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MICROBIOLOGY
Severe acute respiratory syndrome coronavirus-like virus in Chinese horseshoe bats
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*Department of Microbiology, Research Centre of Infection and Immunology, State Key Laboratory of Emerging Infectious Diseases, and ¶Department of Pathology, University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong Special Administrative Region, China
Communicated by Lap-Chee Tsui, University of Hong Kong, Hong Kong Special Administrative Region, China (received for review June 22, 2005)
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Abstract |
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The isolation of SARS-CoV from caged animals, including Himalayan palm civets and a raccoon dog, from wild live markets in mainland China suggested that these animals are the reservoir for the origin of the SARS epidemic (9). However, subsequent studies suggested that the civet may have served only as an amplification host for SARS-CoV and provided the environment for major genetic variations permitting efficient animal-to-human and human-to-human transmissions (10-13). Because civets are often mixed with different species in overcrowded conditions at markets, we conducted a surveillance study for CoV in noncaged animals from the wild areas of the Hong Kong Special Administrative Region (HKSAR). In this report, we describe the identification and molecular characterization of a SARS-CoV-related virus from Chinese horseshoe bats in Hong Kong and propose that this virus be named bat SARS CoV (bat-SARS-CoV).
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Methods |
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RNA Extraction, RT-PCR, and DNA Sequencing. Nasopharyngeal and anal swabs were tested for CoV RNA by RT-PCR. Viral RNA extraction was performed by using the QIAamp viral RNA mini kit (Qiagen, Valencia, CA) according to the manufacturer's instructions. cDNA was generated by using random hexamers and the SuperScript II kit (Invitrogen) as described in ref. 7.
CoV screening was performed by using conserved primers (5'-GGTTGGGACTATCCTAAGTGTGA-3' and 5'-CCATCATCAGATAGAATCATCATA-3') targeted to a 440-bp fragment of the pol gene as described in ref. 7. Standard precautions were taken to avoid PCR contamination, and no false-positive was observed in negative controls. The sequences of the PCR products were compared with known sequences of the pol genes of CoV in GenBank.
Viral Cultures. Attempts to isolate bat-SARS-CoV were made by inoculating RT-PCR-positive specimens to FRhK-4, HRT-18G, Huh-7, Vero E6, C6/36 and Caco-2 cells, and chicken embryonated eggs. Viral replication was detected by observation for cytopathic effects and quantitative RT-PCR described below.
Complete Genome Sequencing and Genome Analysis. The complete genome of bat-SARS-CoV was sequenced by using RNA extracted from three anal swabs from three bats (B24, B41, and B43) as template. RNA was converted to cDNA by a combined random-priming and oligo(dT)-priming strategy described in ref. 7. A total of 63 sets of primers, available on request, were used for PCR. The 5' end of the viral genome was confirmed by rapid amplification of cDNA ends by using the 5'/3' RACE kit (Roche Diagnostics). Sequences were assembled and manually edited to produce complete sequences of the three viral genomes, which have been deposited into GenBank (Table 3, which is published as supporting information on the PNAS web site). The nucleotide and deduced amino acid sequences were compared with those of other CoV in GenBank (Table 3) by multiple sequence alignment using CLUSTALW software (www.ebi.ac.uk/clustalw). Phylogenetic tree construction was performed by using the neighbor-joining method with GROWTREE software (Genetics Computer Group, Madison, WI) using Jukes-Cantor correction. Prediction of signal peptides and cleavage sites was performed by using SIGNALP software, transmembrane domains by using TMPRED and TMHMM software, potential N-glycosylation sites by using SCANPROSITE software, and protein family analysis by using PFAM and INTERPROSCAN software (15-21).
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Western Blot Analysis Using Recombinant Nucleocapsid (N) Protein of bat-SARS-CoV. Cloning and purification of (His)6-tagged recombinant N protein of bat-SARS-CoV were performed as described in ref. 22. Primers (5'-CGCGGATCCGATGTCTGATAATGGACCC-3' and 5'-CGGAATTCTTATGCCTGAGTAGAATCA-3') were used to amplify the N gene of bat-SARS-CoV by RT-PCR. Western blot analysis, using 900 ng of purified bat-SARS-CoV (His)6-tagged N protein and sera at 1:1,000 dilution, was performed as described in ref. 22. Antigen-antibody interaction was detected with 1:4,000 horseradish peroxidase-conjugated protein G (Zymed) and an enhanced chemiluminescence fluorescence system (Amersham Pharmacia).
