期刊
BMC SYSTEMS BIOLOGY
卷 6, 期 -, 页码 -出版社
BMC
DOI: 10.1186/1752-0509-6-117
关键词
Influenza; Host response; Microarray; pH1N1; Systems biology
资金
- Ministry of Education, Culture, Sports, Science and Technology
- ERATO (Japan Science and Technology Agency)
- Contract Research Fund for the Program of Founding Research Centers for Emerging and Reemerging Infectious Diseases
- Public Health Service research grants from the National Institute of Allergy and Infectious Diseases
- Grants-in-Aid for Scientific Research [22136003, 24780296, 22136001] Funding Source: KAKEN
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.
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