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. 2018 Apr;556(7700):255-258.
doi: 10.1038/s41586-018-0010-9. Epub 2018 Apr 4.

Fatal swine acute diarrhoea syndrome caused by an HKU2-related coronavirus of bat origin

Peng Zhou  1 , Hang Fan  2 , Tian Lan  3   4 , Xing-Lou Yang  1 , Wei-Feng Shi  5 , Wei Zhang  1 , Yan Zhu  1 , Ya-Wei Zhang  2 , Qing-Mei Xie  3   4 , Shailendra Mani  6 , Xiao-Shuang Zheng  1 , Bei Li  1 , Jin-Man Li  2 , Hua Guo  1 , Guang-Qian Pei  2 , Xiao-Ping An  2 , Jun-Wei Chen  3   4 , Ling Zhou  3   4 , Kai-Jie Mai  3   4 , Zi-Xian Wu  3   4 , Di Li  3   4 , Danielle E Anderson  6 , Li-Biao Zhang  7 , Shi-Yue Li  8 , Zhi-Qiang Mi  2 , Tong-Tong He  2 , Feng Cong  9 , Peng-Ju Guo  9 , Ren Huang  9 , Yun Luo  1 , Xiang-Ling Liu  1 , Jing Chen  1 , Yong Huang  2 , Qiang Sun  2 , Xiang-Li-Lan Zhang  2 , Yuan-Yuan Wang  2 , Shao-Zhen Xing  2 , Yan-Shan Chen  3   4 , Yuan Sun  3   4 , Juan Li  5 , Peter Daszak  10 , Lin-Fa Wang  11 , Zheng-Li Shi  12 , Yi-Gang Tong  13   14 , Jing-Yun Ma  15   16
Affiliations

Fatal swine acute diarrhoea syndrome caused by an HKU2-related coronavirus of bat origin

Peng Zhou et al. Nature. 2018 Apr.