Enzyme Immunoassay (EIA) Using Recombinant N Protein of bat-SARS-CoV. Sera from eight bats of four different species, six rodents, and two monkeys negative for bat-SARS-CoV antibody by Western blot analysis were used to set up the baseline for the EIA performed as described in ref. 22. Nunc immunoplates coated with 20 ng of purified (His)6-tagged recombinant bat-SARS-CoV N protein per well were used. Detection was performed by using 1:2,000 horseradish peroxidase-conjugated protein G and 3,3',5,5'-tetramethylbenzidine, both from Zymed. Each sample was tested in duplicate, and the mean absorbance for each serum was calculated.
Specificity of Recombinant bat-SARS-CoV N Protein-Based Western Blot Analysis and EIA. To evaluate the specificity of the recombinant N protein-based Western blot assay and EIA, convalescent human serum samples from patients with recent infections by HCoV-OC43 (n = 13), HCoV-229E (n = 9), HCoV-NL63 (n = 5), and CoV-HKU1 (n = 11), positive for specific antibodies against the respective CoV, were subject to Western blot assay and EIA against recombinant N protein of bat-SARS-CoV.
Neutralization Assays. Because attempts to passage bat-SARS-CoV in cell cultures were not successful, neutralization assays for human SARS-CoV were carried out as described in ref. 9. Animal sera serially diluted from 1:20 to 1:640 were mixed with 100 tissue culture 50% infective dose of SARS-CoV isolate HKU-39849. Human sera from SARS patients with neutralizing antibody titer of 1:160 were included as a positive control. After incubation for 1 h at 37°C, the mixture was inoculated in triplicate onto 96-well plates of FRhK-4 cell cultures. Results were recorded after 3 days of incubation at 37°C.
Quantitative RT-PCR. Quantitaive RT-PCR was performed on anal swabs of bats positive for bat-SARS-CoV by RT-PCR or antibody by EIA. cDNA was amplified in SYBR Green I fluorescence reactions (Roche) using specific primers (5'-TGTGACAGAGCCATGCCTAA-3' and 5'-ATCTTATTACCATCAGTTGAAAGA-3') as described in ref. 7. A plasmid with the target sequence was used for generating the standard curve. At the end of the assay, PCR products (280-bp fragment of pol) were subjected to melting curve analysis (65-95°C, 0.1°C/s) to confirm the specificity of the assay.
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Results |
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The three genomes had 88% nucleotide and 93% amino acid identities to 10 human and civet SARS-CoV isolated from different locations and at differing times (Table 3). Most differences between the bat-SARS-CoV genomes and human and civet SARS-CoV genomes were observed in the S gene, ORF 3, and ORF 8 (Table 4), which also were the regions where most variations were observed in human SARS-CoV and civet SARS-CoV genomes (10). Compared with SARS-CoV from humans and civets, there were 11 insertions and 15 deletions in the bat-SARS-CoV genome, located in the 5' noncoding region, nsp3 of ORF 1ab, S gene, ORF 3, and ORF 8. However, the 29-bp region, deleted in most human SARS-CoV, is present, as in civet SARS-CoV (Fig. 5, which is published as supporting information on the PNAS web site).
ORF 3 (274 aa) had 81% identities to ORF 3a of SARS-CoV. ORF 3b of SARS-CoV is prematurely terminated in bat-SARS-CoV because of nucleotide substitution at position 25748 (TCA 
TAA) (Fig. 6, which is published as supporting information on the PNAS web site). Because the transcription regulatory sequence is not found upstream of ORF 3b, this ORF of SARS-CoV may not be functional.
Among all ORFs, ORF 8 (121 aa) had the lowest identity to the corresponding protein of SARS-CoV. Similar to civet SARS-CoV, a 29-bp insertion, absent in most human SARS-CoV, was found, resulting in a longer ORF than ORF 8a of human SAR-CoV with the absence of ORF 8b (Fig. 7, which is published as supporting information on the PNAS web site). As for the 29-bp insertion (5'-CCAATACATTACTATTCGGACTGGTTTAT-3'), there were 12 nucleotide substitutions, compared with its counterpart in civet SARS-CoV (5'-CCTACTGGTTACCAACCTGAATGGAATAT-3'). The ORF 8 displayed only 33% amino acid identities to that of civet SARS-CoV, which suggests that the encoded proteins may function differently in these viruses.
