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Farmed fur animals harbour viruses with zoonotic spillover potential

Nature volume 634, pages 228–233 (2024)Cite this article

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Abstract

Animals such as raccoon dogs, mink and muskrats are farmed for fur and are sometimes used as food or medicinal products1,2, yet they are also potential reservoirs of emerging pathogens3. Here we performed single-sample metatranscriptomic sequencing of internal tissues from 461 individual fur animals that were found dead due to disease. We characterized 125 virus species, including 36 that were novel and 39 at potentially high risk of cross-species transmission, including zoonotic spillover. Notably, we identified seven species of coronaviruses, expanding their known host range, and documented the cross-species transmission of a novel canine respiratory coronavirus to raccoon dogs and of bat HKU5-like coronaviruses to mink, present at a high abundance in lung tissues. Three subtypes of influenza A virus—H1N2, H5N6 and H6N2—were detected in the lungs of guinea pig, mink and muskrat, respectively. Multiple known zoonotic viruses, such as Japanese encephalitis virus and mammalian orthoreovirus4,5, were detected in guinea pigs. Raccoon dogs and mink carried the highest number of potentially high-risk viruses, while viruses from the Coronaviridae, Paramyxoviridae and Sedoreoviridae families commonly infected multiple hosts. These data also reveal potential virus transmission between farmed animals and wild animals, and from humans to farmed animals, indicating that fur farming represents an important transmission hub for viral zoonoses.

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Fig. 1: Geographical distribution of animal sampling, fur animal composition, tissue type, library characteristics and viral read counts in this study.
Fig. 2: The vertebrate-associated virome of fur animals.
Fig. 3: Potentially high-risk virus species and their epidemiological characteristics.

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Data availability

The data reported in this paper have been deposited in the GenBase of the National Genomics Data Center, Beijing Institute of Genomics, Chinese Academy of Sciences/China National Center for Bioinformation (CNCB) under accession numbers C_AA074934.1 to C_AA076255.1. These data are publicly accessible online (https://ngdc.cncb.ac.cn/genbase). The raw sequencing read data have been deposited at the Genome Sequence Archive (Genomics, Proteomics & Bioinformatics 2021) of CNCB under the BioProject accession number PRJCA026706. The sequences of four IAVs have been submitted to the GISAID database, and assigned isolate IDs EPI_ISL_19176289, EPI_ISL_19176290, EPI_ISL_19176291 and EPI_ISL_19176294. All multiple-sequence alignments (fasta format), phylogenetic trees and source data related to figures in the main text have been deposited at GitHub (https://github.com/Jin2024-doct/-fur-animals-virus-dataset.git). The map of China is available from the Data Center for Resources and Environmental Sciences at the Chinese Academy of Sciences (http://www.resdc.cn). Source data are provided with this paper.

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Acknowledgements

S.S., J.Z., W.W., K.Y., M.L., Z.C., Y.L. and A.H. are financially supported by the National Key Research and Development Program of China (grant no. 2021YFD1801101), the Program of Shanghai Academic Research Leader (23XD1420700), the Young Top-Notch Talents of National Ten Thousand Talent Program; S.S was also supported by the National Natural Science Foundation of China (NSFC grant no. 31922081). W.T.-H. and G.Y. are supported by Young Elite Scientists Sponsorship Program by CAST (2023QNRC001). P.L. and M.A.S. are partially supported by the US National Institutes of Health grant R01 AIAI153044. J.H.-O.P. is supported by the Swedish research council Vetenskapsrådet (grant no. 2020-02593); E.H. by a National Health and Medical Research Council (NHMRC) Investigator award (GNT2017197) and by AIR@InnoHK administered by the Innovation and Technology Commission, Hong Kong Special Administrative Region, China. We acknowledge support from the staff at Advanced Micro Devices, with the donation of parallel computing resources through their AMD HPC Fund used for this research. The Y.B. laboratory was involved in collecting and handling some samples of potential high-risk viruses, such as the HKU5-COV and H5N6 IAV, in accordance with regulations (approved by the Ethics Committee of the Institute of Microbiology, Chinese Academy of Sciences, HP-SQIMCAS2024111), and was financially supported by the National Key Research and Development Program of China (2021YFC2300903). S.S. (alternative email: ssh5658485@163.com) is the lead contact for this paper.

