U.S. Department of Energy

Pacific Northwest National Laboratory

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

TitleSpecific mutations in H5N1 mainly impact the magnitude and velocity of the host response in mice.
Publication TypeJournal Article
Year of Publication2013
AuthorsTchitchek N, Eisfeld AJ, Tisoncik-Go J, Josset L, Gralinski LE, Bécavin C, Tilton SC, Webb-Robertson B-J, Ferris MT, Totura AL, Li C, Neumann G, Metz TO, Smith RD, Waters KM, Baric R, Kawaoka Y, Katze MG
JournalBMC Syst Biol
KeywordsAnimals, Female, Host-Pathogen Interactions, Influenza A Virus, H1N1 Subtype, Influenza A Virus, H5N1 Subtype, Kinetics, Lung, Mice, Mice, Inbred C57BL, Mutation, RNA, Messenger, Species Specificity, Viral Load, Viral Proteins, Virus Replication

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.

Alternate JournalBMC Syst Biol
PubMed ID23895213
PubMed Central IDPMC3750405
Grant List8 P41 GM103493-10 / GM / NIGMS NIH HHS / United States
HHSN272200800060C / / PHS HHS / United States
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