title: Differences in cytokine production in human macrophages and in virulence in mice are attributable to the acidic polymerase protein of highly pathogenic influenza A virus subtype H5N1.
abstract: BACKGROUND
  The pathogenesis of influenza A virus subtype H5N1 (hereafter, "H5N1") infection in humans is not completely understood, although hypercytokinemia is thought to play a role. We previously reported that most H5N1 viruses induce high cytokine responses in human macrophages, whereas some H5N1 viruses induce only a low level of cytokine production similar to that induced by seasonal viruses.
  
  
  METHODS
  To identify the viral molecular determinants for cytokine induction of H5N1 viruses in human macrophages, we generated a series of reassortant viruses between the high cytokine inducer A/Vietnam/UT3028II/03 clone 2 (VN3028IIcl2) and the low inducer A/Indonesia/UT3006/05 (IDN3006) and evaluated cytokine expression in human macrophages.
  
  
  RESULTS
  Viruses possessing the acidic polymerase (PA) gene of VN3028IIcl2 exhibited high levels of hypercytokinemia-related cytokine expression in human macrophages, compared with IDN3006, but showed no substantial differences in viral growth in these cells. Further, the PA gene of VN3028IIcl2 conferred enhanced virulence in mice.
  
  
  CONCLUSIONS
  These results demonstrate that the PA gene of VN3028IIcl2 affects cytokine production in human macrophages and virulence in mice. These findings provide new insights into the cytokine-mediated pathogenesis of H5N1 infection in humans.
authors.affiliation: Division of Virology, Department of Microbiology and Immunology, University of Tokyo, Tokyo 108-8639, Japan.
authors.forename: Saori
authors.initials: S
authors.lastname: Sakabe
authors.forename: Ryo
authors.initials: R
authors.lastname: Takano
authors.forename: Tokiko
authors.initials: T
authors.lastname: Nagamura-Inoue
authors.forename: Naohide
authors.initials: N
authors.lastname: Yamashita
authors.forename: Chairul A
authors.initials: CA
authors.lastname: Nidom
authors.forename: Mai thi
authors.initials: Mt
authors.lastname: Quynh Le
authors.forename: Kiyoko
authors.initials: K
authors.lastname: Iwatsuki-Horimoto
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kawaoka
mesh_terms: D000818:Animals; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D004847:Epithelial Cells / Q000276:immunology / Q000821:virology; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D053124:Influenza A Virus, H5N1 Subtype / Q000235:genetics / Q000472:pathogenicity* / Q000502:physiology; D007251:Influenza, Human / Q000276:immunology / Q000821:virology*; D008264:Macrophages / Q000276:immunology* / Q000821:virology; D061985:Madin Darby Canine Kidney Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D009976:Orthomyxoviridae Infections / Q000276:immunology / Q000662:veterinary* / Q000821:virology; D012324:RNA-Dependent RNA Polymerase / Q000235:genetics*; D016865:Reassortant Viruses / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity; D014764:Viral Proteins / Q000235:genetics*; D014774:Virulence / Q000235:genetics
chemical_list: D016207:Cytokines; C061290:PA protein, influenza viruses; D014764:Viral Proteins; D012324:RNA-Dependent RNA Polymerase