Probable #Pangolin Origin of #SARS-CoV-2 Associated With the #COVID19 #Outbreak (Curr Biol., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Curr Biol 2020 Mar 13 [Online ahead of print]

Probable Pangolin Origin of SARS-CoV-2 Associated With the COVID-19 Outbreak

Tao Zhang 1, Qunfu Wu 1, Zhigang Zhang 2

Affiliations: 1 State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, School of Life Sciences, Yunnan University, No. 2 North Cuihu Road, Kunming, Yunnan 650091, China. 2 State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, School of Life Sciences, Yunnan University, No. 2 North Cuihu Road, Kunming, Yunnan 650091, China. Electronic address: zhangzhigang@ynu.edu.cn.

PMID: 32197085 DOI: 10.1016/j.cub.2020.03.022

 

Abstract

An outbreak of coronavirus disease 2019 (COVID-19) caused by the 2019 novel coronavirus (SARS-CoV-2) began in the city of Wuhan in China and has widely spread worldwide. Currently, it is vital to explore potential intermediate hosts of SARS-CoV-2 to control COVID-19 spread. Therefore, we reinvestigated published data from pangolin lung samples from which SARS-CoV-like CoVs were detected by Liu et al. [1]. We found genomic and evolutionary evidence of the occurrence of a SARS-CoV-2-like CoV (named Pangolin-CoV) in dead Malayan pangolins. Pangolin-CoV is 91.02% and 90.55% identical to SARS-CoV-2 and BatCoV RaTG13, respectively, at the whole-genome level. Aside from RaTG13, Pangolin-CoV is the most closely related CoV to SARS-CoV-2. The S1 protein of Pangolin-CoV is much more closely related to SARS-CoV-2 than to RaTG13. Five key amino acid residues involved in the interaction with human ACE2 are completely consistent between Pangolin-CoV and SARS-CoV-2, but four amino acid mutations are present in RaTG13. Both Pangolin-CoV and RaTG13 lost the putative furin recognition sequence motif at S1/S2 cleavage site that can be observed in the SARS-CoV-2. Conclusively, this study suggests that pangolin species are a natural reservoir of SARS-CoV-2-like CoVs.

Keywords: COVID-19; SARS-CoV-2; origin; pangolin.

Copyright © 2020 Elsevier Inc. All rights reserved.

Conflict of interest statement – Declaration of Interests: The authors declare no competing interests.

Keywords: SARS-CoV-2; COVID-19; Coronavirus; Pangolins.

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#Coronavirus #endoribonuclease targets viral polyuridine sequences to evade activating #host sensors (Proc Natl Acad Sci USA, abstract)

[Source: Proceedings of the National Academy of Sciences of the United States of America, full page: (LINK). Abstract, edited.]

Coronavirus endoribonuclease targets viral polyuridine sequences to evade activating host sensors

Matthew Hackbart, Xufang Deng, and Susan C. Baker

PNAS first published March 20, 2020 | DOI: https://doi.org/10.1073/pnas.1921485117

Edited by Stanley Perlman, University of Iowa, Iowa City, IA, and accepted by Editorial Board Member Linda J. Saif March 5, 2020 (received for review December 9, 2019)

 

Significance

Cells carry sensors that are primed to detect invading viruses. To avoid being recognized, coronaviruses express factors that interfere with host immune sensing pathways. Previous studies revealed that a coronavirus endoribonuclease (EndoU) delays activation of the host sensor system, but the mechanism was not known. Here, we report that EndoU cleaves a viral polyuridine sequence that would otherwise activate host immune sensors. This information may be used in developing inhibitors that target EndoU activity and prevent diseases caused by coronaviruses.