Because the S protein had only 79-80% amino acid identities with that of SARS-CoV and encodes the receptor-binding site, the complete S genes were sequenced from 11 additional samples. When these 14 sequences were compared with human and civet SARS-CoV, 958 nucleotide polymorphisms (59% nonsynonymous) were noted (Tables 6 and 7, which are published as supporting information on the PNAS web site). A total of 890 (58% nonsynonymous) of the 958 nucleotide polymorphisms appeared to distinguish between bat-SARS-CoV and SARS-CoV, suggesting that the S of bat-SARS-CoV is distinct from that of human and civet SARS-CoV. Whereas 35 of the 43 nucleotide polymorphisms among the 10 human and civet SARS-CoV sequences were nonsynonymous changes, only 2 of the 8 nucleotide polymorphisms among the 14 sequences of bat-SARS-CoV were nonsynonymous (Table 8, which is published as supporting information on the PNAS web site). Similar to SARS-CoV, the basic amino acid cleavage site found in S protein of group 2 and 3 CoV is absent. Nevertheless, a recent study detected a cleaved S2 fragment in the lysate of cells infected with SARS-CoV, suggesting proteolytic processing of S protein of SARS-CoV in host cells. The proposed cleavage site in SARS-CoV (RS667-668) also is found in bat-SARS-CoV (RS653-654) (27). Further studies are required to determine whether the S protein of bat-SARS-CoV also is cleaved into S1 and S2 subunits. For SARS-CoV, both angiotensin-converting enzyme 2 (ACE2) and CD209L (L-SIGN) were shown to be receptors (28, 29). Although the important amino acid residues for binding to CD209L are yet to be defined, a 193-aa fragment in the S1 domain of SARS-CoV (residues 318-510) has been found essential for binding to ACE2 (30). A shorter homologous fragment of 176 aa with 73% identities was identified in bat-SARS-CoV (Fig. 8, which is published as supporting information on the PNAS web site). Within this fragment, the two residues that contribute most substantially to ACE2 association (E452 and D454) (30) and five of the seven cysteines in SARS-CoV also are present. However, the other two cysteines (C467 and C474) in SARS-CoV, alterations of which are shown to prevent efficient precipitation of ACE2 (30), are absent in bat-SARS-CoV.
The rest of the bat-SARS-CoV genome shared similar features with SARS-CoV. A putative transcription regulatory sequence motif, 5'-ACGAAC-3', identical to that of SARS-CoV (31), was found at the 3' end of the putative 5' leader sequence and precedes each ORF except ORF 7b.
Serological Studies. Only 1 of the 13 human serum samples from patients with recent infections by HCoV-OC43 was positive in the recombinant bat-SARS-CoV N protein-based EIA (with titer of 1:400) and Western blot analysis (with a very faint band). None of the other 12 sera from patients with recent infections by HCoV-OC43, the 9 sera from patients with recent infections by HCoV-229E, the 5 sera from patients with recent infections by HCoV-NL63, and the 11 sera from patients with recent infections by CoV-HKU1, tested positive by the recombinant bat-SARS-CoV N protein-based EIA or Western blot analysis. Antibody detection in animal serum samples with sufficient quantities was performed by bat-SARS-CoV N protein-based Western blot analysis and EIA, and neutralization tests against human SARS-CoV. Among tested sera from Chinese horseshoe bats, 12 (67%) of 18 were positive for bat-SARS-CoV antibody by Western blot analysis (Fig. 3) and 31 (84%) of 37 by EIA with titer 
1:400, compared with only 8 (42%) of 19 for human SARS-CoV-neutralizing antibody with titer 1:20 (Table 1). Interestingly, bats with neutralizing antibody had a lower viral load in their anal swabs (P = 0.016; Student's t test). Quantitative RT-PCR also identified the presence of bat-SARS-CoV in five additional bats negative by RT-PCR. Antibodies were not detected in samples from other bat species or animals from the present surveillance study.
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Discussion |
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A CoV closely related to SARS-CoV, bat-SARS-CoV, was identified from 23 of 59 (39%) anal swabs from the species R. sinicus in this study. Serological studies showed that 67% and 84% of tested sera from Chinese horseshoe bats were positive for antibodies against recombinant bat-SARS-CoV N protein by Western blot analysis and EIA, respectively. The presence of cross-reacting neutralizing antibodies to human SARS-CoV is not unexpected, because there is high degree of homology between the predicted proteins of bat-SARS-CoV and SARS-CoV. Despite this cross-reaction, using sera of patients infected with group 1 (HCoV-229E and HCoV-NL63) and group 2 (HCoV-OC43 and CoV-HKU1) CoV, we showed that the Western blot assay and EIA were likely to be specific for SARS-CoV-like viruses. Such results are in line with previous findings that cross-reactions of HCoV-229E and HCoV-OC43 to human SARS-CoV N protein were uncommon (32, 33). Although cross-reactions between bat-SARS-CoV and yet unidentified, closely related CoV cannot be excluded, it is unlikely that significant proportions of positive reactions by the present Western blot analysis and EIA were due to cross-reacting antibodies against the group 1 CoV identified in bats. Moreover, only bat-SARS-CoV genomes but not human or civet SARS-CoV were detected in bats positive for antibodies against bat-SARS-CoV N protein in the present study.
