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Review

Bat Coronaviruses in China

by
Yi Fan
1,2,
Kai Zhao
1,2,
Zheng-Li Shi
1,2 and
Peng Zhou
1,2,*
1
CAS Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China
2
University of Chinese Academy of Sciences, Beijing 100049, China
*
Author to whom correspondence should be addressed.
Viruses 2019, 11(3), 210; https://doi.org/10.3390/v11030210
Submission received: 29 January 2019 / Revised: 26 February 2019 / Accepted: 26 February 2019 / Published: 2 March 2019
(This article belongs to the Special Issue Viruses and Bats 2019)
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Abstract

:
During the past two decades, three zoonotic coronaviruses have been identified as the cause of large-scale disease outbreaks–Severe Acute Respiratory Syndrome (SARS), Middle East Respiratory Syndrome (MERS), and Swine Acute Diarrhea Syndrome (SADS). SARS and MERS emerged in 2003 and 2012, respectively, and caused a worldwide pandemic that claimed thousands of human lives, while SADS struck the swine industry in 2017. They have common characteristics, such as they are all highly pathogenic to humans or livestock, their agents originated from bats, and two of them originated in China. Thus, it is highly likely that future SARS- or MERS-like coronavirus outbreaks will originate from bats, and there is an increased probability that this will occur in China. Therefore, the investigation of bat coronaviruses becomes an urgent issue for the detection of early warning signs, which in turn minimizes the impact of such future outbreaks in China. The purpose of the review is to summarize the current knowledge on viral diversity, reservoir hosts, and the geographical distributions of bat coronaviruses in China, and eventually we aim to predict virus hotspots and their cross-species transmission potential.

1. Introduction

Fifteen years after the first highly pathogenic human coronavirus caused the severe acute respiratory syndrome coronavirus (SARS-CoV) outbreak, another severe acute diarrhea syndrome coronavirus (SADS-CoV) devastated livestock production by causing fatal diseases in pigs. Both outbreaks began in China and were caused by coronaviruses of bat origin [1,2]. This increased the urgency to study bat coronaviruses in China to understand their potential of causing another virus outbreak.
In this review, we collected information from past epidemiology studies on bat coronaviruses in China, including the virus species identified, their host species, and their geographical distributions. We also discuss the future prospects of bat coronaviruses cross-species transmission and spread in China.

2. Why Study Bat Coronaviruses in China?

2.1. Coronavirus Taxonomy

Coronaviruses (CoVs) belong to the subfamily Orthocoronavirinae in the family Coronaviridae and the order Nidovirales. CoVs have an enveloped, crown-like viral particle from which they were named after. The CoV genome is a positive-sense, single-strand RNA (+ssRNA), 27–32 kb in size, which is the second largest of all RNA virus genomes. Typically, two thirds of the genomic RNA encodes for two large overlapping polyproteins, ORF1a and ORF1b, that are processed into the viral polymerase (RdRp) and other nonstructural proteins involved in RNA synthesis or host response modulation. The other third of the genome encodes for four structural proteins (spike (S), envelope (E), membrane (M), and nucleocapsid (N)) and other accessory proteins. While the ORF1a/ORF1b and the four structural proteins are relatively consistent, the length of the CoV genome is largely dependent on the number and size of accessory proteins [3].
Compared with other RNA viruses, the expanded genome size of CoVs is believed to be associated with increased replication fidelity, after acquiring genes encoding RNA-processing enzymes [4]. Genome expansion further facilitates the acquisition of genes encoding accessory proteins that are beneficial for CoVs to adapt to a specific host [5]. As a result, genome changes caused by recombination, gene interchange, and gene insertion or deletion are common among CoVs. The CoV subfamily is expanding rapidly, due to the application of next generation sequencing which has increased the detection and identification of new CoV species. As a result, CoV taxonomy is constantly changing. According to the latest International Committee of Taxonomy of Viruses (ICTV) classification, there are four genera (α-, β-, δ-, and γ-) consisting of thirty-eight unique species in the subfamily [6]. The number of species will continue to increase, as there are still many unclassified CoVs [7,8].
CoVs cause disease in a variety of domestic and wild animals as well as in humans, where α- and β-CoVs mainly infect mammals and γ- and δ-CoVs mainly infect birds (Table 1). Two highly pathogenic β-CoVs, SARS-CoV, and MERS-CoV have caused pandemics in humans since 2002 [1,9]. Originating in China and then spreading to other parts of the world, SARS-CoV infected around 8000 individuals with an overall mortality of 10% during the 2002–2003 pandemic [1]. Since its emergence in 2012 in the Middle East, MERS-CoV spread to 27 countries, resulting in 2249 laboratory-confirmed cases of infection with an average mortality of 35.5% (until September 2018) [9]. Besides these two viruses, α-CoVs 229E and NL63 and β-CoVs OC43 and HKU1 can also cause respiratory diseases in humans [10]. Moreover, CoVs cause pandemic disease in domestic and wild animals (Table 1). SADS-CoV was recently identified as the etiological agent responsible for a large-scale outbreak of fatal disease in pigs in China that caused the death of more than 20,000 piglets [2]. Porcine epidemic diarrhea virus (PEDV) and transmissible gastroenteritis virus (TGEV) that belong to α-CoV and porcine δ-CoV (PDCoV) are also important emerging and re-emerging viruses in pigs that pose significant economic threat to the swine industry [11]. In addition, avian infectious bronchitis virus (IBV, γ-CoV) causes a highly contagious disease that affects poultry production worldwide [12]. Coronaviruses have also been associated with catarrhal gastroenteritis in mink (MCoV) and whale deaths (BWCoV-SW1) [13,14].

2.2. Linking Bats to Coronaviruses

Bat are the only mammals with the capability of powered flight, which enables them to have a longer range of migration compared to land mammals. Bats are also the second largest order of mammals, accounting for about a fifth of all mammalian species, and are distributed worldwide. Phylogenetic analysis classified bats into two large suborders—the Yinpterochiroptera, consisting of one Pteropodidae (megabat) and five Rhinolophoidea (microbat) families, and the Yangochiroptera comprising a total of thirteen microbat families [15].
It is hypothesized that flight provided the selection pressure for coexistence with viruses, while the migratory ability of bats has particular relevance in the context of disease transmission [16]. Indeed, bats were linked to a few highly pathogenic human diseases, supporting this hypothesis. Some of these well characterized bat viruses, including bat lyssaviruses (Rabies virus), henipaviruses (Nipah virus and Hendra virus), CoVs (SARS-CoV, MERS-CoV, and SADS-CoV), and filoviruses (Marburg virus, Ebola virus, and Mengla virus), pose a great threat to human health [16,17]. A comprehensive analysis of mammalian host–virus relationships demonstrated that bats harbor a significantly higher proportion of zoonotic viruses than other mammalian orders [18]. Viruses from most of the viral families can be found in bats [16].
Bats are now recognized as important reservoir hosts of CoVs (Table 1). Although civet cats were initially identified as the animal origin of SARS-CoV, bats were soon found to be the most likely natural reservoir hosts of this virus [19,20,21]. Long-term surveillance revealed an average 10% SARS-related CoV nucleotide positivity in bats, including some viruses that can use same human entry receptor ACE2 as SARS-CoV [7,22]. Similarly, bats have been proposed to harbor the progenitor viruses of MERS-CoV, although dromedary camels can transmit this virus to humans directly [9]. The most recent SADS-CoV spillover was traced back to bats [2]. In addition, bats also carry α-CoVs that are related to pathogenic human 229E- and NL63-CoVs, as well as pandemic swine coronavirus PEDV [23,24]. In summary, bats carry major α- (10 out of 17) and β- (7 out of 12) CoV species that may spillover to humans and cause disease (Table 1). Attributed to the wide distribution of bats, CoVs can be found worldwide, including China [25].