Abstract

Coronaviruses (CoVs) are positive-sense RNA viruses that can emerge from endemic reservoirs and infect zoonotically, causing significant morbidity and mortality. CoVs encode an endoribonuclease designated EndoU that facilitates evasion of host pattern recognition receptor MDA5, but the target of EndoU activity was not known. Here, we report that EndoU cleaves the 5′-polyuridines from negative-sense viral RNA, termed PUN RNA, which is the product of polyA-templated RNA synthesis. Using a virus containing an EndoU catalytic-inactive mutation, we detected a higher abundance of PUN RNA in the cytoplasm compared to wild-type−infected cells. Furthermore, we found that transfecting PUN RNA into cells stimulates a robust, MDA5-dependent interferon response, and that removal of the polyuridine extension on the RNA dampens the response. Overall, the results of this study reveal the PUN RNA to be a CoV MDA5-dependent pathogen-associated molecular pattern (PAMP). We also establish a mechanism for EndoU activity to cleave and limit the accumulation of this PAMP. Since EndoU activity is highly conserved in all CoVs, inhibiting this activity may serve as an approach for therapeutic interventions against existing and emerging CoV infections.

coronavirus – endoribonuclease – EndoU – nsp15 – interferon

 

Footnotes

1 To whom correspondence may be addressed. Email: sbaker1@luc.edu.

Author contributions: M.H., X.D., and S.C.B. designed research; M.H. performed research; M.H., X.D., and S.C.B. contributed new reagents/analytic tools; M.H. analyzed data; M.H. and S.C.B. wrote the paper; and X.D. edited the paper.

The authors declare no competing interest.

This article is a PNAS Direct Submission. S.P. is a guest editor invited by the Editorial Board.

Data deposition: The RNA sequencing data reported in this paper have been deposited in the National Center for Biotechnology Information Gene Expression Omnibus (GEO) database, https://www.ncbi.nlm.nih.gov/geo (accession no. GSE144886).

This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.1921485117/-/DCSupplemental.

Keywords: Coronavirus; Viral pathogenesis.

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#Evolution of the novel #coronavirus from the ongoing #Wuhan #outbreak and modeling of its #spike protein for #risk of #human #transmission (Sci China Life Sci., summary)

[Source: Science China Life Sciences, full page: (LINK). Summary, edited.]

Evolution of the novel coronavirus from the ongoing Wuhan outbreak and modeling of its spike protein for risk of human transmission

Xintian Xu1†, Ping Chen2,5†, Jingfang Wang3†, Jiannan Feng4, Hui Zhou2, Xuan Li2*, Wu Zhong4* & Pei Hao1,5*

1 Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Shanghai 200031, China; 2 Key Laboratory of Synthetic Biology, CAS Center for Excellence in Molecular Plant Sciences, Chinese Academy of Sciences, Shanghai 200032, China; 3 Key Laboratory of Systems Biomedicine, Ministry of Education, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai 200240, China; 4 National Engineering Research Center for the Emergence Drugs, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China; 5 The Joint Program in Infection and Immunity: a. Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou 510623, China; b. Institute Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China

Received January 16, 2020; accepted January 20, 2020; published online January 21, 2020

Citation: Xu, X., Chen, P., Wang, J., Feng, J., Zhou, H., Li, X., Zhong, W., and Hao, P. (2020).  Evolution of the novel coronavirus from the ongoing Wuhan outbreak and modeling of its spike protein for risk of human transmission. Sci China Life Sci 63, 457–460. https://doi.org/10.1007/s11427-020-1637-5

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Dear Editor, The occurrence of concentrated pneumonia cases in Wuhan city, Hubei province of China was first reported on December 30, 2019 by the Wuhan Municipal Health Commission (WHO, 2020). The pneumonia cases were found to be linked to a large seafood and animal market in Wuhan, and measures for sanitation and disinfection were taken swiftly by the local government agency. The Centers for Disease
Control and Prevention (CDC) and Chinese health authorities later determined and announced that a novel coronavirus (CoV), denoted as Wuhan CoV, had caused the pneumonia outbreak in Wuhan city (CDC, 2020). Scientists from multiple groups had obtained the virus samples from hospitalized patients (Normile, 2020). The isolated viruses were morphologically identical when observed under electron microscopy.

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Keywords: SARS-CoV-2; COVID-19; Coronavirus; Sarbecovirus.

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#Coronavirus Endoribonuclease and Deubiquitinating #Interferon #Antagonists Differentially Modulate the Host Response during #Replication in #Macrophages (J Virol., abstract)

[Source: Journal of Virology, full page: (LINK). Abstract, edited.]