The phylogenetic distance from SARS-CoV and the presence of the 29-bp insertion in ORF 8 of bat-SARS-CoV genomes suggest that bat-SARS-CoV is unlikely to be a result of transmission of SARS-CoV from humans to bats. Instead, bat-SARS-CoV and civet SARS-CoV are likely to have a common ancestor. Because these positive samples were collected within a short period, it is not possible to estimate the evolutionary rate of bat-SARS-CoV and the time of possible interspecies transmission. BCoV is suspected to have jumped to humans as HCoV-OC43 in 1890, according to estimation from molecular clock analysis (34). The phylogenetic distance between BCoV and HCoV-OC43 is comparable to that between bat-SARS-CoV and SARS-CoV (Fig. 2). Although the HKSAR is an urbanized, subtropical city, it has extensive natural areas with 52 terrestrial mammals, including 22 bat species. Chinese horseshoe bat (R. sinicus), belonging to the family Rhinolophidae of the order Chiroptera under Microchiroptera (microbats), is an insectivorous species widely distributed in forested areas throughout the HKSAR and China (www.hkbiodiversity.net). R. sinicus was previously called R. rouxii subspecies sinicus, but recent karyotyping study has elevated its status to a separate species (35). Although no local data on its migration patterns are available, members of Rhinolophus may migrate up to 30 km for hibernation in winter (36, 37). Interestingly, the nearest wildlife market previously found to have animals with SARS-CoV in Shenzhen is only 17 km away from the locations with bats harboring bat-SARS-CoV in the HKSAR (Fig. 1a). All samples that were positive for bat-SARS-CoV were collected during winter and spring. Nevertheless, the present data do not allow direct inference on the direction of interspecies transmission of SARS-CoV-like viruses or their ancestral relationships.
The pathogenicity and host range of bat-SARS-CoV remain to be determined. In this study, the virus could be detected only in anal swabs, suggesting that it may have enteric tropism, in line with findings in SARS-CoV (38). All bats with bat-SARS-CoV did not display obvious signs of disease. Although analysis of the S gene revealed the presence of most amino acid residues in SARS-CoV crucial for binding ACE2, more extensive surveillance studies and receptor-binding experiments are necessary to determine the host range and potential of interspecies transmission of bat-SARS-CoV.
Bats, the only flying mammals, account for 20% of the 4,800 mammalian species recorded in the world. They are an important reservoir of emerging zoonotic viruses, including rabies virus, lyssavirus, Hendra and Nipah viruses, St. Louis encephalitis virus, and fungi such as Histoplasma (39, 40). The feces of bats (excrementum vespertilionis 
) are used in traditional Chinese medicine (www.aompress.com/pdf/singleherbs.pdf). The Chinese and Manadonese populations of Malaysia and Indonesia consider bat meat a delicacy. Many Chinese also believe that eating bat meat can cure asthma, kidney ailments, and general malaise (41). In this study, three different CoV were identified from wild bats in the HKSAR, suggesting that these animals are an important reservoir for CoV. Continuous surveillance for CoV in these flying mammals with roosting behavior is indicated to assess their potential threats to human health.
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Acknowledgements |
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Footnotes |
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Abbreviations: CoV, coronavirus; HCoV, human CoV; BCoV, bovine CoV; SARS, severe acute respiratory syndrome; HKSAR, Hong Kong Special Administrative Region; S, spike; N, nucleocapsid; EIA, enzyme immunoassay; ACE2, angiotensin-converting enzyme 2.
Data deposition: The sequences reported in this paper have been deposited in the GenBank database (accession nos. DQ022305 [GenBank] , DQ084199 [GenBank] , and DQ084200 [GenBank] ).
S.K.P.L., P.C.Y.W., and K.-Y.Y. contributed equally to this work. 
|| To whom correspondence should be addressed. E-mail: kyyuen{at}hkucc.hku.hk.
© 2005 by The National Academy of Sciences of the USA
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