MERS-CoV accessory orfs play key role for infection and pathogenesis

Vineet Menachery, Hugh D. Mitchell, Adam S. Cockrell, Lisa E. Gralinski, Boyd L. Yount, Rachel L. Graham, Eileen T. McAnarney, Madeline G. Douglas, Trevor Scobey, Anne Beall, Kenneth Dinnon, Jacob F. Kocher, Andrew E. Hale, Kelly G. Stratton, Katrina M. Waters, Ralph S. Baric

Research output: Contribution to journalArticle

24 Citations (Scopus)

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-κBmediated 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.

Original languageEnglish (US)
Article numbere00665-17
JournalmBio
Volume8
Issue number4
DOIs
StatePublished - Jul 1 2017

Fingerprint

Contagious Ecthyma
Coronavirus Infections
Open Reading Frames
Infection
Coronavirus
Inflammation
Attenuated Vaccines
Zoonoses
Interferons
Disease Outbreaks
Vaccines
Public Health
Viruses
Therapeutics

Keywords

  • Coronavirus
  • Live vector vaccines
  • MERS-CoV
  • Reverse genetics
  • SARS-CoV

ASJC Scopus subject areas

  • Microbiology
  • Virology

Cite this

Menachery, V., Mitchell, H. D., Cockrell, A. S., Gralinski, L. E., Yount, B. L., Graham, R. L., ... Baric, R. S. (2017). MERS-CoV accessory orfs play key role for infection and pathogenesis. mBio, 8(4), [e00665-17]. https://doi.org/10.1128/mBio.00665-17

MERS-CoV accessory orfs play key role for infection and pathogenesis. / Menachery, Vineet; Mitchell, Hugh D.; Cockrell, Adam S.; Gralinski, Lisa E.; Yount, Boyd L.; Graham, Rachel L.; McAnarney, Eileen T.; Douglas, Madeline G.; Scobey, Trevor; Beall, Anne; Dinnon, Kenneth; Kocher, Jacob F.; Hale, Andrew E.; Stratton, Kelly G.; Waters, Katrina M.; Baric, Ralph S.

In: mBio, Vol. 8, No. 4, e00665-17, 01.07.2017.

Research output: Contribution to journalArticle

Menachery, V, Mitchell, HD, Cockrell, AS, Gralinski, LE, Yount, BL, Graham, RL, McAnarney, ET, Douglas, MG, Scobey, T, Beall, A, Dinnon, K, Kocher, JF, Hale, AE, Stratton, KG, Waters, KM & Baric, RS 2017, 'MERS-CoV accessory orfs play key role for infection and pathogenesis', mBio, vol. 8, no. 4, e00665-17. https://doi.org/10.1128/mBio.00665-17
Menachery V, Mitchell HD, Cockrell AS, Gralinski LE, Yount BL, Graham RL et al. MERS-CoV accessory orfs play key role for infection and pathogenesis. mBio. 2017 Jul 1;8(4). e00665-17. https://doi.org/10.1128/mBio.00665-17
Menachery, Vineet ; Mitchell, Hugh D. ; Cockrell, Adam S. ; Gralinski, Lisa E. ; Yount, Boyd L. ; Graham, Rachel L. ; McAnarney, Eileen T. ; Douglas, Madeline G. ; Scobey, Trevor ; Beall, Anne ; Dinnon, Kenneth ; Kocher, Jacob F. ; Hale, Andrew E. ; Stratton, Kelly G. ; Waters, Katrina M. ; Baric, Ralph S. / MERS-CoV accessory orfs play key role for infection and pathogenesis. In: mBio. 2017 ; Vol. 8, No. 4.
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