title: Aberrant innate immune response in lethal infection of macaques with the 1918 influenza virus.
abstract: The 1918 influenza pandemic was unusually severe, resulting in about 50 million deaths worldwide. The 1918 virus is also highly pathogenic in mice, and studies have identified a multigenic origin of this virulent phenotype in mice. 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 viruses, may be a feature shared by the virulent influenza viruses.
authors.affiliation: Respiratory Viruses, Public Health Agency of Canada, Winnipeg, Manitoba R3E 3R2, Canada.
authors.forename: Darwyn
authors.initials: D
authors.lastname: Kobasa
authors.forename: Steven M
authors.initials: SM
authors.lastname: Jones
authors.forename: Kyoko
authors.initials: K
authors.lastname: Shinya
authors.forename: John C
authors.initials: JC
authors.lastname: Kash
authors.forename: John
authors.initials: J
authors.lastname: Copps
authors.forename: Hideki
authors.initials: H
authors.lastname: Ebihara
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Hatta
authors.forename: Jin Hyun
authors.initials: JH
authors.lastname: Kim
authors.forename: Peter
authors.initials: P
authors.lastname: Halfmann
authors.forename: Masato
authors.initials: M
authors.lastname: Hatta
authors.forename: Friederike
authors.initials: F
authors.lastname: Feldmann
authors.forename: Judie B
authors.initials: JB
authors.lastname: Alimonti
authors.forename: Lisa
authors.initials: L
authors.lastname: Fernando
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Michael G
authors.initials: MG
authors.lastname: Katze
authors.forename: Heinz
authors.initials: H
authors.lastname: Feldmann
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kawaoka
mesh_terms: D000818:Animals; D018925:Chemokines / Q000097:blood; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D053118:Influenza A Virus, H1N1 Subtype / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity*; D007251:Influenza, Human / Q000097:blood / Q000276:immunology* / Q000821:virology*; D008168:Lung / Q000378:metabolism / Q000473:pathology / Q000821:virology; D008252:Macaca fascicularis / Q000276:immunology* / Q000821:virology*; D051379:Mice; D008807:Mice, Inbred BALB C; D020411:Oligonucleotide Array Sequence Analysis; D015996:Survival Rate; D013997:Time Factors; D014779:Virus Replication
chemical_list: D018925:Chemokines; D016207:Cytokines