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

doi:10.1186/1752-0509-6-117

BMC Syst Biol. 2012; 6: 117.

Published online 2012 August 31. doi: 10.1186/1752-0509-6-117

PMCID: PMC3481363

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

Jason E Shoemaker,¹ Satoshi Fukuyama,^#¹ Amie J Eisfeld,^#² Yukiko Muramoto,³ Shinji Watanabe,^1,² Tokiko Watanabe,^1,² Yukiko Matsuoka,^1,^2,⁴ Hiroaki Kitano,^1,^4,^5,^6,⁷ and Yoshihiro Kawaoka^1,^2,^3,^8,⁹

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

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

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

⁴The Systems Biology Institute, Tokyo, Japan

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

⁶Sony Computer Science Laboratories, Inc, Tokyo, Japan

⁷Okinawa Institute of Science and Technology, Okinawa, Japan

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

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

Corresponding author.

^#Contributed equally.

Jason E Shoemaker: jshoe/at/ims.u-tokyo.ac.jp; Satoshi Fukuyama: satoshif/at/ims.u-tokyo.ac.jp; Amie J Eisfeld: aefenney/at/svm.vetmed.wisc.edu; Yukiko Muramoto: muramo/at/ims.u-tokyo.ac.jp; Shinji Watanabe: watanabs/at/ims.u-tokyo.ac.jp; Tokiko Watanabe: tokikow/at/ims.u-tokyo.ac.jp; Yukiko Matsuoka: myukiko/at/sbi.jp; Hiroaki Kitano: kitano/at/sbi.jp; Yoshihiro Kawaoka: kawaokay/at/vetmed.wisc.edu

Received February 28, 2012; Accepted August 18, 2012.

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

This article has been cited by other articles in PMC.

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.

Keywords: Influenza, Host response, Microarray, pH1N1, Systems biology

Articles from BMC Systems Biology are provided here courtesy of
BioMed Central