Abstract

Cross-species transmission of viruses from wildlife animal reservoirs poses a marked threat to human and animal health 1 . Bats have been recognized as one of the most important reservoirs for emerging viruses and the transmission of a coronavirus that originated in bats to humans via intermediate hosts was responsible for the high-impact emerging zoonosis, severe acute respiratory syndrome (SARS) 2-10 . Here we provide virological, epidemiological, evolutionary and experimental evidence that a novel HKU2-related bat coronavirus, swine acute diarrhoea syndrome coronavirus (SADS-CoV), is the aetiological agent that was responsible for a large-scale outbreak of fatal disease in pigs in China that has caused the death of 24,693 piglets across four farms. Notably, the outbreak began in Guangdong province in the vicinity of the origin of the SARS pandemic. Furthermore, we identified SADS-related CoVs with 96-98% sequence identity in 9.8% (58 out of 591) of anal swabs collected from bats in Guangdong province during 2013-2016, predominantly in horseshoe bats (Rhinolophus spp.) that are known reservoirs of SARS-related CoVs. We found that there were striking similarities between the SADS and SARS outbreaks in geographical, temporal, ecological and aetiological settings. This study highlights the importance of identifying coronavirus diversity and distribution in bats to mitigate future outbreaks that could threaten livestock, public health and economic growth.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1. Detection of SADS-CoV infection in pigs in Guangdong, China.
a, Records of daily death toll on the four farms from 28 October 2016 to 2 May 2017. b, Detection of SADS-CoV by qPCR. The y axis shows the log(copy number per 106 copies of 18S rRNA). n = 12 sick piglets, 5 sick sows, 16 recovered sows and 10 healthy piglets. c, Tissue distribution of SADS-CoV in diseased pigs. n = 3. Data are mean ± s.d.; dots represent individual values. d, Detection of SADS-CoV antibodies. n = 46 sows from whom serum was first taken in the first three weeks of the outbreak (First bleed), n = 8 sows from whom serum was taken again (Second bleed) at more than one month after the onset of the outbreak, n = 8 sera from healthy pig controls, n = 35 human sera from pig farmers. Source data
Fig. 2
Fig. 2. Genome and phylogenetic analysis of SADS-CoV and SADSr-CoV.
a, Genome organization and comparison. Colour-coding for different genomic regions as follows. Green, non-structural polyproteins ORF1a and ORF1b; yellow, structural proteins S, E, M and N; blue, accessory proteins NS3a, NS7a and NS7b; Orange, untranslated regions. The level of sequence identity of SADSr-CoV to SADS-CoV is illustrated by different patterns of boxes: Solid colour, highly similar; Dotted fill, moderately similar; Dashed fill, least similar. b, Phylogenetic analysis of 57 S1 sequences (33 from SADS-CoV and 24 from SADSr-CoV). Different colours represent different host species as shown on the left. Scale bar, nucleotide substitutions per site.
Fig. 3
Fig. 3. Immunohistopathology of SADS-CoV infected tissues.
a–d, Sections of jejunum tissue from control (a, c) and infected (b, d) farm piglets four days after inoculation were stained with haematoxylin and eosin (a, b) or rabbit anti-SADSr-CoV N serum (red), DAPI (blue) and mouse antibodies against epithelial cell markers cytokeratin 8, 18 and 19 (green) in (c, d). SADS-CoV N protein is evident in epithelial cells and deeper in the tissue of infected piglets, which exhibit villus shortening. Scale bars, 200 μm (a, b) and 50 μm (c, d). The experiment was conducted three times independently with similar results.
Extended Data Fig. 1
Extended Data Fig. 1. Map of outbreak locations and sampling sites in Guangdong province, China and the co-circulation of PEDV and SADS-CoV during the initial outbreak on farm A.
a, SADS-affected farms are labelled (farms A–D) with blue swine silhouettes following the temporal sequence of the outbreaks. Bat sampling sites are indicated with black bat silhouettes. The bat SADSr-CoV that is most closely related to SADS-CoV (sample 162140) originated in Conghua. The red flag marks Foshan city, the site of the SARS index case. b, Pooled intestinal samples (n = 5 or more biological independent samples) were collected at dates given on the x axis from deceased piglets and analysed by qPCR. The viral load for each piglet is shown as copy number per milligram of intestine tissue (y axis).
Extended Data Fig. 2
Extended Data Fig. 2. Bayesian phylogenetic tree of the full-length genome and the ORF1a and ORF1b sequences of SADS-CoV and related coronaviruses.
a, Bayesian phylogenetic tree of the full-length genome. b, Bayesian phylogenetic tree of the ORF1a and ORF1b sequences. Trees were constructed using MrBayes with the average standard deviation of split frequencies under 0.01. The host of each sequence is represented as a silhouette. Newly sequenced SADS-CoVs are highlighted in red, bat SADSr-CoVs are shown in blue and previously published sequences are shown in black. Scale bars, nucleotide substitutions per site.
Extended Data Fig. 3
Extended Data Fig. 3. Phylogeny and haplotype network analyses of the 33 SADS-CoV strains from the four farms.
a, Phylogenetic tree constructed using MrBayes. The GTR+GAMMA model was applied and 20 million steps were run, with the first 10% removed as burn in. Viruses from different farms are labelled with different colours. Scale bar, nucleotide substitutions per site. b, Median-joining haplotype network constructed using ProART. In this analysis, ɛ = 0 was used. The size of the circles represents the number of samples. The larger the circle, the more samples it includes.
Extended Data Fig. 4
Extended Data Fig. 4. Recombination analysis for SADS-CoV and related CoVs.
The potential genetic recombination events were detected using RDP. For each virus strain, different colours represent different sources of the genomes. Source data
Extended Data Fig. 5
Extended Data Fig. 5. Isolation and antigenic characterization of SADS-CoV.
a, b, Vero cells are shown 20 h after infection with mock (a) or SADS-CoV (b). c, d, Mock or SADS-CoV-infected samples stained with rabbit serum raised against the recombinant SADSr-CoV N protein (red) and DAPI (blue). The experiment was conducted independently three times with similar results. Scale bars, 100 μm. Source data
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