Enhanced virulence of influenza A viruses with the haemagglutinin of the 1918 pandemic virus

Darwyn Kobasa, Ayato Takada, Kyoko Shinya, Masato Hatta, Peter Halfmann, Steven Theriault, Hiroshi Suzuki, Hidekazu Nishimura, Keiko Mitamura, Norio Sugaya, Taichi Usui, Takeomi Murata, Yasuko Maeda, Shinji Watanabe, M. Suresh, Takashi Suzuki, Yasuo Suzuki, Heinz Feldmann and Yoshihiro Kawaoka ()
Additional contact information
Darwyn Kobasa: University of Wisconsin
Ayato Takada: Institute of Medical Science, University of Tokyo
Kyoko Shinya: Institute of Medical Science, University of Tokyo
Masato Hatta: University of Wisconsin
Peter Halfmann: University of Wisconsin
Steven Theriault: University of Manitoba
Hiroshi Suzuki: Niigata University
Hidekazu Nishimura: Sendai National Hospital
Keiko Mitamura: Nippon Kokan Hospital
Norio Sugaya: Nippon Kokan Hospital
Taichi Usui: Shizuoka University
Takeomi Murata: Shizuoka University
Yasuko Maeda: Institute of Medical Science, University of Tokyo
Shinji Watanabe: University of Wisconsin
M. Suresh: University of Wisconsin
Takashi Suzuki: Japan Science and Technology Agency
Yasuo Suzuki: Japan Science and Technology Agency
Heinz Feldmann: University of Manitoba
Yoshihiro Kawaoka: University of Wisconsin

Nature, 2004, vol. 431, issue 7009, 703-707

Abstract: Abstract The ‘Spanish’ influenza pandemic of 1918–19 was the most devastating outbreak of infectious disease in recorded history. At least 20 million people1 died from their illness, which was characterized by an unusually severe and rapid clinical course. The complete sequencing of several genes of the 1918 influenza virus has made it possible to study the functions of the proteins encoded by these genes in viruses generated by reverse genetics, a technique that permits the generation of infectious viruses entirely from cloned complementary DNA. Thus, to identify properties of the 1918 pandemic influenza A strain that might be related to its extraordinary virulence, viruses were produced containing the viral haemagglutinin2 (HA) and neuraminidase3 (NA) genes of the 1918 strain. The HA of this strain supports the pathogenicity of a mouse-adapted virus in this animal4,5. Here we demonstrate that the HA of the 1918 virus confers enhanced pathogenicity in mice to recent human viruses that are otherwise non-pathogenic in this host. Moreover, these highly virulent recombinant viruses expressing the 1918 viral HA could infect the entire lung and induce high levels of macrophage-derived chemokines and cytokines, which resulted in infiltration of inflammatory cells and severe haemorrhage, hallmarks of the illness produced during the original pandemic6.

Date: 2004
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DOI: 10.1038/nature02951

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