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Conserved host response to highly pathogenic avian influenza virus infection in human cell culture, mouse and macaque model systems

Jason E McDermott1, Harish Shankaran1, Amie J Eisfeld2, Sarah E Belisle3, Gabriele Neuman2, Chengjun Li2, Shannon McWeeney45, Carol Sabourin6, Yoshihiro Kawaoka2789, Michael G Katze103 and Katrina M Waters1*

Author Affiliations

1 Computational Biology and Bioinformatics Group, Pacific Northwest National Laboratory, Richland, Washington, USA

2 Department of Pathobiological Sciences, Influenza Research Institute, University of Wisconsin-Madison, Madison, Wisconsin, USA

3 Department of Microbiology, University of Washington, Seattle, Washington, USA

4 Oregon Health and Science University, Division of Biostatistics, Department of Public Health and Preventive Medicine, Portland, Oregon, USA

5 Oregon Health and Science University, Knight Cancer Institute, Portland, Oregon, USA

6 Battelle, Columbus, Ohio, USA

7 Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan

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

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

10 Washington National Primate Research Center, University of Washington, Seattle, Washington, USA

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BMC Systems Biology 2011, 5:190  doi:10.1186/1752-0509-5-190

Published: 11 November 2011



Understanding host response to influenza virus infection will facilitate development of better diagnoses and therapeutic interventions. Several different experimental models have been used as a proxy for human infection, including cell cultures derived from human cells, mice, and non-human primates. Each of these systems has been studied extensively in isolation, but little effort has been directed toward systematically characterizing the conservation of host response on a global level beyond known immune signaling cascades.


In the present study, we employed a multivariate modeling approach to characterize and compare the transcriptional regulatory networks between these three model systems after infection with a highly pathogenic avian influenza virus of the H5N1 subtype. Using this approach we identified functions and pathways that display similar behavior and/or regulation including the well-studied impact on the interferon response and the inflammasome. Our results also suggest a primary response role for airway epithelial cells in initiating hypercytokinemia, which is thought to contribute to the pathogenesis of H5N1 viruses. We further demonstrate that we can use a transcriptional regulatory model from the human cell culture data to make highly accurate predictions about the behavior of important components of the innate immune system in tissues from whole organisms.


This is the first demonstration of a global regulatory network modeling conserved host response between in vitro and in vivo models.

systems biology; influenza infection; host response; network inference; comparative transcriptomics