SARS-CoV-2 Mac1 is required for IFN antagonism and efficient virus replication in cell culture and in mice
This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas. 2302083120/-/DCSupplemental.
| Autores: | , , , , , , , , , , , , , , , |
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| Tipo de recurso: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2023 |
| País: | España |
| Institución: | Consejo Superior de Investigaciones Científicas (CSIC) |
| Repositorio: | DIGITAL.CSIC. Repositorio Institucional del CSIC |
| OAI Identifier: | oai:digital.csic.es:10261/363879 |
| Acceso en línea: | http://hdl.handle.net/10261/363879 https://api.elsevier.com/content/abstract/scopus_id/85168781208 |
| Access Level: | acceso abierto |
| Palabra clave: | ADP-ribosylation SARS-CoV-2 coronavirus interferon macrodomain |
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SARS-CoV-2 Mac1 is required for IFN antagonism and efficient virus replication in cell culture and in mice |
| title |
SARS-CoV-2 Mac1 is required for IFN antagonism and efficient virus replication in cell culture and in mice |
| spellingShingle |
SARS-CoV-2 Mac1 is required for IFN antagonism and efficient virus replication in cell culture and in mice Alhammad, Yousef M. ADP-ribosylation SARS-CoV-2 coronavirus interferon macrodomain |
| title_short |
SARS-CoV-2 Mac1 is required for IFN antagonism and efficient virus replication in cell culture and in mice |
| title_full |
SARS-CoV-2 Mac1 is required for IFN antagonism and efficient virus replication in cell culture and in mice |
| title_fullStr |
SARS-CoV-2 Mac1 is required for IFN antagonism and efficient virus replication in cell culture and in mice |
| title_full_unstemmed |
SARS-CoV-2 Mac1 is required for IFN antagonism and efficient virus replication in cell culture and in mice |
| title_sort |
SARS-CoV-2 Mac1 is required for IFN antagonism and efficient virus replication in cell culture and in mice |
| dc.creator.none.fl_str_mv |
Alhammad, Yousef M. Parthasarathy, Srivatsan Ghimire, Roshan Kerr, Catherine M. O'Connor, Joseph J. Pfannenstiel, Jessica J. Chanda, Debarati Miller, Caden A. Baumlin, Nathalie Salathe, Matthias Unckless, Robert L. Zúñiga Lucas, Sonia Enjuanes Sánchez, Luis More, Sunil Channappanavar, Rudragouda Fehr, Anthony R. |
| author |
Alhammad, Yousef M. |
| author_facet |
Alhammad, Yousef M. Parthasarathy, Srivatsan Ghimire, Roshan Kerr, Catherine M. O'Connor, Joseph J. Pfannenstiel, Jessica J. Chanda, Debarati Miller, Caden A. Baumlin, Nathalie Salathe, Matthias Unckless, Robert L. Zúñiga Lucas, Sonia Enjuanes Sánchez, Luis More, Sunil Channappanavar, Rudragouda Fehr, Anthony R. |
| author_role |
author |
| author2 |
Parthasarathy, Srivatsan Ghimire, Roshan Kerr, Catherine M. O'Connor, Joseph J. Pfannenstiel, Jessica J. Chanda, Debarati Miller, Caden A. Baumlin, Nathalie Salathe, Matthias Unckless, Robert L. Zúñiga Lucas, Sonia Enjuanes Sánchez, Luis More, Sunil Channappanavar, Rudragouda Fehr, Anthony R. |
| author2_role |
author author author author author author author author author author author author author author author |
| dc.contributor.none.fl_str_mv |
Ministerio de Ciencia e Innovación (España) European Commission Zuñiga, Sonia [0000-0003-2549-6826] Enjuanes, Luis [0000-0002-0854-0226] Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72] |
| dc.subject.none.fl_str_mv |
ADP-ribosylation SARS-CoV-2 coronavirus interferon macrodomain |
| topic |
ADP-ribosylation SARS-CoV-2 coronavirus interferon macrodomain |
| description |
This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas. 2302083120/-/DCSupplemental. |
| publishDate |
2023 |
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2023 2024 2024 |
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info:eu-repo/semantics/article http://purl.org/coar/resource_type/c_6501 Publisher's version info:eu-repo/semantics/publishedVersion |
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article |
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publishedVersion |
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http://hdl.handle.net/10261/363879 https://api.elsevier.com/content/abstract/scopus_id/85168781208 |
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http://hdl.handle.net/10261/363879 https://api.elsevier.com/content/abstract/scopus_id/85168781208 |
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Inglés |
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Inglés |
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#PLACEHOLDER_PARENT_METADATA_VALUE# info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2019-107001RB-I00 Proceedings of the National Academy of Sciences of the United States of America application/pdf https://www.pnas.org/doi/10.1073/pnas.2302083120 Sí |
