1. Department of Pathobiological Sciences, University of Wisconsin, Madison, Wisconsin 53706, USA
2. Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan
3. CREST, Japan Science and Technology Agency, Saitama, 332-0012, Japan
4. Special Pathogens Program, National Microbiology Laboratory, Health Canada and Department of Medical Microbiology, University of Manitoba, Winnipeg, Manitoba R3E 3R2, Canada
5. Department of Public Health, School of Medicine, Niigata University, Niigata, 951-8510, Japan
6. Viral Research Center Clinical Research Division, Sendai National Hospital, Sendai, 983-8520, Japan
7. Department of Pediatrics, Nippon Kokan Hospital, Kawasaki, 210-0852, Japan
8. Department of Applied Biological Chemistry, Shizuoka University, Shizuoka 422-8529, Japan
9. Department of Biochemistry, University of Shizuoka, School of Pharmaceutical Sciences and COE Program in the 21st Century, Yada, Shizuoka-shi 422-8526, Japan
10. Present addresses: National Microbiology Laboratory, Canadian Science Centre for Human and Animal Health, Winnipeg, Manitoba R3E 3R2, Canada (D.K.); Institute for Animal Experimentation, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan (K.S.); Department of Pediatrics, Kawasaki Municipal Hospital, Kawasaki 210-0013, Japan (K.M.); Department of Pediatrics, Keiyu Hospital, Yokohama 220-0012, Japan (N.S.)

Correspondence to: Yoshihiro Kawaoka^1,2,3 Correspondence and requests for materials should be addressed to Y.K. (Email: kawaokay@svm.vetmed.wisc.edu).

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 animal^{4, 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.

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