title: Host regulatory network response to infection with highly pathogenic H5N1 avian influenza virus.
abstract: During the last decade, more than half of humans infected with highly pathogenic avian influenza (HPAI) H5N1 viruses have died, yet virus-induced host signaling has yet to be clearly elucidated. Airway epithelia are known to produce inflammatory mediators that contribute to HPAI H5N1-mediated pathogenicity, but a comprehensive analysis of the host response in this cell type is lacking. Here, we leveraged a system approach to identify and statistically validate signaling subnetworks that define the dynamic transcriptional response of human bronchial epithelial cells after infection with influenza A/Vietnam/1203/2004 (H5N1, VN1203). Importantly, we validated a subset of transcripts from one subnetwork in both Calu-3 cells and mice. A more detailed examination of two subnetworks involved in the immune response and keratinization processes revealed potential novel mediators of HPAI H5N1 pathogenesis and host response signaling. Finally, we show how these results compare to those for a less virulent strain of influenza virus. Using emergent network properties, we provide fresh insight into the host response to HPAI H5N1 virus infection and identify novel avenues for perturbation studies and potential therapeutic interventions for fatal HPAI H5N1 disease.
authors.affiliation: University of Wisconsin-Madison, School of Veterinary Medicine, Department of Pathobiological Sciences, Influenza Research Institute, 575 Science Drive, Madison, WI 53711, USA.
authors.forename: Chengjun
authors.initials: C
authors.lastname: Li
authors.forename: Armand
authors.initials: A
authors.lastname: Bankhead
authors.forename: Amie J
authors.initials: AJ
authors.lastname: Eisfeld
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Hatta
authors.forename: Sophia
authors.initials: S
authors.lastname: Jeng
authors.forename: Jean H
authors.initials: JH
authors.lastname: Chang
authors.forename: Lauri D
authors.initials: LD
authors.lastname: Aicher
authors.forename: Sean
authors.initials: S
authors.lastname: Proll
authors.forename: Amy L
authors.initials: AL
authors.lastname: Ellis
authors.forename: G Lynn
authors.initials: GL
authors.lastname: Law
authors.forename: Katrina M
authors.initials: KM
authors.lastname: Waters
authors.forename: Gabriele
authors.initials: G
authors.lastname: Neumann
authors.forename: Michael G
authors.initials: MG
authors.lastname: Katze
authors.forename: Shannon
authors.initials: S
authors.lastname: McWeeney
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kawaoka
mesh_terms: D000818:Animals; D002460:Cell Line; D004847:Epithelial Cells / Q000502:physiology* / Q000821:virology*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D053124:Influenza A Virus, H5N1 Subtype / Q000276:immunology* / Q000472:pathogenicity*; D051379:Mice; D020545:Respiratory Mucosa / Q000166:cytology; D015398:Signal Transduction; D013312:Stress, Physiological