key: cord-289096-wuegn0jg
authors: Wang, Liang; Su, Shuo; Bi, Yuhai; Wong, Gary; Gao, George F.
title: Bat-Origin Coronaviruses Expand Their Host Range to Pigs
date: 2018-04-18
journal: Trends Microbiol
DOI: 10.1016/j.tim.2018.03.001
sha: 
doc_id: 289096
cord_uid: wuegn0jg

Infections with bat-origin coronaviruses have caused severe illness in humans by ‘host jump’. Recently, novel bat-origin coronaviruses were found in pigs. The large number of mutations on the receptor-binding domain allowed the viruses to infect the new host, posing a potential threat to both agriculture and public health.

Liang Wang, 1 Shuo Su, 2 Yuhai Bi, 1,3 Gary Wong, 3 and George F. Gao 1,3,4, * Infections with bat-origin coronaviruses have caused severe illness in humans by 'host jump'. Recently, novel bat-origin coronaviruses were found in pigs. The large number of mutations on the receptor-binding domain allowed the viruses to infect the new host, posing a potential threat to both agriculture and public health. 

The host range expansion of coronaviruses (CoVs) from wildlife to humans via genetic recombination and/or mutations on the receptor-binding domain in the spike (S) gene is well established and results in several diseases with high fatality rates, such as severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) [ [4] . Thus, pigs are regarded as mixing vessels for IAVs. However, pigs were not known to be susceptible to bat-origin coronaviruses until recently, when two independent groups reported the detection of novel swine enteric alphacoronaviruses (SeACoVs) distinct from known swine coronaviruses (with one group successfully isolating live virus). The SeACoVs were found to be phylogenetically close to bat coronavirus HKU2 [5, 6] . This suggests that bat-origin coronaviruses may have 'jumped' the species barrier to infect pigs.

In February 2017, outbreaks of severe watery diarrhea of suckling piglets were reported in commercial pig farms in Guangdong Province, China. The disease had high case fatality rates (CFRs, over 35% for <10-day-old suckling piglets), and none of the animals were positive for known pathogens responsible for porcine diarrhea [6] . Instead, two genomes of novel SeACoV were detected in the ill piglets by two independent groups, and preliminary analysis showed that the SeACoVs possibly originated from bat HKU coronaviruses [5, 6] . It is currently unclear whether SeACoVs had been circulating undetected in pigs, if the viruses had originated from cross-species transmission, or if the SeACoVs were the result of viral recombination. To understand the molecular origin and evolution of SeA-CoVs, we performed a detailed phylogenetic analysis at the genomic level by using all known alphacoronaviruses and bat-origin coronaviruses which are known to cause severe diseases, such as SARS and MERS. A total of 224, 312, and 778 complete genomes from MERS-CoV, SARS-CoV, and alphacoronaviruses, respectively, were used. Phylogeny was reconstructed using conserved regions in genomes by the maximum likelihood method with 300 replicates ( Figure 1A) . Consistent with previous studies, phylogenetic analysis shows that SeACoVs were closely related to the Rhinolophus bat coronavirus HKU2 isolated in southern China ( Figure 1A ). SeACoV was found to share a common ancestor with human coronavirus 229E/NL63, but these viruses are distant from other known swine alphacoronaviruses, indicating their different origins. Further analysis on the S gene, which determines virus attachment, host cell entry, and 'host jump' of coronaviruses [7] , showed that domain 0 in the S1 subunit has structural similarity to that of NL63. The rest of the domain on the S1 subunit was similar to that of murine hepatitis coronavirus (betaCov) [6] . There were 11 residues of the receptor-binding domain (RBD, also called C-terminal domain, CTD) of SeACoV directly in contact with its receptor (angiotensin-converting enzyme 2) that were mutated or deleted [7] (Figure 1B) . Seven mutations (a deletion of four amino acids, and three substitutions) among the 11 sites in SeACoV were also found in [ 8 1 _ T D $ D I F F ] 229E/NL63, indicating similarities in the receptor-binding mechanism between SeACoV and [ 8 1 _ T D $ D I F F ] [ 7 9 _ T D $ D I F F ] 229E/NL63. Therefore, SeACoV may be able to infect humans and should be closely monitored. Infection of SeACoV in Vero cells (a primate cell line) will provide experimental evidence to support this possibility [6] .

Another requirement for the host range expansion of viruses is physical contact between different host species. The novel SeACoVs were both detected in Guangdong Province, whereas closely related bat coronaviruses were also isolated from Guangdong or Hong Kong ( Figure 1A) . In Guangdong Province, the high density of pig slaughterhouses and the wide distribution of bat species (Figure 2A ) promote the possibility of viral cross-species transmission. Additionally, bats have a wide geographical distribution in southern China, with extensive species diversity, unique behaviors (characteristic flight patterns, diet, roosting, and mobility) [8] , and constant interactions with both pigs and humans (Figure 2A ).

Pigs are well established as mixing vessels and as intermediate hosts for IAVs, and coronaviruses have already been shown to possess potential for recombination in animals [9] . Given that pigs are in frequent contact with human and multiple wildlife species, and that pork is one of the most commonly consumed meats in non-Muslim countries, it is important to assess whether pigs could be mixing vessels for the emergence of novel coronaviruses with high agricultural impact and risks to public health. It has already been reported that pigs are susceptible to infection with human SARS-CoV [10] and MERS-CoV [11] . Additionally, the CD26 receptor sequence alignment of pigs and humans shows 94.5% similarity, which is sufficient for potential cross-species transmission [7] . In southern China, the unique climate, the high density of domestic as well as wild pigs, and extensive bat distribution, together with bats carrying large numbers of recombinant novel coronaviruses [12] , could lead to the emergence of more novel coronaviruses in the future.

The isolation of SeACoV from ill piglets expands our knowledge of the host range of bat-origin coronaviruses, and potentially poses a threat to public health. Despite considerable progress in characterizing cross-species transmission for coronaviruses, several areas need to be addressed, including: (i) whether other unknown coronaviruses are circulating in pigs; (ii) whether pigs are mixing vessels for coronaviruses; (iii) whether SeACoV infects humans and causes severe disease; and (iv) whether SeACoV vaccines should also be developed to control the spread of this virus in pigs. In-depth epidemiological investigation and comprehensive analysis of these novel coronaviruses should be performed to answer these urgent questions.

Using metagenomics to characterize an expanding virosphere

Epidemiology, genetic recombination, and pathogenesis of coronaviruses

Molecular basis of binding between novel human coronavirus MERS-CoV and its receptor CD26

SARS and MERS: recent insights into emerging coronaviruses

The pig as an intermediate host for influenza A viruses between birds and humans

A new bat-HKU2-like coronavirus in swine

Discovery of a novel swine enteric alphacoronavirus (SeACoV) in southern China

Bat-to-human: spike features determining 'host jump' of coronaviruses SARS-CoV, MERS-CoV, and beyond

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