Letter | Published:

Aberrant innate immune response in lethal infection of macaques with the 1918 influenza virus

Nature volume 445, pages 319323 (18 January 2007) | Download Citation

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Abstract

The 1918 influenza pandemic was unusually severe, resulting in about 50 million deaths worldwide1. The 1918 virus is also highly pathogenic in mice, and studies have identified a multigenic origin of this virulent phenotype in mice2,3,4. However, these initial characterizations of the 1918 virus did not address the question of its pathogenic potential in primates. Here we demonstrate that the 1918 virus caused a highly pathogenic respiratory infection in a cynomolgus macaque model that culminated in acute respiratory distress and a fatal outcome. Furthermore, infected animals mounted an immune response, characterized by dysregulation of the antiviral response, that was insufficient for protection, indicating that atypical host innate immune responses may contribute to lethality. The ability of influenza viruses to modulate host immune responses, such as that demonstrated for the avian H5N1 influenza viruses5, may be a feature shared by the virulent influenza viruses.

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References

  1. 1.

    & Updating the accounts: global mortality of the 1918–1920 “Spanish” influenza pandemic. Bull. Hist. Med. 76, 105–115 (2002)

  2. 2.

    et al. Existing antivirals are effective against influenza viruses with genes from the 1918 pandemic virus. Proc. Natl Acad. Sci. USA 99, 13849–13854 (2002)

  3. 3.

    et al. Enhanced virulence of influenza A viruses with the haemagglutinin of the 1918 pandemic virus. Nature 431, 703–707 (2004)

  4. 4.

    et al. Characterization of the reconstructed 1918 Spanish influenza pandemic virus. Science 310, 77–80 (2005)

  5. 5.

    , & Lethal H5N1 influenza viruses escape host anti-viral cytokine responses. Nature Med. 8, 950–954 (2002)

  6. 6.

    , , & Origin and evolution of the 1918 “Spanish” influenza virus hemagglutinin gene. Proc. Natl Acad. Sci. USA 96, 1651–1656 (1999)

  7. 7.

    , , & Characterization of the 1918 “Spanish” influenza virus neuraminidase gene. Proc. Natl Acad. Sci. USA 97, 6785–6790 (2000)

  8. 8.

    et al. Sequence of the 1918 pandemic influenza virus nonstructural gene (NS) segment and characterization of recombinant viruses bearing the 1918 NS genes. Proc. Natl Acad. Sci. USA 98, 2746–2751 (2001)

  9. 9.

    , , , & Characterization of the 1918 “Spanish” influenza virus matrix gene segment. J. Virol. 76, 10717–10723 (2002)

  10. 10.

    , , , & Novel origin of the 1918 pandemic influenza virus nucleoprotein gene. J. Virol. 78, 12462–12470 (2004)

  11. 11.

    et al. Characterization of the 1918 influenza virus polymerase genes. Nature 437, 889–893 (2005)

  12. 12.

    et al. Generation of influenza A viruses entirely from cloned cDNAs. Proc. Natl Acad. Sci. USA 96, 9345–9350 (1999)

  13. 13.

    et al. Pathogenesis of influenza A (H5N1) virus infection in a primate model. J. Virol. 75, 6687–6691 (2001)

  14. 14.

    , , & Pathology of human influenza A (H5N1) virus infection in cynomolgus macaques (Macaca fascicularis). Vet. Pathol. 40, 304–310 (2003)

  15. 15.

    , & The Pathology of Influenza. (Yale Univ. Press, New Haven, Connecticut, 1920)

  16. 16.

    et al. Local and systemic cytokine responses during experimental human influenza A virus infection. Relation to symptom formation and host defense. J. Clin. Invest. 101, 643–649 (1998)

  17. 17.

    , , & Evidence for cytokine mediation of disease expression in adults experimentally infected with influenza A virus. J. Infect. Dis. 180, 10–14 (1999)

  18. 18.

    et al. Genomic analysis of increased host immune and cell death responses induced by 1918 influenza virus. Nature 443, 578–581 (2006)

  19. 19.

    et al. Fatal outcome of human influenza A (H5N1) is associated with high viral load and hypercytokinemia. Nature Med. 12, 1203–1207 (2006)

  20. 20.

