A SARS-like cluster of circulating bat coronaviruses shows potential for human emergence

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Abstract

Ralph Baric, Vineet Menachery and colleagues characterize a SARS-like coronavirus circulating in Chinese horseshoe bats to determine its potential to infect primary human airway epithelial cells, cause disease in mice and respond to available therapeutics.

Supplementary information

The online version of this article (doi:10.1038/nm.3985) contains supplementary material, which is available to authorized users.

Abstract

The emergence of severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome (MERS)-CoV underscores the threat of cross-species transmission events leading to outbreaks in humans. Here we examine the disease potential of a SARS-like virus, SHC014-CoV, which is currently circulating in Chinese horseshoe bat populations ¹. Using the SARS-CoV reverse genetics system ², we generated and characterized a chimeric virus expressing the spike of bat coronavirus SHC014 in a mouse-adapted SARS-CoV backbone. The results indicate that group 2b viruses encoding the SHC014 spike in a wild-type backbone can efficiently use multiple orthologs of the SARS receptor human angiotensin converting enzyme II (ACE2), replicate efficiently in primary human airway cells and achieve in vitro titers equivalent to epidemic strains of SARS-CoV. Additionally, in vivo experiments demonstrate replication of the chimeric virus in mouse lung with notable pathogenesis. Evaluation of available SARS-based immune-therapeutic and prophylactic modalities revealed poor efficacy; both monoclonal antibody and vaccine approaches failed to neutralize and protect from infection with CoVs using the novel spike protein. On the basis of these findings, we synthetically re-derived an infectious full-length SHC014 recombinant virus and demonstrate robust viral replication both in vitro and in vivo. Our work suggests a potential risk of SARS-CoV re-emergence from viruses currently circulating in bat populations.

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The online version of this article (doi:10.1038/nm.3985) contains supplementary material, which is available to authorized users.

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Most cited references 24

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Isolation and characterization of a bat SARS-like coronavirus that uses the ACE2 receptor

Xing-Yi Ge, Jia-Lu Li, Xing-Lou Yang … (2013)

The 2002–3 pandemic caused by severe acute respiratory syndrome coronavirus (SARS-CoV) was one of the most significant public health events in recent history 1 . An ongoing outbreak of Middle East respiratory syndrome coronavirus (MERS-CoV) 2 suggests that this group of viruses remains a major threat and that their distribution is wider than previously recognized. Although bats have been suggested as the natural reservoirs of both viruses 3–5 , attempts to isolate the progenitor virus of SARS-CoV from bats have been unsuccessful. Diverse SARS-like coronaviruses (SL-CoVs) have now been reported from bats in China, Europe and Africa 5–8 , but none are considered a direct progenitor of SARS-CoV because of their phylogenetic disparity from this virus and the inability of their spike proteins (S) to use the SARS-CoV cellular receptor molecule, the human angiotensin converting enzyme II (ACE2) 9,10 . Here, we report whole genome sequences of two novel bat CoVs from Chinese horseshoe bats (Family: Rhinolophidae) in Yunnan, China; RsSHC014 and Rs3367. These viruses are far more closely related to SARS-CoV than any previously identified bat CoVs, particularly in the receptor binding domain (RDB) of the S protein. Most importantly, we report the first recorded isolation of a live SL-CoV (bat SL-CoV-WIV1) from bat fecal samples in Vero E6 cells, which has typical coronavirus morphology, 99.9% sequence identity to Rs3367 and uses the ACE2s from human, civet and Chinese horseshoe bat for cell entry. Preliminary in vitro testing indicates that WIV1 also has a broad species tropism. Our results provide the strongest evidence to date that Chinese horseshoe bats are natural reservoirs of SARS-CoV, and that intermediate hosts may not be necessary for direct human infection by some bat SL-CoVs. They also highlight the importance of pathogen discovery programs targeting high-risk wildlife groups in emerging disease hotspots as a strategy for pandemic preparedness.

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A decade after SARS: strategies for controlling emerging coronaviruses

Rachel Graham, Eric F. Donaldson, Ralph Baric (2013)