2.3. Why China?

Two bat CoVs caused outbreaks in China; it is thus urgent to study the reasons to avoid future outbreaks. China is the third largest territory and is also the most populous nation in the world. A vast homeland plus diverse climates bring about great biodiversity including that of bats and bat-borne viruses—most of the ICTV coronavirus species (22/38) were named by Chinese scientists studying local bats or other mammals. The majority of the CoVs can be found in China (Table 1). Moreover, most of the bat hosts of these CoVs live near humans, potentially transmitting viruses to humans and livestock. Chinese food culture maintains that live slaughtered animals are more nutritious, and this belief may enhance viral transmission.
It is generally believed that bat-borne CoVs will re-emerge to cause the next disease outbreak. In this regard, China is a likely hotspot. The challenge is to predict when and where, so that we can try our best to prevent such outbreaks.

3. Bat Coronaviruses That Are Associated with Diseases

3.1. SARS-Related Coronaviruses

In November 2012, the first case of SARS was recorded in Foshan city, Guangdong Province, China (Figure 1). In 2005, two independent Chinese groups reported the first bat SARS-related CoV (SARSr-CoV) that was closely related to human SARS-CoV, implying a bat origin of the latter [20,21]. Since then, more bat SARSr-CoV isolates were identified in China (Table 1). Genome identities of these bat SARSr-CoVs are as high as 92% to human SARS-CoV, but their major receptor binding spike proteins cannot use the human virus entry receptor ACE2 [67]. Whether they are the progenitor viruses of SARS-CoV is debatable. In 2013, the isolation of a bat SARSr-CoV that uses the ACE2 receptor provided the strongest evidence of the bat origin of SARS-CoV [22]. Furthermore, the building blocks for SARS-CoV were identified from eleven different SARSr-CoV viral strains in a five-year surveillance program in a cave inhabited by multiple species of horseshoe bats in Yunnan Province, China [62].
SARSr-CoVs found in China show great genomic diversity (Figure 2). Sequence identities of the conserved 440 bp RdRp region ranges from 80 to 100% with human SARS-CoV. CoV diversity in bats is thought to be shaped by both species richness and geographical distribution, and CoVs exhibit clustering at the bat genera level, with these genus-specific clusters largely associated with distinct CoV species [25]. Our analysis supports this theory. SARSr-CoVs are present in different bat species but all belong to the family of Rhinolophidae and Hipposideridae (Figure 1). Chaerephon plicata bats were also reported as carriers in one study, but this cannot be conclusively supported without molecular identification of the bat species [8]. In China, horseshoe bat species (Rhinolophus spp.) are widely distributed, including R. sinicus, R. ferrumequinum, R. macrotis, R. pearsoni, and R. pusillus, and are also the most frequent SARSr-CoV carriers throughout the nation [7,8,20,21,22,27,40,43,45,58,59,61,62,63,68] (Figure 1). The most variable regions among bat SARSr-CoVs are the S and ORF8 genes [62]. The S protein in certain strains is capable of using human ACE2 as a receptor and thus poses a direct threat to humans [69]. Interestingly, all the SARSr-CoVs that are capable of using human ACE2 were found in R. sinicus in Yunnan Province [7,22,27,62]. Other SARSr-CoVs that cannot use human ACE2 were distributed in multiple provinces, from north Jilin, Shaanxi, Shanxi to south Hubei, Zhejiang, Yunnan, Guizhou, and Guangdong (Figure 1). Another protein, ORF8, was suggested to be important for interspecies transmission, as most human SARS-CoV epidemic strains contain a signature 29-nucleotide deletion in ORF8 compared to civet SARSr-CoVs, which results in the formation of two separate open reading frames, ORF 8a and 8b [40]. Only two R. ferrumequinum and one R. sinicus from Yunnan Province carried viruses that possess ORF8 proteins with exceptionally high amino acid identities to that of human/civet SARSr-CoVs [40,62]. It was strongly suggested that SARS-CoV most likely originated from Yunnan Rhinolophus bats via recombination events among existing SARSr-CoVs.
These studies revealed that various SARSr-CoVs capable of using human ACE2 are still circulating among bats in China, highlighting the possibly of another SARS-like disease outbreak. Certain areas in Yunnan Province are hotspots for spillover. To support this hypothesis, we provide serological evidence of bat SARSr-CoV infection in humans in Yunnan Province where no prior exposure to SARS-CoV was recorded [70]. The majority of the SARSr-CoVs appear not able to use ACE2, but their infectivity or pathogenesis to humans are still unknown. Frequent interspecies recombination may result in another human infectious coronavirus from these SARSr-CoVs. Furthermore, there are still unanswered questions about SARS, e.g., ‘Why did the first SARS case occur in Guangdong Province, but all the human-ACE2-using SARSr-CoVs were found in Yunnan Province?’ and ’Why does R. sinicus in certain areas carry human-ACE2-using SARSr-CoVs but no other Rhinolophus species carry the same viruses?’ Above all, further extensive surveillance of SARSr-CoVs in China is warranted.

3.2. MERS-Cluster Coronaviruses

Different to bat SARSr-CoV, MERS-cluster CoVs were found in bats before the MERS disease outbreaks. Two bat CoVs, Tylonycteris HKU4 and Pipistrellus HKU5 were first described as putative group 2c CoVs in 2006 in China. They were associated with the HCoV-EMC (MERS-CoV) that started the 2012 pandemic [9,38,39]. It is generally accepted that Middle East dromedary camels were the major animal source for the zoonotic transmission of human MERS, while bats harbor CoVs that shared common ancestry with MERS-CoV [71]. Extensive global surveys revealed a wide distribution of largely diverged MERS-cluster CoVs (lineage 2c CoVs) [71]. Two closely related Neoromicia zuluensis bat CoVs, NeoCoV and PREDICT/PDF-2180, were subsequently found, further supporting the idea that MERS-CoV was descended from an ancestral virus of African bats [72,73]. So far, three species of lineage 2c CoVs have been found in bats, according to the latest CoV taxonomy reports. Based on phylogenetic trees constructed using RdRp, ORF1, S1, and N sequences, bat MERS-related CoVs (MERSr-CoVs) are the closest relatives of MERS-CoV, followed by HKU4-CoV and HKU5-CoV. However, in the S1 region, MERS-CoV was much closer to HKU4-CoV than to MERSr-CoV or HKU5-CoV. Likewise, pseudovirus assays showed that the MERSr-CoV (HKU25 and 422CoV) spike protein can use human DPP4 for entry into hDPP4-expressing cells, although with lower efficiency than that of MERS-CoV or HKU4-CoV spike proteins [49,50]. There is no evidence of HKU5-CoV using the human DPP4 receptor [74].
All three types of bat MERS-cluster CoVs can be found in China (Figure 1 and Figure 2). Their reservoir hosts all belong to the Vespertilionidae family. MERSr-CoV can be found in multiple bat species, including Pipistrellus bats (P. abramus and P. pipistrellus), great evening bats (Ia io), particolored bats (Vespertilio superans), and Chinese pipistrelle bats (Hypsugo pulveratus) [49,50,52]. Due to this wide host spectrum, MERSr-CoV also showed a large genetic diversity, ranging from 72 to 100% in the conserved 440 bp RdRp region. In contrast, HKU4-CoVs were only carried by Tylonycteris bats (T. pachypus and T. robustula) and were relatively conserved [38,39,49] (Figure 2). HKU5-CoVs were found in different Pipistrellus bats (P. abramus, P. pipistrellus, P. minus, and P. spp.) [8,36,38,39,49,51]. Like HKU4-CoVs, they are also relatively conserved. The range of distribution varies, depending on MERS-cluster CoV species. HKU5-CoVs should be the most widely distributed CoVs among the three as their hosts, Pipistrellus bats, live close to humans. However, the reported CoV positive samples can only be found in Guangdong, Hong Kong, and Macau, possibly due to a lack of investigation in other provinces. In contrast, MERSr-CoVs were reported in multiple bat species in Sichuan, Guangdong, and Hong Kong at a much lower level than HKU5-CoVs. Similarly, Tylonycteris bats are a rare bat species that live in bamboo, which restricted the distribution of HKU4-CoVs to certain locations in Guangdong, Guangxi, Yunnan, Guizhou, Hong Kong, and Macau (Figure 1). To sum up, it appears that the risk of MERS-cluster CoV spillover to humans leading to an epidemic in China is low for the following reasons: (1) the geographical distribution of MERSr-CoVs and HKU4-CoVs that have the potential to infect humans (capable of using human entry receptors) is limited, and (2) HKU5-CoVs that widely exist in Chinese bats across the nation have not obtained the ability of using human entry receptors. However, we should not underestimate the possibility of recombination among different bat CoVs that lead to the generation of potential pandemic viruses.

