title: Highly Pathogenic H5N1 and Novel H7N9 Influenza A Viruses Induce More Profound Proteomic Host Responses than Seasonal and Pandemic H1N1 Strains.
abstract: Influenza A viruses (IAV) are important human and animal pathogens with potential for causing pandemics. IAVs exhibit a wide spectrum of clinical illness in humans, from relatively mild infections by seasonal strains to acute respiratory distress syndrome during infections with some highly pathogenic avian influenza (HPAI) viruses. In the present study, we infected A549 human cells with seasonal H1N1 (sH1N1), 2009 pandemic H1N1 (pdmH1N1), or novel H7N9 and HPAI H5N1 strains. We used multiplexed isobaric tags for relative and absolute quantification to measure proteomic host responses to these different strains at 1, 3, and 6 h post-infection. Our analyses revealed that both H7N9 and H5N1 strains induced more profound changes to the A549 global proteome compared to those with low-pathogenicity H1N1 virus infection, which correlates with the higher pathogenicity these strains exhibit at the organismal level. Bioinformatics analysis revealed important modulation of the nuclear factor erythroid 2-related factor 2 (NRF2) oxidative stress response in infection. Cellular fractionation and Western blotting suggested that the phosphorylated form of NRF2 is not imported to the nucleus in H5N1 and H7N9 virus infections. Fibronectin was also strongly inhibited in infection with H5N1 and H7N9 strains. This is the first known comparative proteomic study of the host response to H7N9, H5N1, and H1N1 viruses and the first time NRF2 is shown to be implicated in infection with highly pathogenic strains of influenza.
authors.affiliation: Department of Medical Microbiology and Infectious Diseases, University of Manitoba , Winnipeg, Manitoba, R3E 0J9 Canada.
authors.forename: Philippe François
authors.initials: PF
authors.lastname: Simon
authors.forename: Stuart
authors.initials: S
authors.lastname: McCorrister
authors.affiliation: Department of Biochemistry and Medical Genetics, University of Manitoba , Winnipeg, Manitoba, R3T 2N2 Canada.
authors.forename: Pingzhao
authors.initials: P
authors.lastname: Hu
authors.forename: Patrick
authors.initials: P
authors.lastname: Chong
authors.affiliation: Department of Medical Microbiology and Infectious Diseases, University of Manitoba , Winnipeg, Manitoba, R3E 0J9 Canada.
authors.forename: Alex
authors.initials: A
authors.lastname: Silaghi
authors.forename: Garrett
authors.initials: G
authors.lastname: Westmacott
authors.affiliation: Department of Medical Microbiology and Infectious Diseases, University of Manitoba , Winnipeg, Manitoba, R3E 0J9 Canada.|Manitoba Center for Proteomics and Systems Biology, University of Manitoba , Winnipeg, Manitoba, R3E 3P4 Canada.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Coombs
authors.affiliation: Department of Medical Microbiology and Infectious Diseases, University of Manitoba , Winnipeg, Manitoba, R3E 0J9 Canada.
authors.forename: Darwyn
authors.initials: D
authors.lastname: Kobasa
mesh_terms: D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism / Q000821:virology; D019295:Computational Biology / Q000379:methods; D003600:Cytosol / Q000378:metabolism / Q000821:virology; D004847:Epithelial Cells / Q000378:metabolism* / Q000821:virology; D005353:Fibronectins / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D054884:Host-Pathogen Interactions; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000502:physiology*; D053124:Influenza A Virus, H5N1 Subtype / Q000472:pathogenicity* / Q000502:physiology; D064766:Influenza A Virus, H7N9 Subtype / Q000472:pathogenicity* / Q000502:physiology; D051267:NF-E2-Related Factor 2 / Q000235:genetics* / Q000378:metabolism; D018384:Oxidative Stress; D010766:Phosphorylation; D021381:Protein Transport; D020543:Proteome / Q000235:genetics* / Q000378:metabolism; D020545:Respiratory Mucosa / Q000378:metabolism / Q000821:virology; D015398:Signal Transduction; D014774:Virulence
chemical_list: D005353:Fibronectins; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D020543:Proteome
keywords: FN1; H1N1; H5N1; H7N9; NRF2; avian influenza; fibronectin; oxidative stress