title: Circulating avian influenza viruses closely related to the 1918 virus have pandemic potential.
abstract: Wild birds harbor a large gene pool of influenza A viruses that have the potential to cause influenza pandemics. Foreseeing and understanding this potential is important for effective surveillance. Our phylogenetic and geographic analyses revealed the global prevalence of avian influenza virus genes whose proteins differ only a few amino acids from the 1918 pandemic influenza virus, suggesting that 1918-like pandemic viruses may emerge in the future. To assess this risk, we generated and characterized a virus composed of avian influenza viral segments with high homology to the 1918 virus. This virus exhibited pathogenicity in mice and ferrets higher than that in an authentic avian influenza virus. Further, acquisition of seven amino acid substitutions in the viral polymerases and the hemagglutinin surface glycoprotein conferred respiratory droplet transmission to the 1918-like avian virus in ferrets, demonstrating that contemporary avian influenza viruses with 1918 virus-like proteins may have pandemic potential.
authors.affiliation: Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, 575 Science Drive, Madison, WI 53711, USA; ERATO Infection-Induced Host Responses Project, Japan Science and Technology Agency, Saitama 332-0012, Japan.
authors.forename: Tokiko
authors.initials: T
authors.lastname: Watanabe
authors.affiliation: Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, 575 Science Drive, Madison, WI 53711, USA.
authors.forename: Gongxun
authors.initials: G
authors.lastname: Zhong
authors.affiliation: Department of Veterinary Medicine, University of Cambridge, Madingley Road, Cambridge CB3 0ES, UK.
authors.forename: Colin A
authors.initials: CA
authors.lastname: Russell
authors.affiliation: Department of Pathology, National Institute of Infectious Diseases, Shinjuku, Tokyo 162-8640, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Nakajima
authors.affiliation: Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, 575 Science Drive, Madison, WI 53711, USA.
authors.forename: Masato
authors.initials: M
authors.lastname: Hatta
authors.affiliation: Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, 575 Science Drive, Madison, WI 53711, USA.
authors.forename: Anthony
authors.initials: A
authors.lastname: Hanson
authors.affiliation: Department of Cell and Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Ryan
authors.initials: R
authors.lastname: McBride
authors.affiliation: Department of Zoology, University of Cambridge, Downing Street, Cambridge CB2 3EJ, UK.
authors.forename: David F
authors.initials: DF
authors.lastname: Burke
authors.affiliation: Department of Pathology, National Institute of Infectious Diseases, Shinjuku, Tokyo 162-8640, Japan.
authors.forename: Kenta
authors.initials: K
authors.lastname: Takahashi
authors.affiliation: ERATO Infection-Induced Host Responses Project, Japan Science and Technology Agency, Saitama 332-0012, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Fukuyama
authors.affiliation: ERATO Infection-Induced Host Responses Project, Japan Science and Technology Agency, Saitama 332-0012, Japan.
authors.forename: Yuriko
authors.initials: Y
authors.lastname: Tomita
authors.affiliation: Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, 575 Science Drive, Madison, WI 53711, USA.
authors.forename: Eileen A
authors.initials: EA
authors.lastname: Maher
authors.affiliation: ERATO Infection-Induced Host Responses Project, Japan Science and Technology Agency, Saitama 332-0012, Japan; Laboratory of Veterinary Microbiology, Department of Veterinary Sciences, University of Miyazaki, Miyazaki 889-2192, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Watanabe
authors.affiliation: Department of Veterinary Medicine, Faculty of Agriculture, Iwate University, Iwate 020-8550, Japan; Influenza Virus Research Center, National Institute of Infectious Diseases, Tokyo 208-0011, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Imai
authors.affiliation: Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, 575 Science Drive, Madison, WI 53711, USA.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Neumann
authors.affiliation: Department of Pathology, National Institute of Infectious Diseases, Shinjuku, Tokyo 162-8640, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Hasegawa
authors.affiliation: Department of Cell and Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: James C
authors.initials: JC
authors.lastname: Paulson
authors.affiliation: Department of Zoology, University of Cambridge, Downing Street, Cambridge CB2 3EJ, UK.
authors.forename: Derek J
authors.initials: DJ
authors.lastname: Smith
authors.affiliation: Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, 575 Science Drive, Madison, WI 53711, USA; ERATO Infection-Induced Host Responses Project, Japan Science and Technology Agency, Saitama 332-0012, Japan; Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan; Department of Special Pathogens, International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan. Electronic address: kawaokay@svm.vetmed.wisc.edu.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kawaoka
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D005075:Biological Evolution; D001717:Birds / Q000821:virology; D004195:Disease Models, Animal; D004285:Dogs; D005260:Female; D005289:Ferrets / Q000821:virology; D006801:Humans; D009980:Influenza A virus / Q000187:drug effects / Q000235:genetics* / Q000472:pathogenicity*; D007252:Influenza Vaccines / Q000494:pharmacology; D005585:Influenza in Birds / Q000821:virology*; D007251:Influenza, Human / Q000453:epidemiology / Q000635:transmission / Q000821:virology*; D061985:Madin Darby Canine Kidney Cells / Q000821:virology; D008807:Mice, Inbred BALB C / Q000821:virology; D058873:Pandemics; D010802:Phylogeny; D017386:Sequence Homology, Amino Acid; D014764:Viral Proteins / Q000235:genetics
chemical_list: D000998:Antiviral Agents; D007252:Influenza Vaccines; C502893:PB2 protein, influenza virus; D014764:Viral Proteins