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

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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. Using the SARS-CoV reverse genetics system, 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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Sapna Devi, Anqi Li, Clare L V Westhorpe, Camden Y Lo, Latasha D Abeynaike, Sarah L Snelgrove, Pam Hall, Joshua D Ooi,
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In the published article, in the Online Methods section, it is stated that the dose of DHE used is 20 mg/kg, when in fact DHE was administered at
2 mg/kg. The error has been corrected in the HTML and PDF versions of the article.
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Nat. Med. 21, 1307–1317 (2015); published online 12 October 2015; corrected after print 18 November 2015
In the version of this article initially published, the first author’s name was incorrect. The error has been corrected in the HTML and PDF versions
of the article.
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Arnold Ganser, Eva Brinkmann, Ines Reimann, Tibor Kempf, Hans W Niessen, Jacques Mizrahi, Hans-Joachim Schönfeld,
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error has been corrected in the HTML and PDF versions of the article.
Corrigendum: A SARS-like cluster of circulating bat coronaviruses shows
potential for human emergence
Vineet D Menachery, Boyd L Yount Jr, Kari Debbink, Sudhakar Agnihothram, Lisa E Gralinski, Jessica A Plante, Rachel L Graham,
Trevor Scobey, Xing-Yi Ge, Eric F Donaldson, Scott H Randell, Antonio Lanzavecchia, Wayne A Marasco, Zhengli-Li Shi & Ralph S Baric
Nat. Med.; doi:10.1038/nm.3985; corrected 20 November 2015
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EcoHealth Alliance, to Z.-L.S. The error has been corrected for the print, PDF and HTML versions of this article.
Corrigendum: Long-term glycemic control using polymer-encapsulated
human stem cell–derived beta cells in immune-competent mice
Arturo J Vegas, Omid Veiseh, Mads Gürtler, Jeffrey R Millman, Felicia W Pagliuca, Andrew R Bader, Joshua C Doloff, Jie Li,
Michael Chen, Karsten Olejnik, Hok Hei Tam, Siddharth Jhunjhunwala, Erin Langan, Stephanie Aresta-Dasilva, Srujan Gandham,
James J McGarrigle, Matthew A Bochenek, Jennifer Hollister-Lock, Jose Oberholzer, Dale L Greiner, Gordon C Weir, Douglas A Melton,
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Cell Institute and several individuals for their assistance. The error has been corrected for the print, PDF and HTML versions of this article.
446 VOLUME 22 | NUMBER 4 | APRIL 2016 NATURE MEDICINE
CORRIGENDA
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... Typical symptoms of MERS include fever, cough, diarrhea, and shortness of breath. Some patients with MERS exhibit serious respiratory disease which may result in death [1][2][3][4][5][6][7][8][9][10][11][12][13]. Molecular investigation indicated that bats in Saudi Arabia are infected with several corona viruses and virus from one bat showed 100% nucleotide identity to virus from the human index case-patient indicating that bats might play a role in human infection [7]. ...
... SARS-related corona viruses are thought to be transmitted from bats to humans in origin. Furthermore, some bat SARS-related corona viruses have been previously shown to have the potential to infect humans [5][6][7][8][9][10]. SARS-CoV-2 is transmitted to human directly through respiratory droplets of infected people or indirectly through contact with virus-contaminated surfaces and substances [8]. ...
... The relationship between humans and bats is small. In 2015, a report was published in the Chinese media claiming the addition of the s-co-14 gene to sars-cov could infect humans in addition to mice, but no scientific source supported the report [8,[12][13][14], but Corona virus with the help of an RNA genome has a high potential for mutation and transmission to humans [15]. However, there is speculation that the sars-cov-2 virus is of laboratory origin and was released from a laboratory in Wuhan, China. ...
... A small region within the spike proteins of sarbecoviruses, known as the receptor binding domain (RBD), contains all of the structural information necessary to engage with the host receptor. We and others have experimentally classified the majority of published sarbecovirus RBDs into different clades based on sequence and functional data: clade 1, identified in Asian bats, contains no deletions and binds to host receptor, Angiotensin-Converting Enzyme 2 (ACE2), whereas clade 2, also identified in Asian bats, contains 2 deletions and does not use ACE2 and clade 3 viruses, found more widely in African and European bats, contain 1 deletion and have recently been shown can infect using primarily bat ACE2 [1][2][3][4][5][6][7][8][9][10]. In 2021, several viruses were identified in China that comprise a fourth clade that also interact with ACE2 [11]. ...
