Download Citation

Subjects

  • 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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

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. 1.

    & Innate immune recognition of viral infection. Nat. Immunol. 7, 131–137 (2006).

  2. 2.

    & Innate immune response against nonsegmented negative strand RNA viruses. J. Interferon Cytokine Res. 23, 401–412 (2003).

  3. 3.

    , , , & How cells respond to interferons. Annu. Rev. Biochem. 67, 227–264 (1998).

  4. 4.

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

  5. 5.

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

  6. 6.

    & Sensing RNA virus infections. Nat. Chem. Biol. 3, 20–21 (2007).

  7. 7.

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

  8. 8.

    , , & Nod-like proteins in immunity, inflammation and disease. Nat. Immunol. 7, 1250–1257 (2006).

  9. 9.

    , & Intracellular NOD-like receptors in host defense and disease. Immunity 27, 549–559 (2007).

  10. 10.

    , , & Function of Nod-like receptors in microbial recognition and host defense. Immunol. Rev. 227, 106–128 (2009).

  11. 11.

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

  12. 12.

    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).

  13. 13.

    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).

  14. 14.

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

  15. 15.

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

  16. 16.

    , , , & Respiratory syncytial virus infection in elderly and high-risk adults. N. Engl. J. Med. 352, 1749–1759 (2005).

  17. 17.

    , & 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).

  18. 18.

    , , , & 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).

  19. 19.

    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).

  20. 20.

    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).

  21. 21.

    , & Nods: a family of cytosolic proteins that regulate the host response to pathogens. Curr. Opin. Microbiol. 5, 76–80 (2002).

  22. 22.

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

  23. 23.

    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).

  24. 24.

    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).

  25. 25.

    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).

  26. 26.

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

  27. 27.

    , & Human metapneumovirus induces a profile of lung cytokines distinct from that of respiratory syncytial virus. J. Virol. 79, 14992–14997 (2005).

  28. 28.

    , , , & 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).

  29. 29.

    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).

  30. 30.

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

  31. 31.

    , , & Lung epithelium as a sentinel and effector system in pneumonia--molecular mechanisms of pathogen recognition and signal transduction. Respir. Res. 7, 97 (2006).

  32. 32.

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

  33. 33.

    & The interaction of neutrophils with respiratory epithelial cells in viral infection. Respirology 5, 1–10 (2000).

  34. 34.

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

  35. 35.

    , & Delayed inflammatory response to primary pneumonic plague occurs in both outbred and inbred mice. Infect. Immun. 75, 697–705 (2007).

  36. 36.

    , , & 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).

  37. 37.

    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).

  38. 38.

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

  39. 39.

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

  40. 40.

    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).

  41. 41.

    , , , , , & Influenza A virus activates TLR3-dependent inflammatory and RIG-I-dependent antiviral responses in human lung epithelial cells. J. Immunol. 178, 3368–3372 (2007).

  42. 42.

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

  43. 43.

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

  44. 44.

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

  45. 45.

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

  46. 46.

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

  47. 47.

    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).

  48. 48.

    , , , & Inflammasome recognition of influenza virus is essential for adaptive immune responses. J. Exp. Med. 206, 79–87 (2009).

  49. 49.

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

  50. 50.

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

Download references

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.).

Author information

Affiliations

  1. Department of Microbiology and Immunology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.

    • Ahmed Sabbah
    • , Te Hung Chang
    • , Rosalinda Harnack
    • , Peter H Dube
    • , Yan Xiang
    •  & Santanu Bose
  2. Department of Cellular and Structural Biology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.

    • Victoria Frohlich
    •  & Kaoru Tominaga
  3. Sam and Ann Barshop Institute for Longevity and Aging Studies, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.

    • Kaoru Tominaga

Authors

  1. Search for Ahmed Sabbah in:

  2. Search for Te Hung Chang in:

  3. Search for Rosalinda Harnack in:

  4. Search for Victoria Frohlich in:

  5. Search for Kaoru Tominaga in:

  6. Search for Peter H Dube in:

  7. Search for Yan Xiang in:

  8. Search for Santanu Bose in:

Contributions

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.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–17 and Supplementary Table 1

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/ni.1782

Further reading