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Open Access Highly Accessed Research article

Specific mutations in H5N1 mainly impact the magnitude and velocity of the host response in mice

Nicolas Tchitchek1, Amie J Eisfeld2, Jennifer Tisoncik-Go1, Laurence Josset1, Lisa E Gralinski3, Christophe Bécavin4, Susan C Tilton5, Bobbie-Jo Webb-Robertson5, Martin T Ferris3, Allison L Totura3, Chengjun Li2, Gabriele Neumann2, Thomas O Metz5, Richard D Smith5, Katrina M Waters5, Ralph Baric3, Yoshihiro Kawaoka2 and Michael G Katze16*

Author Affiliations

1 Department of Microbiology, University of Washington, Seattle, WA 98195 USA

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

3 Department of Microbiology and Immunology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

4 Unité des Interactions Bactéries-Cellules, Institut Pasteur, 75015 Paris, France

5 Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA

6 Washington National Primate Research Center, University of Washington, Seattle, WA, USA

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BMC Systems Biology 2013, 7:69  doi:10.1186/1752-0509-7-69

Published: 29 July 2013

Abstract

Background

Influenza infection causes respiratory disease that can lead to death. The complex interplay between virus-encoded and host-specific pathogenicity regulators – and the relative contributions of each toward viral pathogenicity – is not well-understood.

Results

By analyzing a collection of lung samples from mice infected by A/Vietnam/1203/2004 (H5N1; VN1203), we characterized a signature of transcripts and proteins associated with the kinetics of the host response. Using a new geometrical representation method and two criteria, we show that inoculation concentrations and four specific mutations in VN1203 mainly impact the magnitude and velocity of the host response kinetics, rather than specific sets of up- and down- regulated genes. We observed analogous kinetic effects using lung samples from mice infected with A/California/04/2009 (H1N1), and we show that these effects correlate with morbidity and viral titer.

Conclusions

We have demonstrated the importance of the kinetics of the host response to H5N1 pathogenesis and its relationship with clinical disease severity and virus replication. These kinetic properties imply that time-matched comparisons of ‘omics profiles to viral infections give limited views to differentiate host-responses. Moreover, these results demonstrate that a fast activation of the host-response at the earliest time points post-infection is critical for protective mechanisms against fast replicating viruses.

Keywords:
Influenza; Host; Response; Kinetics; Magnitude; Velocity; Transcriptomics; Proteomics; Multidimensional; Scaling