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      Discovery of a rich gene pool of bat SARS-related coronaviruses provides new insights into the origin of SARS coronavirus

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          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          A large number of SARS-related coronaviruses (SARSr-CoV) have been detected in horseshoe bats since 2005 in different areas of China. However, these bat SARSr-CoVs show sequence differences from SARS coronavirus (SARS-CoV) in different genes (S, ORF8, ORF3, etc) and are considered unlikely to represent the direct progenitor of SARS-CoV. Herein, we report the findings of our 5-year surveillance of SARSr-CoVs in a cave inhabited by multiple species of horseshoe bats in Yunnan Province, China. The full-length genomes of 11 newly discovered SARSr-CoV strains, together with our previous findings, reveals that the SARSr-CoVs circulating in this single location are highly diverse in the S gene, ORF3 and ORF8. Importantly, strains with high genetic similarity to SARS-CoV in the hypervariable N-terminal domain (NTD) and receptor-binding domain (RBD) of the S1 gene, the ORF3 and ORF8 region, respectively, were all discovered in this cave. In addition, we report the first discovery of bat SARSr-CoVs highly similar to human SARS-CoV in ORF3b and in the split ORF8a and 8b. Moreover, SARSr-CoV strains from this cave were more closely related to SARS-CoV in the non-structural protein genes ORF1a and 1b compared with those detected elsewhere. Recombination analysis shows evidence of frequent recombination events within the S gene and around the ORF8 between these SARSr-CoVs. We hypothesize that the direct progenitor of SARS-CoV may have originated after sequential recombination events between the precursors of these SARSr-CoVs. Cell entry studies demonstrated that three newly identified SARSr-CoVs with different S protein sequences are all able to use human ACE2 as the receptor, further exhibiting the close relationship between strains in this cave and SARS-CoV. This work provides new insights into the origin and evolution of SARS-CoV and highlights the necessity of preparedness for future emergence of SARS-like diseases.

          Author summary

          Increasing evidence has been gathered to support the bat origin of SARS coronavirus (SARS-CoV) in the past decade. However, none of the currently known bat SARSr-CoVs is thought to be the direct ancestor of SARS-CoV. Herein, we report the identification of a diverse group of bat SARSr-CoVs in a single cave in Yunnan, China. Importantly, all of the building blocks of SARS-CoV genome, including the highly variable S gene, ORF8 and ORF3, could be found in the genomes of different SARSr-CoV strains from this single location. Based on the analysis of full-length genome sequences of the newly identified bat SARSr-CoVs, we speculate that the direct ancestor of SARS-CoV may have arisen from sequential recombination events between the precursors of these bat SARSr-CoVs prior to spillover to an intermediate host. In addition, we found bat SARSr-CoV strains with different S proteins that can all use the receptor of SARS-CoV in humans (ACE2) for cell entry, suggesting diverse SARSr-CoVs capable of direct transmission to humans are circulating in bats in this cave. Our current study therefore offers a clearer picture on the evolutionary origin of SARS-CoV and highlights the risk of future emergence of SARS-like diseases.

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          Most cited references18

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          Isolation and characterization of viruses related to the SARS coronavirus from animals in southern China.

          Y Guan (2003)
          A novel coronavirus (SCoV) is the etiological agent of severe acute respiratory syndrome (SARS). SCoV-like viruses were isolated from Himalayan palm civets found in a live-animal market in Guangdong, China. Evidence of virus infection was also detected in other animals (including a raccoon dog, Nyctereutes procyonoides) and in humans working at the same market. All the animal isolates retain a 29-nucleotide sequence that is not found in most human isolates. The detection of SCoV-like viruses in small, live wild mammals in a retail market indicates a route of interspecies transmission, although the natural reservoir is not known.
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            Severe acute respiratory syndrome coronavirus-like virus in Chinese horseshoe bats.

            Although the finding of severe acute respiratory syndrome coronavirus (SARS-CoV) in caged palm civets from live animal markets in China has provided evidence for interspecies transmission in the genesis of the SARS epidemic, subsequent studies suggested that the civet may have served only as an amplification host for SARS-CoV. In a surveillance study for CoV in noncaged animals from the wild areas of the Hong Kong Special Administration Region, we identified a CoV closely related to SARS-CoV (bat-SARS-CoV) from 23 (39%) of 59 anal swabs of wild Chinese horseshoe bats (Rhinolophus sinicus) by using RT-PCR. Sequencing and analysis of three bat-SARS-CoV genomes from samples collected at different dates showed that bat-SARS-CoV is closely related to SARS-CoV from humans and civets. Phylogenetic analysis showed that bat-SARS-CoV formed a distinct cluster with SARS-CoV as group 2b CoV, distantly related to known group 2 CoV. Most differences between the bat-SARS-CoV and SARS-CoV genomes were observed in the spike genes, ORF 3 and ORF 8, which are the regions where most variations also were observed between human and civet SARS-CoV genomes. In addition, the presence of a 29-bp insertion in ORF 8 of bat-SARS-CoV genome, not in most human SARS-CoV genomes, suggests that it has a common ancestor with civet SARS-CoV. Antibody against recombinant bat-SARS-CoV nucleocapsid protein was detected in 84% of Chinese horseshoe bats by using an enzyme immunoassay. Neutralizing antibody to human SARS-CoV also was detected in bats with lower viral loads. Precautions should be exercised in the handling of these animals.
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              Epidemiology and cause of severe acute respiratory syndrome (SARS) in Guangdong, People's Republic of China, in February, 2003

