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

Nature 445, 319-323 (18 January 2007) | doi:10.1038/nature05495; Received 11 September 2006; Accepted 29 November 2006

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

Darwyn Kobasa¹, Steven M. Jones^2,³, Kyoko Shinya⁵, John C. Kash⁶, John Copps⁸, Hideki Ebihara^2,^9,^10,¹¹, Yasuko Hatta¹², Jin Hyun Kim¹², Peter Halfmann¹², Masato Hatta¹², Friederike Feldmann², Judie B. Alimonti², Lisa Fernando², Yan Li¹, Michael G. Katze^6,⁷, Heinz Feldmann^2,⁴ and Yoshihiro Kawaoka^9,^10,^11,¹²

Respiratory Viruses, and,
Special Pathogens Program National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba R3E 3R2, Canada
Department of Immunology and,
Department of Medical Microbiology, University of Manitoba, Winnipeg, Manitoba R3E 3R2, Canada
The Avian Zoonosis Research Centre, Tottori University, Tottori 680-8550, Japan
Department of Microbiology, School of Medicine, and
Washington National Primate Research Center, University of Washington, Seattle, Washington 98195, USA
National Centre for Foreign Animal Diseases, Canadian Food Inspection Agency, Canadian Science Centre for Human and Animal Health, Winnipeg, Manitoba R3E 3M4, Canada
Division of Virology, Department of Microbiology and Immunology and
International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan
CREST, Japan Science and Technology Agency, Saitama 322-0012, Japan
Department of Pathobiological Sciences, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA

Correspondence to: Yoshihiro Kawaoka^9,^10,^11,¹² Correspondence and requests for materials should be addressed to Y.K. (Email: kawaokay@svm.vetmed.wisc.edu).

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 mice^2,^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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