MERS-CoV Accessory ORFs Play Key Role for Infection and Pathogenesis
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...
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American Society for Microbiology
2017
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oai:doaj.org-article:438eeeef29a24edba2f4d738b85fb4c02021-11-15T15:51:44ZMERS-CoV Accessory ORFs Play Key Role for Infection and Pathogenesis10.1128/mBio.00665-172150-7511https://doaj.org/article/438eeeef29a24edba2f4d738b85fb4c02017-09-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00665-17https://doaj.org/toc/2150-7511ABSTRACT 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.Vineet D. MenacheryHugh D. MitchellAdam S. CockrellLisa E. GralinskiBoyd L. YountRachel L. GrahamEileen T. McAnarneyMadeline G. DouglasTrevor ScobeyAnne BeallKenneth DinnonJacob F. KocherAndrew E. HaleKelly G. StrattonKatrina M. WatersRalph S. BaricAmerican Society for MicrobiologyarticlecoronavirusMERS-CoVSARS-CoVlive vector vaccinesreverse geneticsMicrobiologyQR1-502ENmBio, Vol 8, Iss 4 (2017) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
coronavirus MERS-CoV SARS-CoV live vector vaccines reverse genetics Microbiology QR1-502 |
| spellingShingle |
coronavirus MERS-CoV SARS-CoV live vector vaccines reverse genetics Microbiology QR1-502 Vineet D. 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 MERS-CoV Accessory ORFs Play Key Role for Infection and Pathogenesis |
| description |
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. |
| format |
article |
| author |
Vineet D. 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 |
| author_facet |
Vineet D. 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 |
| author_sort |
Vineet D. Menachery |
| title |
MERS-CoV Accessory ORFs Play Key Role for Infection and Pathogenesis |
| title_short |
MERS-CoV Accessory ORFs Play Key Role for Infection and Pathogenesis |
| title_full |
MERS-CoV Accessory ORFs Play Key Role for Infection and Pathogenesis |
| title_fullStr |
MERS-CoV Accessory ORFs Play Key Role for Infection and Pathogenesis |
| title_full_unstemmed |
MERS-CoV Accessory ORFs Play Key Role for Infection and Pathogenesis |
| title_sort |
mers-cov accessory orfs play key role for infection and pathogenesis |
| publisher |
American Society for Microbiology |
| publishDate |
2017 |
| url |
https://doaj.org/article/438eeeef29a24edba2f4d738b85fb4c0 |
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