title: Integrated network analysis reveals a novel role for the cell cycle in 2009 pandemic influenza virus-induced inflammation in macaque lungs.
abstract: BACKGROUND
  Annually, influenza A viruses circulate the world causing wide-spread sickness, economic loss, and death. One way to better defend against influenza virus-induced disease may be to develop novel host-based therapies, targeted at mitigating viral pathogenesis through the management of virus-dysregulated host functions. However, mechanisms that govern aberrant host responses to influenza virus infection remain incompletely understood. We previously showed that the pandemic H1N1 virus influenza A/California/04/2009 (H1N1; CA04) has enhanced pathogenicity in the lungs of cynomolgus macaques relative to a seasonal influenza virus isolate (A/Kawasaki/UTK-4/2009 (H1N1; KUTK4)).
  
  
  RESULTS
  Here, we used microarrays to identify host gene sequences that were highly differentially expressed (DE) in CA04-infected macaque lungs, and we employed a novel strategy - combining functional and pathway enrichment analyses, transcription factor binding site enrichment analysis and protein-protein interaction data - to create a CA04 differentially regulated host response network. This network describes enhanced viral RNA sensing, immune cell signaling and cell cycle arrest in CA04-infected lungs, and highlights a novel, putative role for the MYC-associated zinc finger (MAZ) transcription factor in regulating these processes.
  
  
  CONCLUSIONS
  Our findings suggest that the enhanced pathology is the result of a prolonged immune response, despite successful virus clearance. Most interesting, we identify a mechanism which normally suppresses immune cell signaling and inflammation is ineffective in the pH1N1 virus infection; a dyregulatory event also associated with arthritis. This dysregulation offers several opportunities for developing strain-independent, immunomodulatory therapies to protect against future pandemics.
authors.affiliation: ERATO Infection-Induced Host Responses Project, Saitama, 332-0012, Japan.
authors.forename: Jason E
authors.initials: JE
authors.lastname: Shoemaker
authors.forename: Satoshi
authors.initials: S
authors.lastname: Fukuyama
authors.forename: Amie J
authors.initials: AJ
authors.lastname: Eisfeld
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Muramoto
authors.forename: Shinji
authors.initials: S
authors.lastname: Watanabe
authors.forename: Tokiko
authors.initials: T
authors.lastname: Watanabe
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Matsuoka
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Kitano
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kawaoka
mesh_terms: D056704:Adaptive Immunity / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001665:Binding Sites; D020170:Caspase 1 / Q000096:biosynthesis; D002453:Cell Cycle; D002633:Chemotaxis / Q000235:genetics; D019295:Computational Biology; D015536:Down-Regulation; D004790:Enzyme Induction / Q000235:genetics; D005260:Female; D005982:Glutathione Transferase / Q000235:genetics; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000821:virology; D053118:Influenza A Virus, H1N1 Subtype / Q000472:pathogenicity*; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000473:pathology* / Q000821:virology*; D008251:Macaca; D009976:Orthomyxoviridae Infections / Q000453:epidemiology*; D058873:Pandemics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; D014157:Transcription Factors; D005982:Glutathione Transferase; D020170:Caspase 1