3.3. HKU2 (SADS)-Related CoV (HKU2r-CoV)

HKU2r-CoVs have only been reported in China and Kenya. From studies in China, HKU2r-CoVs have been frequently found in Rhinolophus bats (R. affinis, R. sinicus, R. rex, and R. pusillus) in several provinces before the SADS outbreak [2,7,8,38,41,44]. So far, the virus has been reported in Hong Kong, Guangdong, Yunnan, and Tibet. There are perhaps more to be discovered in other provinces considering the wide range of Rhinolophus bats. Notably, these bat species, which constantly interact with both livestock and humans in China, also harbor SARSr-CoVs (see Section 3.1). Likewise, HKU2r-CoVs showed a high genetic diversity with SARSr-CoVs (Figure 2). Due to these characteristics, HKU2r-CoVs were listed as viruses that were highly likely to cross species to humans. The novel HKU2r-CoV, swine acute diarrhea syndrome coronavirus (SADS-CoV), was identified as the etiological agent responsible for a large-scale outbreak of fatal disease in pigs in China, Guangdong Province in 2017 [2]. The entry receptor of SADS-CoV has not been identified, yet this virus showed a capacity for infecting a wide range of human, swine, and bat cells (unpublished data). In China, the high density of pig farms and the wide distribution of host bat species promote the possibility of future HKU2r-CoV cross-species transmission [75]. Thus, studies on bat HKU2r-CoVs spillover potential and their pathogenesis are urgent.

4. A SADS-CoV Model of Prediction and Other Hotspot Viruses

To predict the next CoV that will cause a virus outbreak in future, we list the general factors that may contribute to this outbreak. Firstly, bats host a large number of highly diverse CoVs. It is known that CoV genomes regularly undergo recombination during infection, and a rich gene pool can facilitate this process. Secondly, bat species are widely distributed and live close to humans. Thirdly, the viruses are pathogenic and transmissible. In this context, SADS-CoV and SARS-CoV outbreaks in China are not unexpected. By this model, there are other CoVs that have not yet caused virus outbreaks but should be monitored.
Within the family Vespertilionidae, the mouse-eared bats (Myotis) which favor roosting in abandoned human facilities are also a widespread genus of bats besides Pipistrellus bats. They carry a large number and genetically diversified HKU6-CoVs that are closely related to Myotis ricketti α-CoV Sax-2011 [36,38]. Moreover, bent-winged bats (Miniopterus spp.) carry a large variety of α-CoVs. One of the most frequently detected viruses is HKU8-CoV, which was first described circulating in M. pusillus in Hong Kong in 2005. Later, it was also found in M. magnate, M. fuliginosus, and M. schreibersii in Hong Kong, Guangdong, Yunnan, Fujian, and Hubei provinces, showing a great genetic diversity [32,33,34,35,37,41,60] (Figure 1). Besides HKU8-CoVs, bent-winged bats (Miniopterus spp.) also harbor a large amount of Miniopterus bat CoV 1 (BtMiCoV-1), which were called CoV1A or CoV1B previously. This viral species was found almost as frequently as HKU8-CoV in multiple provinces in China in Miniopterus bats, although these viruses showed a relatively small sequence variation between each other [32,33,34,35,37,41,60]. Genetic analysis indicates that BtMiCoV-1, HKU8-CoV, and HKU7-CoV (previous name) are different but closely related CoVs circulating in bent-winged bats and may have descended from a common ancestor [34]. Additionally, Rousettus leschenaultii bats in the family of Pteropodidae harbor HKU9-CoVs. As a fruit bat, Rousettus leschenaultii has a wider flying range than most of the insectivorous bats in China, thus it may carry viruses over long distances. A comparison of the reported HKU9-CoV sequences showed a high genetic diversity within this viral species [55,56,57] (Figure 2). The last CoV that should be mentioned is HKU10-CoV. HKU10-CoVs can be found in bats from different genera (Rousettus leschenaultii and Hipposideros pomona), suggesting interspecies transmission between bats [7,26,27,39]. A genetic difference can also be observed for this virus species (Figure 2). Above all, these viruses fit well in our SADS prediction model and should be monitored in our future studies.

5. Other Bat CoVs in China

In 2016, a novel β-CoV, Ro-BatCoVGCCDC1, was identified from the Rousettus leschenaultii bat. However, we confirmed the host was a closely related Eonycteris spelaea bat upon species identification and then renamed the virus as BtEoCoV-GCCDC1 (Table 1). The uniqueness of this virus is that it contains a gene that most likely originated from the p10 gene of a bat orthoreovirus [53]. A two-year follow-up study also illustrated that BtEoCoV-GCCDC1 persistently circulates among bats. Different to the genetically diverged HKU9-CoV, this virus is highly conserved (Figure 2). BtEoCoV-GCCDC1 has only been found in south Yunnan Province so far [54,55]. In addition, there are other bat CoVs that have been identified in China: Rhinolophus ferrumequinum α-CoV HuB-2013 [8], Myotis ricketti α-CoV Sax-2011 [8,37], Nyctalus velutinus α-CoV SC-2013 [8], Scotophilus bat CoV 512 [37], Hipposideros bat β-CoV Zhejiang2013, and a Murina leucogaster bat CoV, which has been described as the evolutionary ancestor of PEDV [37]. Notably, there are still many unclassified bat CoVs circulating in China, particularly in the northern part of the nation where bat viruses were rarely studied (Figure 1). According to the criteria defined by the ICTV, the CoV family will most likely expand following further investigation of bat CoVs in China.

6. Coexistence of Different Coronaviruses or Other Viruses in Bats

The coexistence of more than two viruses in the same bat is quite common for some bat species. The coexistence of Miniopterus bat CoV 1 and HKU8-CoV in one bat has been frequently reported [7,34]. Another example is the coexistence between Rhinolophus HKU2-CoVs (SADS-CoV) and SARSr-CoVs that caused the virus outbreaks, respectively [2,45]. Real-time monitoring this bat genus is necessary for the prevention of future SARS-like outbreaks. Moreover, two or more distinct genotypes of HKU9-CoVs were reported to coexist in a single Rousettus bat [56]. The coexistence of HKU9-CoVs and a new identified bat filovirus (Mengla virus) that is phylogenetically related to the Ebola and Marburg viruses was also identified from Rousettus bats [17,55]. Given that a bat orthoreovirus p10 gene was incorporated in the BtEoCoV-GCCDC1 genome, recombination between the bat filovirus and HKU9-CoV cannot be excluded. Other pairs were also recorded—HKU8-CoV with unclassified α-CoV [7], HKU2-CoV with unclassified α-CoV [7], HKU10-CoV with unclassified β-CoV [7], and HKU6-CoV with bat adenovirus [36].

