title: Virulence determinants of pandemic A(H1N1)2009 influenza virus in a mouse model.
abstract: A novel swine-origin H1N1 influenza virus [A(H1N1)pdm09 virus] caused the 2009 influenza pandemic. Most patients exhibited mild symptoms similar to seasonal influenza, but some experienced severe clinical signs and, in the worst cases, died. Such differences in symptoms are generally associated with preexisting medical conditions, but recent reports indicate the possible involvement of viral factors in clinical severity. To better understand the mechanism of pathogenicity of the A(H1N1)pdm09 virus, here, we compared five viruses that are genetically similar but were isolated from patients with either severe or mild symptoms. In a mouse model, A/Norway/3487/2009 (Norway3487) virus exhibited greater pathogenicity than did A/Osaka/164/2009 (Osaka164) virus. By exploiting reassortant viruses between these two viruses, we found that viruses possessing the hemagglutinin (HA) gene of Norway3487 in the genetic background of Osaka164 were more pathogenic in mice than other reassortant viruses, indicating a role for HA in the high virulence of Norway3487 virus. Intriguingly, a virus possessing HA, NA, and NS derived from Norway3487 exhibited greater pathogenicity in mice in concert with PB2 and PB1 derived from Osaka164 than did the parental Norway3487 virus. These findings demonstrate that reassortment between A(H1N1)pdm09 viruses can lead to increased pathogenicity and highlight the need for continued surveillance of A(H1N1)pdm09 viruses.
authors.affiliation: Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
authors.forename: Ryuta
authors.initials: R
authors.lastname: Uraki
authors.forename: Maki
authors.initials: M
authors.lastname: Kiso
authors.forename: Kyoko
authors.initials: K
authors.lastname: Shinya
authors.forename: Hideo
authors.initials: H
authors.lastname: Goto
authors.forename: Ryo
authors.initials: R
authors.lastname: Takano
authors.forename: Kiyoko
authors.initials: K
authors.lastname: Iwatsuki-Horimoto
authors.forename: Kazuo
authors.initials: K
authors.lastname: Takahashi
authors.forename: Rod S
authors.initials: RS
authors.lastname: Daniels
authors.forename: Olav
authors.initials: O
authors.lastname: Hungnes
authors.forename: Tokiko
authors.initials: T
authors.lastname: Watanabe
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kawaoka
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000235:genetics / Q000302:isolation & purification / Q000472:pathogenicity*; D051379:Mice; D008807:Mice, Inbred BALB C; D009976:Orthomyxoviridae Infections / Q000473:pathology / Q000821:virology; D016865:Reassortant Viruses / Q000235:genetics / Q000302:isolation & purification / Q000472:pathogenicity; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*; D014774:Virulence; D037521:Virulence Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D014764:Viral Proteins; D037521:Virulence Factors