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

Nature volume 445, pages 319–323 (2007) Cite this article

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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Figure 1: Viral replication in nonhuman primate tissues.
The alternative text for this image may have been generated using AI.
Figure 2: Pathologic examination of lungs infected with the 1918 or K173 virus on day 8 post-infection.
The alternative text for this image may have been generated using AI.
Figure 3: Chemokine and cytokine levels in serum.
The alternative text for this image may have been generated using AI.
Figure 4: Microarray analysis of gene expression in the bronchi of macaques on days 3, 6 and 8 post-infection.
The alternative text for this image may have been generated using AI.

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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

Authors and Affiliations

  1. Respiratory Viruses, Public Health Agency of Canada, Winnipeg, Manitoba, R3E 3R2, Canada

    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, University of Manitoba, Winnipeg, Manitoba, R3E 3R2, Canada

    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, University of Washington, Seattle, Washington, 98195, USA

    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, University of Tokyo, Tokyo, 108-8639, Japan

    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

Authors
  1. Darwyn Kobasa
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Corresponding author

Correspondence to Yoshihiro Kawaoka.

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Kobasa, D., Jones, S., Shinya, K. et al. Aberrant innate immune response in lethal infection of macaques with the 1918 influenza virus. Nature 445, 319–323 (2007). https://doi.org/10.1038/nature05495

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