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Spillover of sarbecoviruses from animals to humans has resulted in outbreaks of severe acute respiratory syndrome SARS-CoVs and the ongoing COVID-19 pandemic. Efforts to identify the origins of SARS-CoV-1 and -2 has resulted in the discovery of numerous animal sarbecoviruses–the majority of which are only distantly related to known human pathogens and do not infect human cells. The receptor binding domain (RBD) on sarbecoviruses engages receptor molecules on the host cell and mediates cell invasion. Here, we tested the receptor tropism and serological cross reactivity for RBDs from two sarbecoviruses found in Russian horseshoe bats. While these two viruses are in a viral lineage distinct from SARS-CoV-1 and -2, the RBD from one virus, Khosta 2, was capable of using human ACE2 to facilitate cell entry. Viral pseudotypes with a recombinant, SARS-CoV-2 spike encoding for the Khosta 2 RBD were resistant to both SARS-CoV-2 monoclonal antibodies and serum from individuals vaccinated for SARS-CoV-2. Our findings further demonstrate that sarbecoviruses circulating in wildlife outside of Asia also pose a threat to global health and ongoing vaccine campaigns against SARS-CoV-2
... Subunit 1 is responsible for binding the virus to host cell receptors; therefore, it is a determining factor of pathogenicity and tropism in coronavirus. It is likely that the recombination identified in subunit 1 had an adaptive impact in BtMf-Yunnan2020, as has been suggested for other coronaviruses [121][122][123][124]. Finally, both BtMf-Yunnan2020 and MlYN20 presented an ORF7 unlike the other myotacoviruses; however, these proteins had a low reciprocal identity. ...
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Significant efforts have been made to characterize viral diversity in bats from China. Many of these studies were prospective and focused mainly on Rhinolophus bats that could be related to zoonotic events. However, other species of bats that are part of ecosystems identified as virus diversity hotspots have not been studied in-depth. We analyzed the virome of a group of Myotis fimbriatus bats collected from the Yunnan Province during 2020. The virome of M. fimbriatus revealed the presence of families of pathogenic viruses such as Coronavirus, Astrovirus, Mastadenovirus, and Picornavirus, among others. The viral sequences identified in M. fimbriatus were characterized by significant divergence from other known viral sequences of bat origin. Complex phylogenetic landscapes implying a tendency of co-specificity and relationships with viruses from other mammals characterize these groups. The most prevalent and abundant virus in M. fimbriatus individuals was an alphacoronavirus. The genome of this virus shows evidence of recombination and is likely the product of ancestral host-switch. The close phylogenetic and ecological relationship of some species of the Myotis genus in China may have played an important role in the emergence of this alphacoronavirus.
... Surprisingly, we are now even expecting to see the eradication of HCV from the planet by antiviral drugs. We have witnessed the frequent emergence of highly pathogenic coronaviruses since the year 2002, and yet more coronavirus outbreaks could potentially occur in the future due to spillover events [36]. Thus, preparing for future pandemics is not an option that we can afford any longer, and therefore, drug development for broadspectrum antiviral agents (or at least pan-coronavirus inhibitors) should be the main focus of efforts to respond to current and future global challenges. ...
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The placenta is a captivating multifunctional organ of fetal origin and plays an essential role during pregnancy by intimately connecting mother and baby. This study explicates placental pathology and information about 25 placentas collected from the mothers infected with novel coronavirus (SARS-COV-2). So far, congenital transmission of SARS-CoV-2 seems to be remarkably uncommon in spite of many cases of COVID-19 during pregnancy. Out of the 25 placental tissue samples collected, none has shown gene expression of SARS-CoV-2 when confirmed by RT-PCR. At the same time, nasal and throat swab samples collected from newborns of SARS-CoV-2-positive mothers correspondingly tested negative by RT-PCR. The shielding properties of placental barriers against viral infections from mothers to newborns remains a mystery. Major histopathological findings have been recorded as choriodecidual tissue with necrosis, intramural fibrin deposition, chorionic villi with fibrosis, and calcification. Moreover, although recent findings are insufficient to prove direct placental transmission of COVID-19, the abundance of angiotensin-converting enzymes-2 (ACE-2) on the placental surface could potentially contribute to unpleasant outcomes during pregnancy as SARSCoV- 2 gains access to human cells via ACE-2. Finally, the significance of these findings is vague and needs further study.
... Coronavirus evolution and emergence in new hosts is driven by different factors such as recombination, horizontal gene transfer, gene duplication and alternative open reading frames which expand their functional and adaptative capacity for the current and new host. During the high viral shedding season, bats are carriers of quasi-species pools of viruses which contribute to their genetic diversity and increase their potential to jump and emerge in a new species [56]. Due to the great genetic diversity observed at both sites as well as the important RNA bat CoV prevalence during the reproductive season, our sites could be potential hotspots of new CoV spillover and potential zoonotic emergence. ...
