MERS-CoV Accessory ORFs Play Key Role for Infection and Pathogenesis

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  • Menachery, Vineet D.
    • Affiliation: Gillings School of Global Public Health, Department of Epidemiology
    • Other Affiliation: Department of Microbiology and Immunology; University of Texas Medical Branch
  • Mitchell, Hugh D.
    • Other Affiliation: Pacific Northwest National Laboratory
  • Cockrell, Adam S.
    • Affiliation: Gillings School of Global Public Health, Department of Epidemiology
  • Gralinski, Lisa E.
    • Affiliation: Gillings School of Global Public Health, Department of Epidemiology
  • Yount, Boyd L.
    • Affiliation: Gillings School of Global Public Health, Department of Epidemiology
  • Graham, Rachel L.
    • Affiliation: Gillings School of Global Public Health, Department of Epidemiology
  • McAnarney, Eileen T.
    • Affiliation: Gillings School of Global Public Health, Department of Epidemiology
  • Douglas, Madeline G.
    • Affiliation: Gillings School of Global Public Health, Department of Epidemiology
  • Scobey, Trevor
    • Affiliation: Gillings School of Global Public Health, Department of Epidemiology
  • Beall, Anne
    • Affiliation: School of Medicine, Department of Microbiology and Immunology
  • Dinnon, Kenneth
    • Affiliation: School of Medicine, Department of Microbiology and Immunology
  • Kocher, Jacob F.
    • Affiliation: Gillings School of Global Public Health, Department of Epidemiology
  • Hale, Andrew E.
    • Affiliation: School of Medicine, Department of Microbiology and Immunology
  • Stratton, Kelly G.
    • Other Affiliation: Pacific Northwest National Laboratory
  • Waters, Katrina M.
    • Other Affiliation: Pacific Northwest National Laboratory
  • Baric, Ralph S.
    • Affiliation: Gillings School of Global Public Health, Department of Epidemiology
    • Other Affiliation: Department of Microbiology and Immunology
Abstract
  • ABSTRACT While dispensable for viral replication, coronavirus (CoV) accessory open reading frame (ORF) proteins often play critical roles during infection and pathogenesis. Utilizing a previously generated mutant, we demonstrate that the absence of all four Middle East respiratory syndrome CoV (MERS-CoV) accessory ORFs (deletion of ORF3, -4a, -4b, and -5 [dORF3-5]) has major implications for viral replication and pathogenesis. Importantly, attenuation of the dORF3-5 mutant is primarily driven by dysregulated host responses, including disrupted cell processes, augmented interferon (IFN) pathway activation, and robust inflammation. In vitro replication attenuation also extends to in vivo models, allowing use of dORF3-5 as a live attenuated vaccine platform. Finally, examination of ORF5 implicates a partial role in modulation of NF-κB-mediated inflammation. Together, the results demonstrate the importance of MERS-CoV accessory ORFs for pathogenesis and highlight them as potential targets for surveillance and therapeutic treatments moving forward. IMPORTANCE The initial emergence and periodic outbreaks of MERS-CoV highlight a continuing threat posed by zoonotic pathogens to global public health. In these studies, mutant virus generation demonstrates the necessity of accessory ORFs in regard to MERS-CoV infection and pathogenesis. With this in mind, accessory ORF functions can be targeted for both therapeutic and vaccine treatments in response to MERS-CoV and related group 2C coronaviruses. In addition, disruption of accessory ORFs in parallel may offer a rapid response platform to attenuation of future emergent strains based on both SARS- and MERS-CoV accessory ORF mutants.
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  • Article
Rights statement
  • In Copyright
Journal title
  • MBio
Journal volume
  • 8
Journal issue
  • 4
Page start
  • e00665-17
Language
  • English
ISSN
  • 2150-7511
  • 2161-2129

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