Release of Severe Acute Respiratory Syndrome Coronavirus Nuclear Import Block Enhances Host Transcription in Human Lung Cells

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  • Amy C. Sims
    • Other Affiliation: Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
  • Susan C. Tilton
    • Other Affiliation: Pacific Northwest National Laboratory, Richland, Washington, USA
  • Vineet D. Menachery
    • Other Affiliation: Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
  • Lisa E. Gralinski
    • Other Affiliation: Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
  • Alexandra Schäfer
    • Other Affiliation: Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
  • Melissa M. Matzke
    • Other Affiliation: Pacific Northwest National Laboratory, Richland, Washington, USA
  • Bobbie-Jo M. Webb-Robertson
    • Other Affiliation: Pacific Northwest National Laboratory, Richland, Washington, USA
  • Jean Chang
    • Other Affiliation: Department of Microbiology, School of Medicine, University of Washington, Seattle, Washington, USA
  • Maria L. Luna
    • Other Affiliation: Pacific Northwest National Laboratory, Richland, Washington, USA
  • Casey E. Long
    • Other Affiliation: Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
  • Anil K. Shukla
    • Other Affiliation: Pacific Northwest National Laboratory, Richland, Washington, USA
  • Armand R. Bankhead III
    • Other Affiliation: Oregon Health Sciences University, Portland, Oregon, USA
  • Susan E. Burkett
    • Other Affiliation: Cystic Fibrosis Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
  • Gregory Zornetzer
    • Other Affiliation: Department of Microbiology, School of Medicine, University of Washington, Seattle, Washington, USA
  • Chien-Te Kent Tseng
    • Other Affiliation: University of Texas Medical Branch, Department of Microbiology and Immunology, Galveston, Texas, USA
  • Thomas O. Metz
    • Other Affiliation: Pacific Northwest National Laboratory, Richland, Washington, USA
  • Raymond Pickles
    • Other Affiliation: Microbiology and Immunology and Cystic Fibrosis Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
  • Shannon McWeeney
    • Other Affiliation: Oregon Health Sciences University, Portland, Oregon, USA
  • Richard D. Smith
    • Other Affiliation: Pacific Northwest National Laboratory, Richland, Washington, USA
  • Michael G. Katze
    • Other Affiliation: Department of Microbiology, School of Medicine, University of Washington, Seattle, Washington, USA ; Washington National Primate Research Center, University of Washington, Seattle, Washington, USA
  • Katrina M. Waters
    • Other Affiliation: Pacific Northwest National Laboratory, Richland, Washington, USA
  • Ralph S. Baric
    • Other Affiliation: Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA ; Microbiology and Immunology University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
Abstract
  • The severe acute respiratory syndrome coronavirus accessory protein ORF6 antagonizes interferon signaling by blocking karyopherin-mediated nuclear import processes. Viral nuclear import antagonists, expressed by several highly pathogenic RNA viruses, likely mediate pleiotropic effects on host gene expression, presumably interfering with transcription factors, cytokines, hormones, and/or signaling cascades that occur in response to infection. By bioinformatic and systems biology approaches, we evaluated the impact of nuclear import antagonism on host expression networks by using human lung epithelial cells infected with either wild-type virus or a mutant that does not express ORF6 protein. Microarray analysis revealed significant changes in differential gene expression, with approximately twice as many upregulated genes in the mutant virus samples by 48 h postinfection, despite identical viral titers. Our data demonstrated that ORF6 protein expression attenuates the activity of numerous karyopherin-dependent host transcription factors (VDR, CREB1, SMAD4, p53, EpasI, and Oct3/4) that are critical for establishing antiviral responses and regulating key host responses during virus infection. Results were confirmed by proteomic and chromatin immunoprecipitation assay analyses and in parallel microarray studies using infected primary human airway epithelial cell cultures. The data strongly support the hypothesis that viral antagonists of nuclear import actively manipulate host responses in specific hierarchical patterns, contributing to the viral pathogenic potential in vivo. Importantly, these studies and modeling approaches not only provide templates for evaluating virus antagonism of nuclear import processes but also can reveal candidate cellular genes and pathways that may significantly influence disease outcomes following severe acute respiratory syndrome coronavirus infection in vivo.
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  • Article
Rights statement
  • In Copyright
Journal title
  • Journal of Virology
Journal volume
  • 87
Journal issue
  • 7
Page start
  • 3885
Page end
  • 3902
Language
  • English
ISSN
  • 0022-538X
  • 1098-5514
  • 1070-6321
Publisher
  • American Society for Microbiology

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