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Integrated network analysis reveals a novel role for the cell cycle in 2009 pandemic influenza virus-induced inflammation in macaque lungs

Jason E Shoemaker1, Satoshi Fukuyama1, Amie J Eisfeld2, Yukiko Muramoto3, Shinji Watanabe12, Tokiko Watanabe12, Yukiko Matsuoka124, Hiroaki Kitano14567* and Yoshihiro Kawaoka12389*

Author Affiliations

1 ERATO Infection-Induced Host Responses Project, Saitama, 332-0012, Japan

2 School of Veterinary Medicine, Department of Pathobiological Sciences, Influenza Research Institute, University of Wisconsin-Madison, Madison, WI, USA

3 Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo, Japan

4 The Systems Biology Institute, Tokyo, Japan

5 Division of Systems Biology, Cancer Institute, Tokyo, Japan

6 Sony Computer Science Laboratories, Inc, Tokyo, Japan

7 Okinawa Institute of Science and Technology, Okinawa, Japan

8 Department of Special Pathogens, International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo, 108-8639, Japan

9 International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo, 108-8639, Japan

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BMC Systems Biology 2012, 6:117  doi:10.1186/1752-0509-6-117

Published: 31 August 2012



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)).


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.


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.

Influenza; Host response; Microarray; pH1N1; Systems biology