Coronavirus Endoribonuclease and Deubiquitinating Interferon Antagonists Differentially Modulate the Host Response during Replication in Macrophages

Aaron Volk, Matthew Hackbart, Xufang Deng, Yazmin Cruz-Pulido, Amornrat O’Brien, Susan C. Baker

DOI: 10.1128/JVI.00178-20

 

ABSTRACT

Coronaviruses encode multiple interferon antagonists that modulate the host response to virus replication. Here, we evaluated the host transcriptional response to infection with murine coronaviruses encoding independent mutations in one of two different viral antagonists: the deubiquitinase (DUB) within nonstructural protein 3 or the endoribonuclease (EndoU) within nonstructural protein 15. We used transcriptomics approaches to compare the scope and kinetics of the host response to the wild-type, DUBmut, and EndoUmut viruses in infected macrophages. We found that the EndoUmut virus activates a focused response predominantly involving type I interferons and interferon-related genes, whereas the WT and DUBmut viruses more broadly stimulate upregulation of over 2,800 genes, including networks associated with activating the unfolded protein response (UPR), and the proinflammatory response associated with viral pathogenesis. This study highlights the role of viral interferon antagonists in shaping the kinetics and magnitude of the host response during virus infection and demonstrates that inactivating a dominant viral antagonist, the coronavirus endoribonuclease, dramatically alters the host response in macrophages.

 

Importance

Macrophages are an important cell type during coronavirus infections because they “notice” the infection and respond by inducing type I interferons, which limits virus replication. In turn, coronaviruses encode proteins that mitigate the cell’s ability to signal an interferon response. Here, we evaluated the host macrophage response to two independent mutant coronaviruses: one with reduced deubiquitinating activity (DUBmut) and the other containing an inactivated endoribonuclease (EndoUmut). We observed a rapid, robust, and focused response to the EndoUmut virus, which was characterized by enhanced expression of interferon and interferon-related genes. In contrast, wild-type virus and the DUBmut virus elicited a more limited interferon response and ultimately activated over 2,800 genes, including players in the unfolded protein response and pro-inflammatory pathways associated with progression of significant disease. This study reveals that EndoU activity substantially contributes to the ability of coronaviruses to evade the host innate response and to replicate in macrophages.

Copyright © 2020 American Society for Microbiology. All Rights Reserved.

Keywords: Coronavirus; Viral pathogenesis; Interferons.

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#Genome #Composition and Divergence of the Novel #Coronavirus (2019-nCoV) Originating in #China (Cell Host Microbe, abstract)

[Source: Cell Host & Microbe, full page: (LINK). Abstract, edited.]

Genome Composition and Divergence of the Novel Coronavirus (2019-nCoV) Originating in China

Aiping Wu 9, Yousong Peng 9, Baoying Huang 9, Xiao Ding 9, Xianyue Wang, Peihua Niu, Jing Meng, Zhaozhong Zhu, Zheng Zhang, Jiangyuan Wang, Jie Sheng, Lijun Quan, Zanxian Xia, Wenjie Tan, Genhong Cheng, Taijiao Jiang

Published: February 07, 2020 / DOI: https://doi.org/10.1016/j.chom.2020.02.001

 

Summary

An in-depth annotation of the newly discovered coronavirus (2019-nCoV) genome has revealed differences between 2019-nCoV and severe acute respiratory syndrome (SARS) or SARS-like coronaviruses. A systematic comparison identified 380 amino acid substitutions between these coronaviruses, which may have caused functional and pathogenic divergence of 2019-nCoV.

Keywords: Coronavirus; SARS; SARS-CoV-2; COVID-19.

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The species Severe acute respiratory syndrome-related #coronavirus: classifying 2019-nCoV and naming it #SARS-CoV-2 (Nat Microbiol., summary)

[Source: Nature Microbiology, full page: (LINK). Summary, edited.]