Preprint
Background: Studies have linked bats to outbreaks in human populations such as SARS-CoV-1 and MERS-CoV and the ongoing SARS-CoV-2 pandemic. Method: We carried out a longitudinal survey from August 2020 to July 2021 at two sites in Zimbabwe with bat-human interactions: Magweto cave and Chirundu farm. A total 1732 and 1866 individual bat faecal samples were collected respectively. Coronaviruses and bat species were amplified using PCR systems respectively. Results: Analysis of the coronavirus sequences revealed a high genetic diversity and we identified different sub-viral groups in the Alphacoronavirus and Betacoronavirus genus. The established sub-viral groups fell within the described Alphacoronavirus sub-genera: Decacovirus, Duvinacovirus, Rhinacovirus, Setracovirus and Minunacovirus and for Betacoronavirus sub-genera: Sarbecoviruses, Merbecovirus and Hibecovirus. Our results showed an overall proportion for CoV positive PCR tests of 23.7% at Chirundu site, 16.5% and 38.9% at Magweto site for small insectivorous bats and Macronycteris gigas respectively. Conclusion: The higher risk of bat coronaviruses exposure for humans ranged from December to March in relation to higher viral shedding peaks of coronaviruses in the parturition, lactation and weaning months of the bat populations at both sites. We also highlight the need to further document viral infectious risk in human/domestic animal populations surrounding bat habitats in Zimbabwe.
... In 2013, a coronavirus (SHC014) with a close relationship to SARS-CoV, which uses human angiotensinconverting enzyme II (ACE2) in the receptor-binding domain of spike proteins to enter cells, was isolated from the horseshoe bat (Ge et al., 2013). Then, in 2015, using reverse genetics, a chimeric virus expressing this SHC014 spike in the backbone of a mouse-adapted SARS-CoV was created, which was shown to efficiently replicate in primary human airway cells by efficiently utilizing the SARS receptor, ACE2 (Menachery et al., 2015). This result was taken as proof of the existence of a virus that could cause a reemergence of SARS and was featured in Nature Review Microbiology's Research Highlights under the heading "The next SARS?" ...
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Unlabelled: The receptor binding domain (RBD) of the spike (S) glycoprotein of severe acute respiratory syndrome coronavirus (SARS-CoV) is a major target of protective immunity in vivo. Although a large number of neutralizing antibodies (nAbs) have been developed, it remains unclear if a single RBD-targeting nAb or two in combination can prevent neutralization escape and, if not, attenuate viral virulence in vivo. In this study, we used a large panel of human nAbs against an epitope that overlaps the interface between the RBD and its receptor, angiotensin-converting enzyme 2 (ACE2), to assess their cross-neutralization activities against a panel of human and zoonotic SARS-CoVs and neutralization escape mutants. We also investigated the neutralization escape profiles of these nAbs and evaluated their effects on receptor binding and virus fitness in vitro and in mice. We found that some nAbs had great potency and breadth in neutralizing multiple viral strains, including neutralization escape viruses derived from other nAbs; however, no single nAb or combination of two blocked neutralization escape. Interestingly, in mice the neutralization escape mutant viruses showed either attenuation (Urbani background) or increased virulence (GD03 background) consistent with the different binding affinities between their RBDs and the mouse ACE2. We conclude that using either single nAbs or dual nAb combinations to target a SARS-CoV RBD epitope that shows plasticity may have limitations for preventing neutralization escape during in vivo immunotherapy. However, RBD-directed nAbs may be useful for providing broad neutralization and prevention of escape variants when combined with other nAbs that target a second conserved epitope with less plasticity and more structural constraint. Importance: The emergence of severe acute respiratory syndrome coronavirus (SARS-CoV) in 2002 and Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012 has resulted in severe human respiratory disease with high death rates. Their zoonotic origins highlight the likelihood of reemergence or further evolution into novel human coronavirus pathogens. Broadly neutralizing antibodies (nAbs) that prevent infection of related viruses represent an important immunostrategy for combating coronavirus infections; however, for this strategy to succeed, it is essential to uncover nAb-mediated escape pathways and to pioneer strategies that prevent escape. Here, we used SARS-CoV as a research model and examined the escape pathways of broad nAbs that target the receptor binding domain (RBD) of the virus. We found that neither single nAbs nor two nAbs in combination blocked escape. Our results suggest that targeting conserved regions with less plasticity and more structural constraint rather than the SARS-CoV RBD-like region(s) should have broader utility for antibody-based immunotherapy.
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