7. Conclusions

Two bat origin CoVs caused large-scale epidemics in China over fourteen years, highlighting the risk of a future bat CoV outbreak in this nation. In this review, we have summarized the current findings related to bat CoV epidemiology in China, aiming to explore the associations between CoV species, bat species, and geographical locations, and eventually we aim to predict the cross-species transmission potential of these bat CoVs. Admittedly, the analysis may be affected by inaccurate or incomplete data. For example, not all research groups performed bat species identification or used Global Positioning System (GPS) during bat sampling. Bats in the north or west provinces were not surveyed either. Nonetheless, we believe this analysis is a good starting point for further research. Moreover, there are other outstanding questions that should be addressed in future studies: (1) given that most of the ICTV classified CoV species are from bats, why there are so many genetically divergent CoVs in bats, (2) the pathogenesis of most bat CoVs in humans remains unknown as the viruses have never been isolated or rescued—apart from the viruses identified during the outbreaks, many viruses pose a threat to human health, (3) although SARS-CoV and SADS-CoV were known to be transmitted from bats to human or swine, their exact transmission routes are unknown, and (4) why bats can maintain CoVs long-term without showing clinical symptoms of diseases. A unique bat immunity model has been proposed. The authors have shown that constitutively expressed bat interferon α may protect bats from infection [76], while some particularly dampened immune pathways may allow bats to have a higher tolerance against viral diseases [77]. While we start to unveil the mystery of unique bat immunity, there is still long way to go before we can fully understand the relationship between bats and coronaviruses.

Author Contributions

P.Z. and Z.-L.S. designed the study. Y.F. and K.Z. analyzed the data. P.Z. and Y.F. prepared the manuscript.

Funding

The work was supported by China’s National Science and Technology Major Project on Infectious Diseases (2018ZX10101004) and the National Natural Science Foundation of China (Excellent Young Scholars to PZ 81822028 and 81661148058).