The species Severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2

Coronaviridae Study Group of the International Committee on Taxonomy of Viruses

Nature Microbiology (2020)

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The present outbreak of a coronavirus-associated acute respiratory disease called coronavirus disease 19 (COVID-19) is the third documented spillover of an animal coronavirus to humans in only two decades that has resulted in a major epidemic. The Coronaviridae Study Group (CSG) of the International Committee on Taxonomy of Viruses, which is responsible for developing the classification of viruses and taxon nomenclature of the family Coronaviridae, has assessed the placement of the human pathogen, tentatively named 2019-nCoV, within the Coronaviridae. Based on phylogeny, taxonomy and established practice, the CSG recognizes this virus as forming a sister clade to the prototype human and bat severe acute respiratory syndrome coronaviruses (SARS-CoVs) of the species Severe acute respiratory syndrome-related coronavirus, and designates it as SARS-CoV-2. In order to facilitate communication, the CSG proposes to use the following naming convention for individual isolates: SARS-CoV-2/host/location/isolate/date. While the full spectrum of clinical manifestations associated with SARS-CoV-2 infections in humans remains to be determined, the independent zoonotic transmission of SARS-CoV and SARS-CoV-2 highlights the need for studying viruses at the species level to complement research focused on individual pathogenic viruses of immediate significance. This will improve our understanding of virus–host interactions in an ever-changing environment and enhance our preparedness for future outbreaks.

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Acknowledgements

Work on DEmARC advancement and coronavirus and nidovirus taxonomies was supported by the EU Horizon 2020 EVAg 653316 project and the LUMC MoBiLe program (to A.E.G.), and on coronavirus and nidovirus taxonomies by a Mercator Fellowship by the Deutsche Forschungsgemeinschaft (to A.E.G.) in the context of the SFB1021 (A01 to J.Z.).

We thank all researchers who released SARS-CoV-2 genome sequences through the GISAID initiative and particularly the authors of the GenBank MN908947 genome sequence: F. Wu, S. Zhao, B. Yu, Y. M. Chen, W. Wang, Z. G. Song, Y. Hu, Z. W. Tao, J. H. Tian, Y. Y. Pei, M. L. Yuan, Y. L. Zhang, F. H. Dai, Y. Liu, Q. M. Wang, J. J. Zheng, L. Xu, E. C. Holmes and Y. Z. Zhang. We thank S. G. Siddell, R. A. M. Fouchier, and J. H. Kuhn for their comments on a manuscript version posted on 11 February 2020 to bioRxiv. A.E.G. and J.Z. thank W. J. M. Spaan, A. J. Davison and E. J. Lefkowitz for support. A.E.G. thanks members of the ICTV ExecutiveCommittee for discussions of classification and nomenclature issues relevant to this paper.

 

Author information

Affiliations: Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, the Netherlands (Alexander E. Gorbalenya); Department of Medical Microbiology, Leiden University Medical Center, Leiden, the Netherlands (Alexander E. Gorbalenya, Anastasia A. Gulyaeva, Chris Lauber & Igor A. Sidorov); Faculty of Bioengineering and Bioinformatics and Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, Russia (Alexander E. Gorbalenya, Andrey M. Leontovich, Dmitry Penzar & Dmitry V. Samborskiy); Department of Microbiology and Immunology, Loyola University of Chicago, Stritch School of Medicine, Maywood, IL, USA (Susan C. Baker); Department of Epidemiology, University of North Carolina, Chapel Hill, NC, USA (Ralph S. Baric); Division of Virology, Department of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, the Netherlands (Raoul J. de Groot); Institute of Virology, Charité – Universitätsmedizin Berlin, Berlin, Germany (Christian Drosten); Viroscience Lab, Erasmus MC, Rotterdam, the Netherlands (Bart L. Haagmans); Texas A&M University-Texarkana, Texarkana, TX, USA (Benjamin W. Neuman); Department of Microbiology and Immunology, University of Iowa, Iowa City, IA, USA (Stanley Perlman); Centre of Influenza Research & School of Public Health, The University of Hong Kong, Hong Kong, People’s Republic of China (Leo L. M. Poon); Department of Molecular and Cell Biology, National Center of Biotechnology (CNB-CSIC), Campus de Cantoblanco, Madrid, Spain (Isabel Sola); Institute of Medical Virology, Justus Liebig University Giessen, Giessen, Germany (John Ziebuhr); Consortia Coronaviridae Study Group of the International Committee on Taxonomy of Viruses (Alexander E. Gorbalenya, Susan C. Baker, Ralph S. Baric, Raoul J. de Groot, Christian Drosten, Anastasia A. Gulyaeva, Bart L. Haagmans, Chris Lauber, Andrey M. Leontovich, Benjamin W. Neuman, Dmitry Penzar, Stanley Perlman, Leo L. M. Poon, Dmitry V. Samborskiy, Igor A. Sidorov, Isabel Sola & John Ziebuhr)