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info:eu-repo/semantics/openAccess |
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openAccess |
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National Academy of Sciences (U.S.) |
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National Academy of Sciences (U.S.) |
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reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC instname:Consejo Superior de Investigaciones Científicas (CSIC) |
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DIGITAL.CSIC. Repositorio Institucional del CSIC |
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SARS-CoV-2 Mac1 is required for IFN antagonism and efficient virus replication in cell culture and in miceAlhammad, Yousef M.Parthasarathy, SrivatsanGhimire, RoshanKerr, Catherine M.O'Connor, Joseph J.Pfannenstiel, Jessica J.Chanda, DebaratiMiller, Caden A.Baumlin, NathalieSalathe, MatthiasUnckless, Robert L.Zúñiga Lucas, SoniaEnjuanes Sánchez, LuisMore, SunilChannappanavar, RudragoudaFehr, Anthony R.ADP-ribosylationSARS-CoV-2coronavirusinterferonmacrodomainThis article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas. 2302083120/-/DCSupplemental.Several coronavirus (CoV) encoded proteins are being evaluated as targets for antiviral therapies for COVID-19. Included in these drug targets is the conserved macrodomain, or Mac1, an ADP-ribosylhydrolase and ADP-ribose binding protein encoded as a small domain at the N terminus of nonstructural protein 3. Utilizing point mutant recombinant viruses, Mac1 was shown to be critical for both murine hepatitis virus (MHV) and severe acute respiratory syndrome (SARS)-CoV virulence. However, as a potential drug target, it is imperative to understand how a complete Mac1 deletion impacts the replication and pathogenesis of different CoVs. To this end, we created recombinant bacterial artificial chromosomes (BACs) containing complete Mac1 deletions (ΔMac1) in MHV, MERS-CoV, and SARS-CoV-2. While we were unable to recover infectious virus from MHV or MERS-CoV ΔMac1 BACs, SARS-CoV-2 ΔMac1 was readily recovered from BAC transfection, indicating a stark difference in the requirement for Mac1 between different CoVs. Furthermore, SARS-CoV-2 ΔMac1 replicated at or near wild-type levels in multiple cell lines susceptible to infection. However, in a mouse model of severe infection, ΔMac1 was quickly cleared causing minimal pathology without any morbidity. ΔMac1 SARS-CoV-2 induced increased levels of interferon (IFN) and IFN-stimulated gene expression in cell culture and mice, indicating that Mac1 blocks IFN responses which may contribute to its attenuation. ΔMac1 infection also led to a stark reduction in inflammatory monocytes and neutrophils. These results demonstrate that Mac1 only minimally impacts SARS-CoV-2 replication, unlike MHV and MERS-CoV, but is required for SARS-CoV-2 pathogenesis and is a unique antiviral drug target.Research reported in this publication was made possible in part by the services of the KU Genome Sequencing Core which is supported by the NIH under award number P30GM145499. We thank the Life Alliance Organ Recovery Agency from the University of Miami, Miami, FL, LifeCenter Northwest from Bellevue, Washington, Nevada Donor Network from Las Vegas, NV, and Midwest Transplant Network from Kansas City, KS, for provid- ing the lungs. NIH grant P20GM103648 (R.C.) NIH grant 2P01AI060699 (L.E.) NIH grant P20GM113117 (A.R.F.) NIH grant K22AI134993 (A.R.F.) NIH grant R35GM138029 (A.R.F.) NIH grant R01HL139365 (M.S.) NIH grant R01HL133240 (M.S.) NIH grant R01HL157942 (M.S.) Cystic Fibrosis Foundation grant SALATH18I0 (M.S.) NSF grant 2135167 (R.L.U.) University of Kansas General Research Fund and Start-up funds (A.R.F.) NIH Graduate Training at the Biology- Chemistry Interface grant T32GM132061 (C.M.K.) University of Kansas College of Liberal Arts and Sciences Graduate Research Fellowship (C.M.K.) Government of Spain (PID2019-107001RB-I00 AEI/FEDER, UE) (L.E.) European Commission (H2020-SC1-2019, ISOLDA Project no. 848166-2) (L.E.).Peer reviewedNational Academy of Sciences (U.S.)Ministerio de Ciencia e Innovación (España)European CommissionZuñiga, Sonia [0000-0003-2549-6826]Enjuanes, Luis [0000-0002-0854-0226]Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202420242023info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/363879https://api.elsevier.com/content/abstract/scopus_id/85168781208reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2019-107001RB-I00Proceedings of the National Academy of Sciences of the United States of Americaapplication/pdfhttps://www.pnas.org/doi/10.1073/pnas.2302083120Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/3638792026-05-22T06:33:51Z |
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