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Drosten, C.; Gunther, S.; Preiser, W.; van der Werf, S.; Brodt, H.R.; Becker, S.; Rabenau, H.; Panning, M.; Kolesnikova, L.; Fouchier, R.A.M.; et al. Identification of a novel coronavirus in patients with severe acute respiratory syndrome. N. Engl. J. Med. 2003, 348, 1967–1976. [Google Scholar] [CrossRef] [PubMed]
  2. Zhou, P.; Fan, H.; Lan, T.; Yang, X.L.; Shi, W.F.; Zhang, W.; Zhu, Y.; Zhang, Y.W.; Xie, Q.M.; Mani, S.; et al. Fatal swine acute diarrhoea syndrome caused by an HKU2-related coronavirus of bat origin. Nature 2018, 556, 255. [Google Scholar] [CrossRef] [PubMed]
  3. Coronavirinae in ViralZone. Available online: https://viralzone.expasy.org/785 (accessed on 28 January 2019).
  4. Subissi, L.; Posthuma, C.C.; Collet, A.; Zevenhoven-Dobbe, J.C.; Gorbalenya, A.E.; Decroly, E.; Snijder, E.J.; Canard, B.; Imbert, I. One severe acute respiratory syndrome coronavirus protein complex integrates processive RNA polymerase and exonuclease activities. Proc. Natl. Acad. Sci. USA 2014, 111, E3900–E3909. [Google Scholar] [CrossRef] [PubMed]
  5. Forni, D.; Cagliani, R.; Clerici, M.; Sironi, M. Molecular Evolution of Human Coronavirus Genomes. Trends Microbiol. 2017, 25, 35–48. [Google Scholar] [CrossRef] [PubMed]
  6. ICTV Virus Taxonomy: 2018 Release. 2018. Available online: https://talk.ictvonline.org/taxonomy/ (accessed on 28 January 2019).
  7. Ge, X.Y.; Wang, N.; Zhang, W.; Hu, B.; Li, B.; Zhang, Y.Z.; Zhou, J.H.; Luo, C.M.; Yang, X.L.; Wu, L.J.; et al. Coexistence of multiple coronaviruses in several bat colonies in an abandoned mineshaft. Virol. Sin. 2016, 31, 31–40. [Google Scholar] [CrossRef] [PubMed]
  8. Wu, Z.; Yang, L.; Ren, X.; He, G.; Zhang, J.; Yang, J.; Qian, Z.; Dong, J.; Sun, L.; Zhu, Y.; et al. Deciphering the bat virome catalog to better understand the ecological diversity of bat viruses and the bat origin of emerging infectious diseases. ISME J. 2016, 10, 609–620. [Google Scholar] [CrossRef] [PubMed]
  9. Zaki, A.M.; van Boheemen, S.; Bestebroer, T.M.; Osterhaus, A.D.M.E.; Fouchier, R.A.M. Isolation of a Novel Coronavirus from a Man with Pneumonia in Saudi Arabia. N. Engl. J. Med. 2012, 367, 1814–1820. [Google Scholar] [CrossRef] [PubMed]
  10. Graham, R.L.; Donaldson, E.F.; Baric, R.S. A decade after SARS: Strategies for controlling emerging coronaviruses. Nat. Rev. Microbiol. 2013, 11, 836–848. [Google Scholar] [CrossRef] [PubMed]
  11. Zhang, Q.; Yoo, D. Immune evasion of porcine enteric coronaviruses and viral modulation of antiviral innate signaling. Virus Res. 2016, 226, 128–141. [Google Scholar] [CrossRef] [PubMed]
  12. Zhao, Y.; Zhang, H.; Zhao, J.; Zhong, Q.; Jin, J.H.; Zhang, G.Z. Evolution of infectious bronchitis virus in China over the past two decades. J. Gen. Virol. 2016, 97, 1566–1574. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  13. Mihindukulasuriya, K.A.; Wu, G.; St Leger, J.; Nordhausen, R.W.; Wang, D. Identification of a novel coronavirus from a beluga whale by using a panviral microarray. J. Virol. 2008, 82, 5084–5088. [Google Scholar] [CrossRef] [PubMed]
  14. Vlasova, A.N.; Halpin, R.; Wang, S.; Ghedin, E.; Spiro, D.J.; Saif, L.J. Molecular characterization of a new species in the genus Alphacoronavirus associated with mink epizootic catarrhal gastroenteritis. J. Gen. Virol. 2011, 92, 1369–1379. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  15. Teeling, E.C.; Springer, M.S.; Madsen, O.; Bates, P.; O’Brien, S.J.; Murphy, W.J. A molecular phylogeny for bats illuminates biogeography and the fossil record. Science 2005, 307, 580–584. [Google Scholar] [CrossRef] [PubMed]
  16. Wang, L.F.; Cowled, C. Bats and Viruses: A New Frontior of Emerging Infectious Diseases; John Wiley Sons Inc.: Hoboken, NJ, USA, 2015. [Google Scholar]
  17. Yang, X.L.; Tan, C.W.; Anderson, D.E.; Jiang, R.D.; Li, B.; Zhang, W.; Zhu, Y.; Lim, X.F.; Zhou, P.; Liu, X.L.; et al. Characterization of a filovirus (Mengla virus) from Rousettus bats in China. Nat. Microbiol. 2019. [Google Scholar] [CrossRef] [PubMed]
  18. Olival, K.J.; Hosseini, P.R.; Zambrana-Torrelio, C.; Ross, N.; Bogich, T.L.; Daszak, P. Host and viral traits predict zoonotic spillover from mammals. Nature 2017, 546, 646–650. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  19. Guan, Y.; Zheng, B.J.; He, Y.Q.; Liu, X.L.; Zhuang, Z.X.; Cheung, C.L.; Luo, S.W.; Li, P.H.; Zhang, L.J.; Guan, Y.J.; et al. Isolation and characterization of viruses related to the SARS coronavirus from animals in southern China. Science 2003, 302, 276–278. [Google Scholar] [CrossRef] [PubMed]
  20. Lau, S.K.P.; Woo, P.C.Y.; Li, K.S.M.; Huang, Y.; Tsoi, H.W.; Wong, B.H.L.; Wong, S.S.Y.; Leung, S.Y.; Chan, K.H.; Yuen, K.Y. Severe acute respiratory syndrome coronavirus-like virus in Chinese horseshoe bats. Proc. Natl. Acad. Sci. USA 2005, 102, 14040–14045. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  21. Li, W.D.; Shi, Z.L.; Yu, M.; Ren, W.Z.; Smith, C.; Epstein, J.H.; Wang, H.Z.; Crameri, G.; Hu, Z.H.; Zhang, H.J.; et al. Bats are natural reservoirs of SARS-like coronaviruses. Science 2005, 310, 676–679. [Google Scholar] [CrossRef] [PubMed]
  22. Ge, X.Y.; Li, J.L.; Yang, X.L.; Chmura, A.A.; Zhu, G.J.; Epstein, J.H.; Mazet, J.K.; Hu, B.; Zhang, W.; Peng, C.; et al. Isolation and characterization of a bat SARS-like coronavirus that uses the ACE2 receptor. Nature 2013, 503, 535. [Google Scholar] [CrossRef] [PubMed]
  23. Lacroix, A.; Duong, V.; Hul, V.; San, S.; Davun, H.; Omaliss, K.; Chea, S.; Hassanin, A.; Theppangna, W.; Silithammavong, S.; et al. Genetic diversity of coronaviruses in bats in Lao PDR and Cambodia. Infect. Genet. Evol. 2017, 48, 10–18. [Google Scholar] [CrossRef] [PubMed]
  24. Tao, Y.; Shi, M.; Chommanard, C.; Queen, K.; Zhang, J.; Markotter, W.; Kuzmin, I.V.; Holmes, E.C.; Tong, S. Surveillance of Bat Coronaviruses in Kenya Identifies Relatives of Human Coronaviruses NL63 and 229E and Their Recombination History. J. Virol. 2017, 91, e01953-16. [Google Scholar] [CrossRef] [PubMed]
  25. Leopardi, S.; Holmes, E.C.; Gastaldelli, M.; Tassoni, L.; Priori, P.; Scaravelli, D.; Zamperin, G.; De Benedictis, P. Interplay between co-divergence and cross-species transmission in the evolutionary history of bat coronaviruses. Infect. Genet. Evol. 2018, 58, 279–289. [Google Scholar] [CrossRef] [PubMed]
  26. Lau, S.K.P.; Li, K.S.M.; Tsang, A.K.L.; Shek, C.T.; Wang, M.; Choi, G.K.Y.; Guo, R.T.; Wong, B.H.L.; Poon, R.W.S.; Lam, C.S.F.; et al. Recent Transmission of a Novel Alphacoronavirus, Bat Coronavirus HKU10, from Leschenault’s Rousettes to Pomona Leaf-Nosed Bats: First Evidence of Interspecies Transmission of Coronavirus between Bats of Different Suborders. J. Virol. 2012, 86, 11906–11918. [Google Scholar] [CrossRef] [PubMed]
  27. He, B.; Zhang, Y.; Xu, L.; Yang, W.; Yang, F.; Feng, Y.; Xia, L.; Zhou, J.; Zhen, W.; Feng, Y.; et al. Identification of diverse alphacoronaviruses and genomic characterization of a novel severe acute respiratory syndrome-like coronavirus from bats in China. J. Virol. 2014, 88, 7070–7082. [Google Scholar] [CrossRef] [PubMed]
