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Title: 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-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 toin vivomodels, 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. Here, 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 andmore » 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.« less

Authors:
 [1];  [2];  [3];  [3];  [3];  [3];  [3];  [3];  [3];  [3];  [3];  [3];  [3];  [2];  [2];  [3];  [4]
  1. Univ. of Texas Medical Branch, Galveston, TX (United States); Univ. of North Carolina, Chapel Hill, NC (United States)
  2. Pacific Northwest National Lab. (PNNL), Richland, WA (United States)
  3. Univ. of North Carolina, Chapel Hill, NC (United States)
  4. Columbia Univ., New York, NY (United States)
Publication Date:
Research Org.:
Pacific Northwest National Lab. (PNNL), Richland, WA (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1406731
Report Number(s):
PNNL-SA-126255
Journal ID: ISSN 2150-7511; WN9030198
Grant/Contract Number:  
AC05-76RL01830
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
mBio (Online)
Additional Journal Information:
Journal Name: mBio (Online); Journal Volume: 8; Journal Issue: 4; Journal ID: ISSN 2150-7511
Publisher:
American Society for Microbiology
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; pathogenesis; vaccine; coronavirus; MERS-CoV; SARS-CoV; live vector vaccines; reverse genetics

Citation Formats

Menachery, Vineet D., Mitchell, Hugh D., Cockrell, Adam S., Gralinski, Lisa E., Yount, Jr., Boyd L., Graham, Rachel L., McAnarney, Eileen T., Douglas, Madeline G., Scobey, Trevor, Beall, Anne, Dinnon, III, Kenneth, Kocher, Jacob F., Hale, Andrew E., Stratton, Kelly G., Waters, Katrina M., Baric, Ralph S., and Racaniello, Vincent R. MERS-CoV Accessory ORFs Play Key Role for Infection and Pathogenesis. United States: N. p., 2017. Web. doi:10.1128/mBio.00665-17.
Menachery, Vineet D., Mitchell, Hugh D., Cockrell, Adam S., Gralinski, Lisa E., Yount, Jr., Boyd L., Graham, Rachel L., McAnarney, Eileen T., Douglas, Madeline G., Scobey, Trevor, Beall, Anne, Dinnon, III, Kenneth, Kocher, Jacob F., Hale, Andrew E., Stratton, Kelly G., Waters, Katrina M., Baric, Ralph S., & Racaniello, Vincent R. MERS-CoV Accessory ORFs Play Key Role for Infection and Pathogenesis. United States. doi:10.1128/mBio.00665-17.
Menachery, Vineet D., Mitchell, Hugh D., Cockrell, Adam S., Gralinski, Lisa E., Yount, Jr., Boyd L., Graham, Rachel L., McAnarney, Eileen T., Douglas, Madeline G., Scobey, Trevor, Beall, Anne, Dinnon, III, Kenneth, Kocher, Jacob F., Hale, Andrew E., Stratton, Kelly G., Waters, Katrina M., Baric, Ralph S., and Racaniello, Vincent R. Tue . "MERS-CoV Accessory ORFs Play Key Role for Infection and Pathogenesis". United States. doi:10.1128/mBio.00665-17. https://www.osti.gov/servlets/purl/1406731.
@article{osti_1406731,
title = {MERS-CoV Accessory ORFs Play Key Role for Infection and Pathogenesis},
author = {Menachery, Vineet D. and Mitchell, Hugh D. and Cockrell, Adam S. and Gralinski, Lisa E. and Yount, Jr., Boyd L. and Graham, Rachel L. and McAnarney, Eileen T. and Douglas, Madeline G. and Scobey, Trevor and Beall, Anne and Dinnon, III, Kenneth and Kocher, Jacob F. and Hale, Andrew E. and Stratton, Kelly G. and Waters, Katrina M. and Baric, Ralph S. and Racaniello, Vincent R.},
abstractNote = {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 toin vivomodels, 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. Here, 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.},
doi = {10.1128/mBio.00665-17},
journal = {mBio (Online)},
number = 4,
volume = 8,
place = {United States},
year = {Tue Aug 22 00:00:00 EDT 2017},
month = {Tue Aug 22 00:00:00 EDT 2017}
}

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