Key Points Two highly pathogenic human coronaviruses, severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV), have emerged in the past decade. The lack of any clinically approved antiviral treatments or vaccines for either virus emphasizes the importance of the design of effective therapeutics and preventives. Bats have been implicated as reservoirs of both SARS-CoV and MERS-CoV as well as related viruses and other human coronaviruses (HCoVs), such as HCoV-229E and HCoV-NL63. The dispersion of bat species over much of the globe probably enhances their potential to act as reservoirs for pathogens, some of which are extremely virulent and potentially lethal to other animals and humans. Multiple animal models for SARS-CoV infection exist, although mouse models have been the most thoroughly characterized. Mouse-adapted SARS-CoV is capable of causing pathology that is representative of human infections in both young and aged animals. Small animal models for MERS-CoV infection have not yet been reported, although the possibility of further ongoing selection in the receptor-binding sequence in the spike protein or other sequences that are important for host specificity might contribute to this limitation. A mild disease phenotype that can include either localized or widespread pneumonia is observed in inoculated macaques. Multiple vaccine strategies have been attempted with coronaviruses, mostly (but not exclusively) targeting the spike glycoprotein. Successful live-attenuated vaccines have utilized reverse genetic strategies to delete the envelope protein or inactivate the exonuclease activity of non-structural protein 14 (nsp14) . MERS-CoV, similarly to SARS-CoV in 2003, has the potential to have a profound impact on the human population; however, its low penetrance thus far suggests that the virus might either ultimately fail to develop a niche in humans or it might still be adapting to human hosts and that the worst of its effects are yet to come. Coronavirus phylogeny shows an incredible diversity in antigenic variants, which leads to limited cross-protection against infection with different strains, even within a phylogenetic subcluster. Consequently, the risk of introducing novel coronaviruses into naive human and animal populations remains high. Supplementary information The online version of this article (doi:10.1038/nrmicro3143) contains supplementary material, which is available to authorized users.

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Severe acute respiratory syndrome

J S M Peiris, Y Guan, K. Yuen (2004)

Severe acute respiratory syndrome (SARS) was caused by a previously unrecognized animal coronavirus that exploited opportunities provided by 'wet markets' in southern China to adapt to become a virus readily transmissible between humans. Hospitals and international travel proved to be 'amplifiers' that permitted a local outbreak to achieve global dimensions. In this review we will discuss the substantial scientific progress that has been made towards understanding the virus—SARS coronavirus (SARS-CoV)—and the disease. We will also highlight the progress that has been made towards developing vaccines and therapies The concerted and coordinated response that contained SARS is a triumph for global public health and provides a new paradigm for the detection and control of future emerging infectious disease threats.

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Author and article information

Contributors

Vineet D Menachery: vineet@email.unc.edu

Ralph S Baric: rbaric@email.unc.edu

Journal

Journal ID (nlm-ta): Nat Med

Journal ID (iso-abbrev): Nat. Med

Title: Nature Medicine

Publisher: Nature Publishing Group US (New York )

ISSN (Print): 1078-8956

ISSN (Electronic): 1546-170X

Publication date (Electronic): 9 November 2015

Publication date (Print): 2015

Volume: 21

Issue: 12

Pages: 1508-1513

Affiliations

[1 ]GRID grid.10698.36, ISNI 0000000122483208, Department of Epidemiology, , University of North Carolina at Chapel Hill, ; Chapel Hill, North Carolina USA

[2 ]GRID grid.10698.36, ISNI 0000000122483208, Department of Microbiology and Immunology, , University of North Carolina at Chapel Hill, ; Chapel Hill, North Carolina USA

[3 ]GRID grid.483504.e, ISNI 0000 0001 2158 7187, National Center for Toxicological Research, Food and Drug Administration, ; Jefferson, Arkansas USA

[4 ]GRID grid.439104.b, ISNI 0000 0004 1798 1925, Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, ; Wuhan, China

[5 ]GRID grid.10698.36, ISNI 0000000122483208, Department of Cell Biology and Physiology, , University of North Carolina at Chapel Hill, ; Chapel Hill, North Carolina USA

[6 ]GRID grid.10698.36, ISNI 0000000122483208, Cystic Fibrosis Center, Marsico Lung Institute, University of North Carolina at Chapel Hill, ; Chapel Hill, North Carolina USA

[7 ]GRID grid.5801.c, ISNI 0000 0001 2156 2780, Institute for Research in Biomedicine, Bellinzona Institute of Microbiology, ; Zurich, Switzerland

[8 ]Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts USA

[9 ]GRID grid.38142.3c, ISNI 000000041936754X, Department of Medicine, , Harvard Medical School, ; Boston, Massachusetts USA

Article

Publisher ID: BFnm3985

DOI: 10.1038/nm.3985

PMC ID: 4797993

PubMed ID: 26552008

SO-VID: 5ee7890d-8bec-47b8-a27b-8e0c7f0eb89b

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This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

History

Date received : 12 June 2015

Date accepted : 8 October 2015

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ScienceOpen disciplines: Medicine

Keywords: policy and public health in microbiology,viral infection,sars virus,translational research

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ScienceOpen disciplines: Medicine

Keywords: policy and public health in microbiology, viral infection, sars virus, translational research

A SARS-like cluster of circulating bat coronaviruses shows potential for human emergence

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Coronaviruses, COVID-19 and SARS-CoV-2

Most cited references 24

Isolation and characterization of a bat SARS-like coronavirus that uses the ACE2 receptor

A decade after SARS: strategies for controlling emerging coronaviruses

Severe acute respiratory syndrome

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