  28. Zeng, Z.Q.; Chen, D.H.; Tan, W.P.; Qiu, S.Y.; Xu, D.; Liang, H.X.; Chen, M.X.; Li, X.; Lin, Z.S.; Liu, W.K.; et al. Epidemiology and clinical characteristics of human coronaviruses OC43, 229E, NL63, and HKU1: A study of hospitalized children with acute respiratory tract infection in Guangzhou, China. Eur. J. Clin. Microbiol. Infect. Dis. 2018, 37, 363–369. [Google Scholar] [CrossRef] [PubMed]
  29. Yip, C.C.; Lam, C.S.; Luk, H.K.; Wong, E.Y.; Lee, R.A.; So, L.Y.; Chan, K.H.; Cheng, V.C.; Yuen, K.Y.; Woo, P.C.; et al. A six-year descriptive epidemiological study of human coronavirus infections in hospitalized patients in Hong Kong. Virol. Sin. 2016, 31, 41–48. [Google Scholar] [CrossRef] [PubMed]
  30. Wang, W.; Lin, X.D.; Guo, W.P.; Zhou, R.H.; Wang, M.R.; Wang, C.Q.; Ge, S.; Mei, S.H.; Li, M.H.; Shi, M.; et al. Discovery, diversity and evolution of novel coronaviruses sampled from rodents in China. Virology 2015, 474, 19–27. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  31. Provacia, L.B.; Smits, S.L.; Martina, B.E.; Raj, V.S.; Doel, P.V.; Amerongen, G.V.; Moorman-Roest, H.; Osterhaus, A.D.; Haagmans, B.L. Enteric coronavirus in ferrets, The Netherlands. Emerg. Infect. Dis. 2011, 17, 1570–1571. [Google Scholar] [CrossRef] [PubMed]
  32. Poon, L.L.; Chu, D.K.; Chan, K.H.; Wong, O.K.; Ellis, T.M.; Leung, Y.H.; Lau, S.K.; Woo, P.C.; Suen, K.Y.; Yuen, K.Y.; et al. Identification of a novel coronavirus in bats. J. Virol. 2005, 79, 2001–2009. [Google Scholar] [CrossRef] [PubMed]
  33. Chu, D.K.; Poon, L.L.; Chan, K.H.; Chen, H.; Guan, Y.; Yuen, K.Y.; Peiris, J.S. Coronaviruses in bent-winged bats (Miniopterus spp.). J. Gen. Virol. 2006, 87, 2461–2466. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  34. Chu, D.K.; Peiris, J.S.; Chen, H.; Guan, Y.; Poon, L.L. Genomic characterizations of bat coronaviruses (1A, 1B and HKU8) and evidence for co-infections in Miniopterus bats. J. Gen. Virol. 2008, 89, 1282–1287. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  35. Du, J.; Yang, L.; Ren, X.; Zhang, J.; Dong, J.; Sun, L.; Zhu, Y.; Yang, F.; Zhang, S.; Wu, Z.; et al. Genetic diversity of coronaviruses in Miniopterus fuliginosus bats. Sci. China Life Sci. 2016, 59, 604–614. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  36. Liang, J.; Yang, X.L.; Li, B.; Liu, Q.; Zhang, Q.; Liu, H.; Kan, H.P.; Wong, K.C.; Chek, S.N.; He, X.; et al. Detection of diverse viruses in alimentary specimens of bats in Macau. Virol. Sin. 2017, 32, 226–234. [Google Scholar] [CrossRef] [PubMed]
  37. Lin, X.D.; Wang, W.; Hao, Z.Y.; Wang, Z.X.; Guo, W.P.; Guan, X.Q.; Wang, M.R.; Wang, H.W.; Zhou, R.H.; Li, M.H.; et al. Extensive diversity of coronaviruses in bats from China. Virology 2017, 507, 1–10. [Google Scholar] [CrossRef] [PubMed]
  38. Woo, P.C.; Lau, S.K.; Li, K.S.; Poon, R.W.; Wong, B.H.; Tsoi, H.W.; Yip, B.C.; Huang, Y.; Chan, K.H.; Yuen, K.Y. Molecular diversity of coronaviruses in bats. Virology 2006, 351, 180–187. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  39. Woo, P.C.; Wang, M.; Lau, S.K.; Xu, H.; Poon, R.W.; Guo, R.; Wong, B.H.; Gao, K.; Tsoi, H.W.; Huang, Y.; et al. Comparative analysis of twelve genomes of three novel group 2c and group 2d coronaviruses reveals unique group and subgroup features. J. Virol. 2007, 81, 1574–1585. [Google Scholar] [CrossRef] [PubMed]
  40. Lau, S.K.; Feng, Y.; Chen, H.; Luk, H.K.; Yang, W.H.; Li, K.S.; Zhang, Y.Z.; Huang, Y.; Song, Z.Z.; Chow, W.N.; et al. Severe Acute Respiratory Syndrome (SARS) Coronavirus ORF8 Protein Is Acquired from SARS-Related Coronavirus from Greater Horseshoe Bats through Recombination. J. Virol. 2015, 89, 10532–10547. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  41. Xu, L.; Zhang, F.; Yang, W.; Jiang, T.; Lu, G.; He, B.; Li, X.; Hu, T.; Chen, G.; Feng, Y.; et al. Detection and characterization of diverse alpha- and betacoronaviruses from bats in China. Virol. Sin. 2016, 31, 69–77. [Google Scholar] [CrossRef] [PubMed]
  42. Zhang, Q.; Hu, R.; Tang, X.; Wu, C.; He, Q.; Zhao, Z.; Chen, H.; Wu, B. Occurrence and investigation of enteric viral infections in pigs with diarrhea in China. Arch. Virol. 2013, 158, 1631–1636. [Google Scholar] [CrossRef] [PubMed]
  43. Tang, X.C.; Zhang, J.X.; Zhang, S.Y.; Wang, P.; Fan, X.H.; Li, L.F.; Li, G.; Dong, B.Q.; Liu, W.; Cheung, C.L.; et al. Prevalence and genetic diversity of coronaviruses in bats from China. J. Virol. 2006, 80, 7481–7490. [Google Scholar] [CrossRef] [PubMed]
  44. Lau, S.K.; Woo, P.C.; Li, K.S.; Huang, Y.; Wang, M.; Lam, C.S.; Xu, H.; Guo, R.; Chan, K.H.; Zheng, B.J.; et al. Complete genome sequence of bat coronavirus HKU2 from Chinese horseshoe bats revealed a much smaller spike gene with a different evolutionary lineage from the rest of the genome. Virology 2007, 367, 428–439. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  45. Lau, S.K.; Li, K.S.; Huang, Y.; Shek, C.T.; Tse, H.; Wang, M.; Choi, G.K.; Xu, H.; Lam, C.S.; Guo, R.; et al. Ecoepidemiology and complete genome comparison of different strains of severe acute respiratory syndrome-related Rhinolophus bat coronavirus in China reveal bats as a reservoir for acute, self-limiting infection that allows recombination events. J. Virol. 2010, 84, 2808–2819. [Google Scholar] [CrossRef] [PubMed]
  46. Lau, S.K.; Woo, P.C.; Li, K.S.; Tsang, A.K.; Fan, R.Y.; Luk, H.K.; Cai, J.P.; Chan, K.H.; Zheng, B.J.; Wang, M.; et al. Discovery of a novel coronavirus, China Rattus coronavirus HKU24, from Norway rats supports the murine origin of Betacoronavirus 1 and has implications for the ancestor of Betacoronavirus lineage A. J. Virol. 2015, 89, 3076–3092. [Google Scholar] [CrossRef] [PubMed]
  47. Bardos, V.; Schwanzer, V.; Pesko, J. Identification of Tettnang virus (‘possible arbovirus’) as mouse hepatitis virus. Intervirology 1980, 13, 275–283. [Google Scholar] [PubMed]
  48. Corman, V.M.; Kallies, R.; Philipps, H.; Gopner, G.; Muller, M.A.; Eckerle, I.; Brunink, S.; Drosten, C.; Drexler, J.F. Characterization of a novel betacoronavirus related to middle East respiratory syndrome coronavirus in European hedgehogs. J. Virol. 2014, 88, 717–724. [Google Scholar] [CrossRef] [PubMed]
  49. Luo, C.M.; Wang, N.; Yang, X.L.; Liu, H.Z.; Zhang, W.; Li, B.; Hu, B.; Peng, C.; Geng, Q.B.; Zhu, G.J.; et al. Discovery of Novel Bat Coronaviruses in South China That Use the Same Receptor as Middle East Respiratory Syndrome Coronavirus. J. Virol. 2018, 92, e00116-18. [Google Scholar] [CrossRef] [PubMed]
  50. Lau, S.K.P.; Zhang, L.B.; Luk, H.K.H.; Xiong, L.F.; Peng, X.W.; Li, K.S.M.; He, X.Y.; Zhao, P.S.H.; Fan, R.Y.Y.; Wong, A.C.P.; et al. Receptor Usage of a Novel Bat Lineage C Betacoronavirus Reveals Evolution of Middle East Respiratory Syndrome-Related Coronavirus Spike Proteins for Human Dipeptidyl Peptidase 4 Binding. J. Infect. Dis. 2018, 218, 197–207. [Google Scholar] [CrossRef] [PubMed]