Contributions

S.C.B., R.S.B., C.D., R.J.D.G., A.E.G., B.L.H., B.W.N., S.P., L.L.M.P., I.S. and J.Z. are members of the CSG, chaired by J.Z.; R. J.D.G., A.E.G., C.L., B.W.N. and J.Z. are members of the NSG, chaired by A.E.G.; A.E.G. and J.Z. are members of the ICTV. A.E.G., A.A.G., C.L., A.M.L., D.P., D.V.S. and I.A.S. are members of the DEmARC team led by A.E.G. D.V.S. generated the classification of SARS-CoV-2 using a computational pipeline developed by A.A.G. and using software developed by the DEmARC team; the CSG considered and approved this classification, and subsequently debated and decided on the virus name. A.E.G. and J.Z. wrote the manuscript. A.E.G. and D.V.S. generated the figures. All authors reviewed the manuscript and approved its submission for publication.

Corresponding authors

Correspondence to Alexander E. Gorbalenya or John Ziebuhr.

Ethics declarations

Competing interests: The authors declare no competing interests.

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Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Cite this article Gorbalenya, A.E., Baker, S.C., Baric, R.S. et al. The species Severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2. Nat Microbiol (2020). https://doi.org/10.1038/s41564-020-0695-z

Keywords: Coronavirus; SARS-CoV-2.

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The #Antiviral Compound #Remdesivir Potently Inhibits #RNA-dependent RNA #Polymerase From #MERS #Coronavirus (J Biol Chem., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

J Biol Chem  2020 Feb 24 [Online ahead of print]

The Antiviral Compound Remdesivir Potently Inhibits RNA-dependent RNA Polymerase From Middle East Respiratory Syndrome Coronavirus

Calvin J Gordon 1, Egor P Tchesnokov 1, Joy Y Feng 2, Danielle P Porter 3, Matthias Gotte 4

Affiliations: 1 University of Alberta, Canada. 2 Biology, Gilead Sciences, United States. 3 Gilead, United States. 4 Medical Microbiology and Immunology, University of Alberta, Canada.

PMID: 32094225 DOI: 10.1074/jbc.AC120.013056

 

Abstract

Antiviral drugs for managing infections with human coronaviruses are not yet approved, posing a serious challenge to current global efforts aimed at containing the outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Remdesivir (RDV) is an investigational compound with a broad spectrum of antiviral activities against RNA viruses, including SARS-CoV and Middle East respiratory syndrome (MERS-CoV). RDV is a nucleotide analog inhibitor of RNA-dependent RNA polymerases (RdRps). Here, we co-expressed the MERS-CoV nonstructural proteins nsp5, nsp7, nsp8, and nsp12 (RdRp) in insect cells as a part a polyprotein to study the mechanism of inhibition of MERS-CoV RdRp by RDV. We initially demonstrated that nsp8 and nsp12 form an active complex. The triphosphate form of the inhibitor (RDV-TP) competes with its natural counterpart ATP. Of note, the selectivity value for RDV-TP obtained here with a steady-state approach suggests that it is more efficiently incorporated than ATP and two other nucleotide analogues. Once incorporated at position i, the inhibitor caused RNA synthesis arrest at position i+3. Hence, the likely mechanism of action is delayed RNA chain termination. The additional three nucleotides may protect the inhibitor from excision by the viral 3′-5′ exonuclease activity. Together, these results help to explain the high potency of RDV against RNA viruses in cell-based assays.

Keywords: Ebola virus (EBOV); Middle East respiratory syndrome coronavirus (MERS-CoV), SARS-CoV-2; RNA-dependent RNA polymerase (RdRp), viral replicase; coronavirus, positive-sense RNA virus; drug development; enzyme inhibitor; nucleoside/nucleotide analogue; plus-stranded RNA virus; remdesivir, antiviral drug, RNA chain-termination; viral polymerase.

Published under license by The American Society for Biochemistry and Molecular Biology, Inc.

Keywords: MERS-CoV; Coronavirus; Antivirals; Remdesivir.

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