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Research Article

The Conserved Coronavirus Macrodomain Promotes Virulence and Suppresses the Innate Immune Response during Severe Acute Respiratory Syndrome Coronavirus Infection

Anthony R. Fehr, Rudragouda Channappanavar, Gytis Jankevicius, Craig Fett, Jincun Zhao, Jeremiah Athmer, David K. Meyerholz, Ivan Ahel, Stanley Perlman
Mark R. Denison, Editor
Anthony R. Fehr
aDepartment of Microbiology, University of Iowa, Iowa City, Iowa, USA
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Rudragouda Channappanavar
aDepartment of Microbiology, University of Iowa, Iowa City, Iowa, USA
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Gytis Jankevicius
cSir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom
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Craig Fett
aDepartment of Microbiology, University of Iowa, Iowa City, Iowa, USA
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Jincun Zhao
aDepartment of Microbiology, University of Iowa, Iowa City, Iowa, USA
dState Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Yuexiu District, Guangzhou, Guangdong, China
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Jeremiah Athmer
aDepartment of Microbiology, University of Iowa, Iowa City, Iowa, USA
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David K. Meyerholz
bDepartment of Pathology, University of Iowa, Iowa City, Iowa, USA
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Ivan Ahel
cSir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom
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Stanley Perlman
aDepartment of Microbiology, University of Iowa, Iowa City, Iowa, USA
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Mark R. Denison
Vanderbilt University Medical Center
Roles: Editor
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DOI: 10.1128/mBio.01721-16
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ABSTRACT

ADP-ribosylation is a common posttranslational modification that may have antiviral properties and impact innate immunity. To regulate this activity, macrodomain proteins enzymatically remove covalently attached ADP-ribose from protein targets. All members of the Coronavirinae, a subfamily of positive-sense RNA viruses, contain a highly conserved macrodomain within nonstructural protein 3 (nsp3). However, its function or targets during infection remain unknown. We identified several macrodomain mutations that greatly reduced nsp3’s de-ADP-ribosylation activity in vitro. Next, we created recombinant severe acute respiratory syndrome coronavirus (SARS-CoV) strains with these mutations. These mutations led to virus attenuation and a modest reduction of viral loads in infected mice, despite normal replication in cell culture. Further, macrodomain mutant virus elicited an early, enhanced interferon (IFN), interferon-stimulated gene (ISG), and proinflammatory cytokine response in mice and in a human bronchial epithelial cell line. Using a coinfection assay, we found that inclusion of mutant virus in the inoculum protected mice from an otherwise lethal SARS-CoV infection without reducing virus loads, indicating that the changes in innate immune response were physiologically significant. In conclusion, we have established a novel function for the SARS-CoV macrodomain that implicates ADP-ribose in the regulation of the innate immune response and helps to demonstrate why this domain is conserved in CoVs.

IMPORTANCE The macrodomain is a ubiquitous structural domain that removes ADP-ribose from proteins, reversing the activity of ADP-ribosyltransferases. All coronaviruses contain a macrodomain, suggesting that ADP-ribosylation impacts coronavirus infection. However, its function during infection remains unknown. Here, we found that the macrodomain is an important virulence factor for a highly pathogenic human CoV, SARS-CoV. Viruses with macrodomain mutations that abrogate its ability to remove ADP-ribose from protein were unable to cause lethal disease in mice. Importantly, the SARS-CoV macrodomain suppressed the innate immune response during infection. Our data suggest that an early innate immune response can protect mice from lethal disease. Understanding the mechanism used by this enzyme to promote disease will open up novel avenues for coronavirus therapies and give further insight into the role of macrodomains in viral pathogenesis.

  • Copyright © 2016 Fehr et al.

This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

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The Conserved Coronavirus Macrodomain Promotes Virulence and Suppresses the Innate Immune Response during Severe Acute Respiratory Syndrome Coronavirus Infection
Anthony R. Fehr, Rudragouda Channappanavar, Gytis Jankevicius, Craig Fett, Jincun Zhao, Jeremiah Athmer, David K. Meyerholz, Ivan Ahel, Stanley Perlman
mBio Dec 2016, 7 (6) e01721-16; DOI: 10.1128/mBio.01721-16

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The Conserved Coronavirus Macrodomain Promotes Virulence and Suppresses the Innate Immune Response during Severe Acute Respiratory Syndrome Coronavirus Infection
Anthony R. Fehr, Rudragouda Channappanavar, Gytis Jankevicius, Craig Fett, Jincun Zhao, Jeremiah Athmer, David K. Meyerholz, Ivan Ahel, Stanley Perlman
mBio Dec 2016, 7 (6) e01721-16; DOI: 10.1128/mBio.01721-16
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