  51. Lau, S.K.P.; Li, K.S.M.; Tsang, A.K.L.; Lam, C.S.F.; Ahmed, S.; Chen, H.L.; Chan, K.H.; Woo, P.C.Y.; Yuen, K.Y. Genetic Characterization of Betacoronavirus Lineage C Viruses in Bats Reveals Marked Sequence Divergence in the Spike Protein of Pipistrellus Bat Coronavirus HKU5 in Japanese Pipistrelle: Implications for the Origin of the Novel Middle East Respiratory Syndrome Coronavirus. J. Virol. 2013, 87, 8638–8650. [Google Scholar] [PubMed] [Green Version]
  52. Yang, L.; Wu, Z.Q.; Ren, X.W.; Yang, F.; Zhang, J.P.; He, G.M.; Dong, J.; Sun, L.L.; Zhu, Y.F.; Zhang, S.Y.; et al. MERS-Related Betacoronavirus in Vespertilio superans Bats, China. Emerg. Infect. Dis. 2014, 20, 1260–1262. [Google Scholar] [CrossRef] [PubMed]
  53. Huang, C.; Liu, W.J.; Xu, W.; Jin, T.; Zhao, Y.; Song, J.; Shi, Y.; Ji, W.; Jia, H.; Zhou, Y.; et al. A Bat-Derived Putative Cross-Family Recombinant Coronavirus with a Reovirus Gene. PLoS Pathog. 2016, 12, e1005883. [Google Scholar] [CrossRef] [PubMed]
  54. Obameso, J.O.; Li, H.; Jia, H.; Han, M.; Zhu, S.; Huang, C.; Zhao, Y.; Zhao, M.; Bai, Y.; Yuan, F.; et al. The persistent prevalence and evolution of cross-family recombinant coronavirus GCCDC1 among a bat population: A two-year follow-up. Sci. China Life Sci. 2017, 60, 1357–1363. [Google Scholar] [CrossRef] [PubMed]
  55. Luo, Y.; Li, B.; Jiang, R.D.; Hu, B.J.; Luo, D.S.; Zhu, G.J.; Hu, B.; Liu, H.Z.; Zhang, Y.Z.; Yang, X.L.; et al. Longitudinal Surveillance of Betacoronaviruses in Fruit Bats in Yunnan Province, China During 2009–2016. Virol. Sin. 2018, 33, 87–95. [Google Scholar] [CrossRef] [PubMed]
  56. Lau, S.K.; Poon, R.W.; Wong, B.H.; Wang, M.; Huang, Y.; Xu, H.; Guo, R.; Li, K.S.; Gao, K.; Chan, K.H.; et al. Coexistence of different genotypes in the same bat and serological characterization of Rousettus bat coronavirus HKU9 belonging to a novel Betacoronavirus subgroup. J. Virol. 2010, 84, 11385–11394. [Google Scholar] [CrossRef] [PubMed]
  57. Ge, X.; Li, Y.; Yang, X.; Zhang, H.; Zhou, P.; Zhang, Y.; Shi, Z. Metagenomic analysis of viruses from bat fecal samples reveals many novel viruses in insectivorous bats in China. J. Virol. 2012, 86, 4620–4630. [Google Scholar] [CrossRef] [PubMed]
  58. Ren, W.; Li, W.D.; Yu, M.; Hao, P.; Zhang, Y.; Zhou, P.; Zhang, S.Y.; Zhao, G.P.; Zhong, Y.; Wang, S.Y.; et al. Full-length genome sequences of two SARS-like coronaviruses in horseshoe bats and genetic variation analysis. J. Gen. Virol. 2006, 87, 3355–3359. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  59. Yuan, J.F.; Hon, C.C.; Li, Y.; Wang, D.M.; Xu, G.L.; Zhang, H.J.; Zhou, P.; Poon, L.L.M.; Lam, T.T.Y.; Leung, F.C.C.; et al. Intraspecies diversity of SARS-like coronaviruses in Rhinolophus sinicus and its implications for the origin of SARS coronaviruses in humans. J. Gen. Virol. 2010, 91, 1058–1062. [Google Scholar] [CrossRef] [PubMed]
  60. Wu, Z.G.; Yang, L.; Ren, X.W.; Zhang, J.P.; Yang, F.; Zhang, S.Y.; Jin, Q. ORF8-Related Genetic Evidence for Chinese Horseshoe Bats as the Source of Human Severe Acute Respiratory Syndrome Coronavirus. J. Infect. Dis. 2016, 213, 579–583. [Google Scholar] [CrossRef] [PubMed]
  61. Yang, X.L.; Hu, B.; Wang, B.; Wang, M.N.; Zhang, Q.; Zhang, W.; Wu, L.J.; Ge, X.Y.; Zhang, Y.Z.; Daszak, P.; et al. Isolation and Characterization of a Novel Bat Coronavirus Closely Related to the Direct Progenitor of Severe Acute Respiratory Syndrome Coronavirus. J. Virol. 2016, 90, 3253–3256. [Google Scholar] [CrossRef] [PubMed]
  62. Hu, B.; Zeng, L.P.; Yang, X.L.; Ge, X.Y.; Zhang, W.; Li, B.; Xie, J.Z.; Shen, X.R.; Zhang, Y.Z.; Wang, N.; et al. Discovery of a rich gene pool of bat SARS-related coronaviruses provides new insights into the origin of SARS coronavirus. PLoS Pathog. 2017, 13, e1006698. [Google Scholar] [CrossRef] [PubMed]
  63. Hu, D.; Zhu, C.Q.; Ai, L.L.; He, T.; Wang, Y.; Ye, F.Q.; Yang, L.; Ding, C.X.; Zhu, X.H.; Lv, R.C.; et al. Genomic characterization and infectivity of a novel SARS-like coronavirus in Chinese bats. Emerg. Microbes Infect. 2018, 7, 154. [Google Scholar] [CrossRef] [PubMed]
  64. Hu, D.; Zhu, C.; Wang, Y.; Ai, L.; Yang, L.; Ye, F.; Ding, C.; Chen, J.; He, B.; Zhu, J.; et al. Virome analysis for identification of novel mammalian viruses in bats from Southeast China. Sci. Rep. 2017, 7, 10917. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  65. Woo, P.C.; Lau, S.K.; Lam, C.S.; Lau, C.C.; Tsang, A.K.; Lau, J.H.; Bai, R.; Teng, J.L.; Tsang, C.C.; Wang, M.; et al. Discovery of seven novel Mammalian and avian coronaviruses in the genus deltacoronavirus supports bat coronaviruses as the gene source of alphacoronavirus and betacoronavirus and avian coronaviruses as the gene source of gammacoronavirus and deltacoronavirus. J. Virol. 2012, 86, 3995–4008. [Google Scholar] [PubMed]
  66. Woo, P.C.; Lau, S.K.; Tsang, C.C.; Lau, C.C.; Wong, P.C.; Chow, F.W.; Fong, J.Y.; Yuen, K.Y. Coronavirus HKU15 in respiratory tract of pigs and first discovery of coronavirus quasispecies in 5′-untranslated region. Emerg. Microbes Infect. 2017, 6, e53. [Google Scholar] [CrossRef] [PubMed]
  67. Ren, W.; Qu, X.; Li, W.; Han, Z.; Yu, M.; Zhou, P.; Zhang, S.Y.; Wang, L.F.; Deng, H.; Shi, Z. Difference in receptor usage between severe acute respiratory syndrome (SARS) coronavirus and SARS-like coronavirus of bat origin. J. Virol. 2008, 82, 1899–1907. [Google Scholar] [CrossRef] [PubMed]
  68. Yang, L.; Wu, Z.Q.; Ren, X.W.; Yang, F.; He, G.M.; Zhang, J.P.; Dong, J.; Sun, L.L.; Zhu, Y.F.; Du, J.; et al. Novel SARS-like Betacoronaviruses in Bats, China, 2011. Emerg. Infect. Dis. 2013, 19, 989–991. [Google Scholar] [CrossRef] [PubMed]
  69. Menachery, V.D.; Yount, B.L., Jr.; Debbink, K.; Agnihothram, S.; Gralinski, L.E.; Plante, J.A.; Graham, R.L.; Scobey, T.; Ge, X.Y.; Donaldson, E.F.; et al. A SARS-like cluster of circulating bat coronaviruses shows potential for human emergence. Nat. Med. 2015, 21, 1508–1513. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  70. Wang, N.; Li, S.Y.; Yang, X.L.; Huang, H.M.; Zhang, Y.J.; Guo, H.; Luo, C.M.; Miller, M.; Zhu, G.; Chmura, A.A.; et al. Serological Evidence of Bat SARS-Related Coronavirus Infection in Humans, China. Virol. Sin. 2018, 33, 104–107. [Google Scholar] [CrossRef] [PubMed]
  71. Reusken, C.B.; Raj, V.S.; Koopmans, M.P.; Haagmans, B.L. Cross host transmission in the emergence of MERS coronavirus. Curr. Opin. Virol. 2016, 16, 55–62. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  72. Corman, V.M.; Ithete, N.L.; Richards, L.R.; Schoeman, M.C.; Preiser, W.; Drosten, C.; Drexler, J.F. Rooting the phylogenetic tree of middle East respiratory syndrome coronavirus by characterization of a conspecific virus from an African bat. J. Virol. 2014, 88, 11297–11303. [Google Scholar] [CrossRef] [PubMed]
  73. Anthony, S.J.; Gilardi, K.; Menachery, V.D.; Goldstein, T.; Ssebide, B.; Mbabazi, R.; Navarrete-Macias, I.; Liang, E.; Wells, H.; Hicks, A.; et al. Further Evidence for Bats as the Evolutionary Source of Middle East Respiratory Syndrome Coronavirus. MBio 2017, 8, e00373-17. [Google Scholar] [CrossRef] [PubMed]
