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dc: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." ;
dc:creator "['Fehr, Anthony R.', 'Channappanavar, Rudragouda', 'Jankevicius, Gytis', 'Fett, Craig', 'Zhao, Jincun', 'Athmer, Jeremiah', 'Meyerholz, David K.', 'Ahel, Ivan', 'Perlman, Stanley']" ;
dc:identifier ,
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dc:issued "2016-01-01"^^xsd:date ;
dc:license "CC BY" ;
dc:title "The Conserved Coronavirus Macrodomain Promotes Virulence and Suppresses the Innate Immune Response during Severe Acute Respiratory Syndrome Coronavirus Infection" ;
sso:has_full_text "False" ;
sso:journal "mBio" ;
sso:sha "494420ff931d8a803437b8830be805b57db29969" ;
sso:source_x "PMC" .