title: Disease severity is associated with differential gene expression at the early and late phases of infection in nonhuman primates infected with different H5N1 highly pathogenic avian influenza viruses.
abstract: Occasional transmission of highly pathogenic avian H5N1 influenza viruses to humans causes severe pneumonia with high mortality. To better understand the mechanisms via which H5N1 viruses induce severe disease in humans, we infected cynomolgus macaques with six different H5N1 strains isolated from human patients and compared their pathogenicity and the global host responses to the virus infection. Although all H5N1 viruses replicated in the respiratory tract, there was substantial heterogeneity in their replicative ability and in the disease severity induced, which ranged from asymptomatic to fatal. A comparison of global gene expression between severe and mild disease cases indicated that interferon-induced upregulation of genes related to innate immunity, apoptosis, and antigen processing/presentation in the early phase of infection was limited in severe disease cases, although interferon expression was upregulated in both severe and mild cases. Furthermore, coexpression analysis of microarray data, which reveals the dynamics of host responses during the infection, demonstrated that the limited expression of these genes early in infection led to a failure to suppress virus replication and to the hyperinduction of genes related to immunity, inflammation, coagulation, and homeostasis in the late phase of infection, resulting in a more severe disease. Our data suggest that the attenuated interferon-induced activation of innate immunity, apoptosis, and antigen presentation in the early phase of H5N1 virus infection leads to subsequent severe disease outcome.
  
  
  OBJECTIVE
  Highly pathogenic avian H5N1 influenza viruses sometimes transmit to humans and cause severe pneumonia with ca. 60% lethality. The continued circulation of these viruses poses a pandemic threat; however, their pathogenesis in mammals is not fully understood. We, therefore, investigated the pathogenicity of six H5N1 viruses and compared the host responses of cynomolgus macaques to the virus infection. We identified differences in the viral replicative ability of and in disease severity caused by these H5N1 viruses. A comparison of global host responses between severe and mild disease cases identified the limited upregulation of interferon-stimulated genes early in infection in severe cases. The dynamics of the host responses indicated that the limited response early in infection failed to suppress virus replication and led to hyperinduction of pathological condition-related genes late in infection. These findings provide insight into the pathogenesis of H5N1 viruses in mammals.
authors.affiliation: Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Muramoto
authors.affiliation: ERATO Infection-Induced Host Responses Project, Japan Science and Technology Agency, Saitama, Japan.
authors.forename: Jason E
authors.initials: JE
authors.lastname: Shoemaker
authors.affiliation: National Institute of Hygiene and Epidemiology, Hanoi, Vietnam.
authors.forename: Mai Quynh
authors.initials: MQ
authors.lastname: Le
authors.affiliation: Department of Pathology, Shiga University of Medical Science, Ohtsu, Shiga, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Itoh
authors.affiliation: Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Tamura
authors.affiliation: Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Sakai-Tagawa
authors.affiliation: Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan.
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Imai
authors.affiliation: Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan.
authors.forename: Ryuta
authors.initials: R
authors.lastname: Uraki
authors.affiliation: Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Takano
authors.affiliation: ERATO Infection-Induced Host Responses Project, Japan Science and Technology Agency, Saitama, Japan.
authors.forename: Eiryo
authors.initials: E
authors.lastname: Kawakami
authors.affiliation: Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan.
authors.forename: Mutsumi
authors.initials: M
authors.lastname: Ito
authors.affiliation: Department of Pathology, Shiga University of Medical Science, Ohtsu, Shiga, Japan.
authors.forename: Kiyoko
authors.initials: K
authors.lastname: Okamoto
authors.affiliation: Department of Pathology, Shiga University of Medical Science, Ohtsu, Shiga, Japan.
authors.forename: Hirohito
authors.initials: H
authors.lastname: Ishigaki
authors.affiliation: Division of Bacteriology, Department of Infectious Diseases Control, International Research Center for Infectious Diseases, Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan.
authors.forename: Hitomi
authors.initials: H
authors.lastname: Mimuro
authors.affiliation: Division of Bacterial Infection Biology, Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan Nippon Institute for Biological Science, Ome, Tokyo, Japan Medical Mycology Research Center, Chiba University, Chuo-ku, Chiba, Japan.
authors.forename: Chihiro
authors.initials: C
authors.lastname: Sasakawa
authors.affiliation: ERATO Infection-Induced Host Responses Project, Japan Science and Technology Agency, Saitama, Japan.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Matsuoka
authors.affiliation: Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Noda
authors.affiliation: ERATO Infection-Induced Host Responses Project, Japan Science and Technology Agency, Saitama, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Fukuyama
authors.affiliation: Department of Pathology, Shiga University of Medical Science, Ohtsu, Shiga, Japan.
authors.forename: Kazumasa
authors.initials: K
authors.lastname: Ogasawara
authors.affiliation: ERATO Infection-Induced Host Responses Project, Japan Science and Technology Agency, Saitama, Japan The Systems Biology Institute, Tokyo, Japan Division of Systems Biology, Cancer Institute, Tokyo, Japan Sony Computer Science Laboratories, Inc., Tokyo, Japan Okinawa Institute of Science and Technology, Okinawa, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Kitano
authors.affiliation: Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan ERATO Infection-Induced Host Responses Project, Japan Science and Technology Agency, Saitama, Japan Department of Special Pathogens, International Research Center for Infectious Diseases, Institute of Medical Science, The University of Tokyo, Tokyo, Japan Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin, USA kawaoka@ims.u-tokyo.ac.jp.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kawaoka
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D017209:Apoptosis / Q000276:immunology; D002478:Cells, Cultured; D004285:Dogs; D015870:Gene Expression / Q000235:genetics* / Q000276:immunology; D015967:Gene Expression Regulation, Viral / Q000235:genetics* / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology; D007249:Inflammation / Q000276:immunology / Q000821:virology; D053124:Influenza A Virus, H5N1 Subtype / Q000235:genetics* / Q000276:immunology; D008251:Macaca / Q000276:immunology / Q000821:virology; D008252:Macaca fascicularis / Q000276:immunology / Q000821:virology; D061985:Madin Darby Canine Kidney Cells; D009976:Orthomyxoviridae Infections / Q000276:immunology / Q000821:virology*; D011323:Primates / Q000276:immunology / Q000821:virology*; D012137:Respiratory System / Q000276:immunology / Q000821:virology; D012720:Severity of Illness Index; D014779:Virus Replication / Q000235:genetics / Q000276:immunology