    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)

  21. 21.

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

  22. 22.

    et al. Influenza A virus lacking the NS1 gene replicates in interferon-deficient systems. Virology 252, 324–330 (1998)

  23. 23.

    , , & Intracellular warfare between human influenza viruses and human cells: the roles of the viral NS1 protein. Virology 309, 181–189 (2003)

  24. 24.

    , , & Binding of the influenza A virus NS1 protein to PKR mediates the inhibition of its activation by either PACT or double-stranded RNA. Virology 349, 13–21 (2006)

  25. 25.

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

  26. 26.

    et al. Integrated molecular signature of disease: analysis of influenza virus-infected macaques through functional genomics and proteomics. J. Virol. 80, 10813–10828 (2006)

  27. 27.

    & A simple method of estimating fifty per cent endpoints. Am. J. Hyg. 27, 493–497 (1938)

  28. 28.

    et al. Global suppression of the host antiviral response by Ebola- and Marburgviruses: increased antagonism of the type I interferon response is associated with enhanced virulence. J. Virol. 80, 3009–3020 (2006)

  29. 29.

    et al. Minimum information about a microarray experiment (MIAME)—toward standards for microarray data. Nature Genet. 29, 365–371 (2001)

  30. 30.

    , , , & BABELOMICS: a suite of web tools for functional annotation and analysis of groups of genes in high-throughput experiments. Nucleic Acids Res. 33, W460–W464 (2005)

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Acknowledgements

We thank D. Dick, J. Gren, A. Grolla and P. Melito for help with animal care, and V. Carter, M. Thomas and S. Proll for microarray technical assistance. We also thank J. Gilbert for editing the manuscript. This work was supported by the Public Health Agency of Canada (D.K., S.M.J. and H.F.), by grants-in-aid for scientific research on priority areas from the Ministries of Education, Culture, Sports, Science, and Technology, Japan (Y.K. and K.S.), by CREST (Japan Science and Technology Agency; Y.K.), and by private grants to Y.K.

Microarray data were deposited at Arrayexpress with accession number E-TABM-181.

Author information

Affiliations

  1. Respiratory Viruses, and,

    • Darwyn Kobasa
    •  & Yan Li
  2. Special Pathogens Program National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba R3E 3R2, Canada

    • Steven M. Jones
    • , Hideki Ebihara
    • , Friederike Feldmann
    • , Judie B. Alimonti
    • , Lisa Fernando
    •  & Heinz Feldmann
  3. Department of Immunology and,

    • Steven M. Jones
  4. Department of Medical Microbiology, University of Manitoba, Winnipeg, Manitoba R3E 3R2, Canada

    • Heinz Feldmann
  5. The Avian Zoonosis Research Centre, Tottori University, Tottori 680-8550, Japan

    • Kyoko Shinya
  6. Department of Microbiology, School of Medicine, and

    • John C. Kash
    •  & Michael G. Katze
  7. Washington National Primate Research Center, University of Washington, Seattle, Washington 98195, USA

    • Michael G. Katze
  8. National Centre for Foreign Animal Diseases, Canadian Food Inspection Agency, Canadian Science Centre for Human and Animal Health, Winnipeg, Manitoba R3E 3M4, Canada

    • John Copps
  9. Division of Virology, Department of Microbiology and Immunology and

    • Hideki Ebihara
    •  & Yoshihiro Kawaoka
  10. International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan

    • Hideki Ebihara
    •  & Yoshihiro Kawaoka
  11. CREST, Japan Science and Technology Agency, Saitama 322-0012, Japan

    • Hideki Ebihara
    •  & Yoshihiro Kawaoka
  12. Department of Pathobiological Sciences, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA

    • Yasuko Hatta
    • , Jin Hyun Kim
    • , Peter Halfmann
    • , Masato Hatta
    •  & Yoshihiro Kawaoka

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Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Yoshihiro Kawaoka.

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DOI

https://doi.org/10.1038/nature05495

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