  74. Yang, Y.; Du, L.; Liu, C.; Wang, L.; Ma, C.; Tang, J.; Baric, R.S.; Jiang, S.; Li, F. Receptor usage and cell entry of bat coronavirus HKU4 provide insight into bat-to-human transmission of MERS coronavirus. Proc. Natl. Acad. Sci. USA 2014, 111, 12516–12521. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  75. Wang, L.; Su, S.; Bi, Y.; Wong, G.; Gao, G.F. Bat-Origin Coronaviruses Expand Their Host Range to Pigs. Trends Microbiol. 2018, 26, 466–470. [Google Scholar] [CrossRef] [PubMed]
  76. Zhou, P.; Tachedjian, M.; Wynne, J.W.; Boyd, V.; Cui, J.; Smith, I.; Cowled, C.; Ng, J.H.; Mok, L.; Michalski, W.P.; et al. Contraction of the type I IFN locus and unusual constitutive expression of IFN-alpha in bats. Proc. Natl. Acad. Sci. USA 2016, 113, 2696–2701. [Google Scholar] [CrossRef] [PubMed]
  77. Xie, J.; Li, Y.; Shen, X.; Goh, G.; Zhu, Y.; Cui, J.; Wang, L.F.; Shi, Z.L.; Zhou, P. Dampened STING-Dependent Interferon Activation in Bats. Cell Host Microbe 2018, 23, 297–301. [Google Scholar] [CrossRef] [PubMed]
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Figure 1. Geographical distribution of bat coronaviruses (CoVs) and their corresponding bat hosts in China. Each red box represents one CoV positive sample found in that particular bat species. One dot matrix was drawn for each province where a CoV positive sample had been reported. Guangdong Province, where SARS and SADS began, is circled in red. Abbreviations of bat species and virus species are indicated.
Figure 1. Geographical distribution of bat coronaviruses (CoVs) and their corresponding bat hosts in China. Each red box represents one CoV positive sample found in that particular bat species. One dot matrix was drawn for each province where a CoV positive sample had been reported. Guangdong Province, where SARS and SADS began, is circled in red. Abbreviations of bat species and virus species are indicated.
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Figure 2. Genetic diversity of bat CoV in China. Sequences of 440 bp conserved the viral polymerase (RdRp) region for each CoV species were compared to related reference sequences. Reference genomes used: BtCoV-HKU10, NC_018871.1; BtRfCoV-HuB13, NC_028814.1; BtMiCoV-1, EU420138.1; BtMiCoV-HKU8, NC_010438.1; BtRhCoV-HKU2, MF094682.1; BtHpCoV-ZJ13, NC_025217.1; MERSr-CoV, NC_038294.1; BtPiCoV-HKU5, NC_009020.1; BtTyCoV-HKU4, NC_009019.1; BtRoCoV-GCCDC1, MG762606.1; BtRoCoV-HKU9, NC_009021.1; and SARSr-CoV, NC_004718.3. Notably, samples that were positive for BtMy-Sax11, BtNy-Sc13, and BtScCoV-512 were also identified in China. These were not taken into account here as too few sequences were available.
Figure 2. Genetic diversity of bat CoV in China. Sequences of 440 bp conserved the viral polymerase (RdRp) region for each CoV species were compared to related reference sequences. Reference genomes used: BtCoV-HKU10, NC_018871.1; BtRfCoV-HuB13, NC_028814.1; BtMiCoV-1, EU420138.1; BtMiCoV-HKU8, NC_010438.1; BtRhCoV-HKU2, MF094682.1; BtHpCoV-ZJ13, NC_025217.1; MERSr-CoV, NC_038294.1; BtPiCoV-HKU5, NC_009020.1; BtTyCoV-HKU4, NC_009019.1; BtRoCoV-GCCDC1, MG762606.1; BtRoCoV-HKU9, NC_009021.1; and SARSr-CoV, NC_004718.3. Notably, samples that were positive for BtMy-Sax11, BtNy-Sc13, and BtScCoV-512 were also identified in China. These were not taken into account here as too few sequences were available.
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Table
Table 1. International Committee of Taxonomy of Viruses (ICTV) classification of coronaviruses species, reservoir hosts, and presence reported in China.
Table 1. International Committee of Taxonomy of Viruses (ICTV) classification of coronaviruses species, reservoir hosts, and presence reported in China.
Coronavirus SpeciesAbbreviationsHumanBatsOther AnimalsReported in China
Bat coronavirus HKU10BtCoV-HKU10 Yes Yes [7,8,26,27]α-CoV
Bat coronavirus CDPHE15BtCoV-CDPHE15 Yes No
Rhinolophus ferrumequinum alphacoronavirus HuB-2013BtRfCoV-HuB13 Yes Yes [8]
* Human coronavirus 229EHCoV-229EYes Yes [28,29]
Lucheng Rn rat coronavirusLRNV Yes (rat)Yes [30]
Ferret coronavirusFRCoV Yes (ferret)No [31]
* Mink coronavirus 1MCoV Yes (mink)No [14]
Miniopterus bat coronavirus 1BtMiCoV-1 Yes Yes [7,8,32,33,34,35,36,37]
Miniopterus bat coronavirus HKU8BtMiCoV-HKU8 Yes Yes [7,8,33,34,35,37,38,39,40,41]
Myotis ricketti alphacoronavirus Sax-2011BtMy-Sax11 Yes Yes [8,37]
Nyctalus velutinus alphacoronavirus SC-2013BtNy-Sc13 Yes Yes [8]
* Porcine epidemic diarrhea virusPEDV Yes (pig)Yes [42]
Scotophilus bat coronavirus 512BtScCoV-512 Yes Yes [37]
* Rhinolophus bat coronavirus HKU2 (SADS)BtRhCoV-HKU2 YesYesYes [2,7,8,38,43,44,45]
* Human coronavirus NL63HCoV-NL63Yes Yes [28,29]
NL63-related bat coronavirus strain BtKYNL63-9bBtKYNL63 Yes No [24]
* Alphacoronavirus 1 (Transmissible gastroenteritis virus)TGEV Yes (pig)Yes [42]
China Rattus coronavirus HKU24RtCoV-HKU24 Yes (rat)Yes [46]β-CoV
* Human coronavirus HKU1HCoV-HKU1Yes Yes [28,29]
* Murine coronavirus (Murine hepatitis coronavirus)MHV Yes (mouse)No [47]
Bat Hp-betacoronavirus Zhejiang2013BtHpCoV-ZJ13 Yes Yes [8]
Hedgehog coronavirus 1EriCoV-1 Yes (hedgehog)No [48]
* Middle East respiratory syndrome-related coronavirusMERSr-CoVYesYes Yes [49,50]
Pipistrellus bat coronavirus HKU5BtPiCoV-HKU5 Yes Yes [38,39,49,51,52]
Tylonycteris bat coronavirus HKU4BtTyCoV-HKU4 Yes Yes [36,38,39,49,50,51]
Rousettus bat coronavirus GCCDC1# BtEoCoV-GCCDC1 Yes Yes [53,54,55]
Rousettus bat coronavirus HKU9BtRoCoV-HKU9 Yes Yes [39,55,56,57]
* Severe acute respiratory syndrome-related coronavirusSARSr-CoVYesYes Yes [7,8,20,21,22,27,37,40,45,58,59,60,61,62,63,64]
* Betacoronavirus 1 (Human coronavirus OC43)HCoV-OC43Yes Yes [28,29]
Wigeon coronavirus HKU20WiCoV-HKU20 Yes (bird)Yes [65]δ-CoV
Bulbul coronavirus HKU11BuCoV-HKU11 Yes (bird)Yes [65]
Coronavirus HKU15PoCoV-HKU15 Yes (pig)Yes [66]
Munia coronavirus HKU13MuCoV-HKU13 Yes (bird)Yes [65]
White-eye coronavirus HKU16WECoV-HKU13 Yes (bird)Yes [65]
Night heron coronavirus HKU19NHCoV-HKU19 Yes (bird)Yes [65]
Common moorhen coronavirus HKU21CMCoV-HKU21 Yes (bird)Yes [65]
*? Beluga whale coronavirus SW1BWCoV-SW1 Yes (whale)No [13]γ-CoV
* Avian infectious bronchitis virusIBV Yes (bird)Yes [12]
* The disease-causing CoVs are indicated and the three zoonotic CoVs are in bold. *? BWCoV-SW1 was found in a sick whale, but whether it was the etiological agent of the infection was not proven. # Carrier of this virus was confirmed as Eonycteris spelaea, but not Rousettus bats. The virus was renamed accordingly.

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Fan, Y.; Zhao, K.; Shi, Z.-L.; Zhou, P. Bat Coronaviruses in China. Viruses 2019, 11, 210. https://doi.org/10.3390/v11030210

AMA Style

Fan Y, Zhao K, Shi Z-L, Zhou P. Bat Coronaviruses in China. Viruses. 2019; 11(3):210. https://doi.org/10.3390/v11030210

Chicago/Turabian Style

Fan, Yi, Kai Zhao, Zheng-Li Shi, and Peng Zhou. 2019. "Bat Coronaviruses in China" Viruses 11, no. 3: 210. https://doi.org/10.3390/v11030210

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