              Summary Background An epidemic of severe acute respiratory syndrome (SARS) has been associated with an outbreak of atypical pneumonia originating in Guangdong Province, People's Republic of China. We aimed to identify the causative agent in the Guangdong outbreak and describe the emergence and spread of the disease within the province. Methods We analysed epidemiological information and collected serum and nasopharyngeal aspirates from patients with SARS in Guangdong in mid-February, 2003. We did virus isolation, serological tests, and molecular assays to identify the causative agent. Findings SARS had been circulating in other cities of Guangdong Province for about 2 months before causing a major outbreak in Guangzhou, the province's capital. A novel coronavirus, SARS coronavirus (CoV), was isolated from specimens from three patients with SARS. Viral antigens were also directly detected in nasopharyngeal aspirates from these patients. 48 of 55 (87%) patients had antibodies to SARS CoV in their convalescent sera. Genetic analysis showed that the SARS CoV isolates from Guangzhou shared the same origin with those in other countries, and had a phylogenetic pathway that matched the spread of SARS to the other parts of the world. Interpretation SARS CoV is the infectious agent responsible for the epidemic outbreak of SARS in Guangdong. The virus isolated from patients in Guangdong is the prototype of the SARS CoV in other regions and countries.
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                Author and article information

                Contributors
                Role: Data curationRole: Formal analysisRole: InvestigationRole: ValidationRole: VisualizationRole: Writing – original draft
                Role: InvestigationRole: Methodology
                Role: InvestigationRole: Resources
                Role: Formal analysisRole: Resources
                Role: Investigation
                Role: Investigation
                Role: Investigation
                Role: Investigation
                Role: Resources
                Role: Investigation
                Role: InvestigationRole: Resources
                Role: Investigation
                Role: Resources
                Role: Funding acquisitionRole: Writing – review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: Writing – review & editing
                Role: ConceptualizationRole: Formal analysisRole: Funding acquisitionRole: SoftwareRole: Writing – review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: MethodologyRole: Project administrationRole: SupervisionRole: VisualizationRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS Pathog
                PLoS Pathog
                plos
                plospath
                PLoS Pathogens
                Public Library of Science (San Francisco, CA USA )
                1553-7366
                1553-7374
                30 November 2017
                November 2017
                : 13
                : 11
                : e1006698
                Affiliations
                [1 ] CAS Key Laboratory of Special Pathogens and Biosafety, Center for Emerging Infectious Diseases of Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China
                [2 ] Yunnan Institute of Endemic Diseases Control and Prevention, Dali, China
                [3 ] Dali University, Dali, China
                [4 ] EcoHealth Alliance, New York, New York, United States of America
                [5 ] Programme in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore
                Charite Universitatsmedizin Berlin, GERMANY
                Author notes

                The authors have declared that no competing interests exist.

                Author information
                http://orcid.org/0000-0002-2046-5695
                http://orcid.org/0000-0001-8176-9951
                http://orcid.org/0000-0001-8089-163X
                Article
                PPATHOGENS-D-17-00265
                10.1371/journal.ppat.1006698
                5708621
                29190287
                e7d09fd3-35a0-4339-afbb-21544e07aa04
                © 2017 Hu et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 10 February 2017
                : 17 October 2017
                Page count
                Figures: 9, Tables: 1, Pages: 27
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 81290341, 31621061
                Award Recipient :
                Funded by: China Mega-Project for Infectious Disease
                Award ID: 2014ZX10004001-003
                Award Recipient :
                Funded by: Scientific and technological basis special project from the Ministry of Science and Technology of China
                Award ID: 2013FY113500
                Award Recipient :
                Funded by: the Strategic Priority Research Program of the Chinese Academy of Sciences
                Award ID: XDPB0301
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100000009, Foundation for the National Institutes of Health;
                Award ID: NIAID R01AI110964
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100000200, United States Agency for International Development;
                Award ID: Emerging Pandemic Threats (EPT) PREDICT program
                Award Recipient :
                Funded by: Chinese Academy of Scieces
                Award ID: Pioneer Hundred Talents Program
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100001381, National Research Foundation Singapore;
                Award ID: NRF-CRP10-2012-05
                Award Recipient :
                This work was jointly funded by National Natural Science Foundation of China (81290341, 31621061) to ZLS, China Mega-Project for Infectious Disease (2014ZX10004001-003) to ZLS, Scientific and technological basis special project (2013FY113500) to YZZ and ZLS from the Ministry of Science and Technology of China, the Strategic Priority Research Program of the Chinese Academy of Sciences (XDPB0301) to ZLS, the National Institutes of Health (NIAID R01AI110964), the USAID Emerging Pandemic Threats (EPT) PREDICT program to PD and ZLS, CAS Pioneer Hundred Talents Program to JC, NRF-CRP grant (NRF-CRP10-2012-05) to LFW and WIV “One-Three-Five” Strategic Program (WIV-135-TP1) to JC and ZLS. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
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                Biology and life sciences
                Organisms
                Viruses
                RNA viruses
                Coronaviruses
                SARS coronavirus
                Biology and life sciences
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                Microbial pathogens
                Viral pathogens
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                SARS coronavirus
                Medicine and health sciences
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                Biology and Life Sciences
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                Custom metadata
                All relevant data are within the paper and its Supporting Information files. The complete genome sequences of the 11 bat SARS-related coronaviruses newly identified in this study have been deposited in the GenBank database and assigned accession numbers KY417142 to KY417152, respectively.

                Infectious disease & Microbiology
                Infectious disease & Microbiology

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