Author information

Author notes

  1. These authors contributed equally: Jin Zhao, Wenbo Wan, Kang Yu, Philippe Lemey, John H.-O. Pettersson, Yuhai Bi, Edward C. Holmes

  2. These authors jointly supervised this work: Yuhai Bi, Edward C. Holmes, Wan-Ting He, Shuo Su

Authors and Affiliations

  1. Department of Epidemiology, School of Public Health, Shanghai Institute of Infectious Disease and Biosecurity, Fudan University, Shanghai, China

    Jin Zhao, Wenbo Wan, Kang Yu, Meng Lu, Zhuohang Chen, Yuxing Li, Ayidana Haerheng, Na He & Shuo Su

  2. State Key Laboratory of Natural Medicines, School of Pharmacy, China Pharmaceutical University, Nanjing, China

    Kang Yu, Ge Yan, JianJun Dai & Wan-Ting He

  3. Department of Microbiology, Immunology and Transplantation, Rega Institute, Laboratory for Clinical and Epidemiological Virology, KU Leuven, Leuven, Belgium

    Philippe Lemey

  4. Clinical Microbiology, Department of Medical Sciences, University of Uppsala, Uppsala, Sweden

    John H.-O. Pettersson

  5. Clinical Microbiology and Hospital Hygiene, Uppsala University Hospital, Uppsala, Sweden

    John H.-O. Pettersson

  6. Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria, Australia

    John H.-O. Pettersson

  7. CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China

    Yuhai Bi

  8. Jiangsu Engineering Laboratory of Animal Immunology, Institute of Immunology, College of Veterinary Medicine, Academy for Advanced Interdisciplinary Studies, Nanjing Agricultural University, Nanjing, China

    Xinxin Li & Mengdi Zheng

  9. Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, China

    Changchun Tu

  10. Department of Biostatistics, Fielding School of Public Health, and Departments of Biomathematics and Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA

    Marc A. Suchard

  11. School of Medical Sciences, The University of Sydney, Sydney, New South Wales, Australia

    Edward C. Holmes

  12. Laboratory of Data Discovery for Health Limited, Hong Kong SAR, China

    Edward C. Holmes

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  1. Jin Zhao
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Contributions

S.S. and W.T.-H. designed and supervised the research. Y.B., J.Z., X.L. and M.Z. collected samples. J.Z., X.L., M.Z. and G.Y. performed the Sanger sequencing and molecular detection. J.Z., W.W., K.Y., M.L. and W.T.-H. performed the genome assembly, annotation and analysis of abundance. J.Z., P.L., W.T.-H. and S.S. performed the genomic and evolutionary analysis and interpretation. J.H.-O.P., Z.C., Y.L., C.T., A.H., N.H. and M.A.S. assisted in the data interpretation. S.S., W.T.-H., J.Z., J.H.-O.P., E.C.H., Y.B., W.W., K.Y. and M.L. wrote the paper. All of the authors reviewed and edited the paper.

Corresponding authors

Correspondence to Wan-Ting He or Shuo Su.

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Extended data figures and tables

Extended Data Fig. 1 Abundance of vertebrate-associated viruses in fur animals at the species level.

The abundance of each virus was calculated and normalized based on the number of mapped reads per million total reads (RPM) and presented on the Log-10 scale. Different colour blocks represent different types of viruses and source organs. Source data are provided in the Source Data file.

Source Data

Extended Data Fig. 2 Newly discovered viruses, the infection spectrum of the animals studied and the extent of coinfection.

(a) The infection spectrum of the studied animals, with animals represented by images. Viruses are shown at the nodes, with the node colour specifying the viral family. The size of the nodes represents the number of animals infected by the virus, and the width of the edges indicates the number of libraries of the host infected by the connected virus. (b) The viral families newly identified in the specific host. Each segment of the pie chart corresponds to a distinct animal species, depicted with unique colour, and the donuts with similar lighter colour, signify the newly discovered viral families. (c) Virus co-infection. Viruses are shown at the nodes, with the node colour specifying the viral family. The size of the nodes represents the frequency of co-infections with any other virus, while edge width represents the frequency of co-infections between the two viruses.

Extended Data Fig. 3 Inter-specific phylogenetic trees of 12 major families of vertebrate-associated RNA viruses.

Phylogenetic trees were inferred for each family of RNA viruses based on amino acid sequences of the RNA-dependent RNA polymerase protein. All trees are midpoint-rooted for clarity and display bootstrap values for major branches. Coloured dots represent viruses with different host origins. The scale bar represents the number of amino acid substitutions per site.

Extended Data Fig. 4 Phylogenetic trees of vertebrate-associated RNA viruses from the Flaviviridae and Orthomyxoviridae in fur animals.

Phylogenetic trees of viruses in the (a) Flaviviridae and (b) Orthomyxoviridae were inferred from the amino acid sequences of the RNA-dependent RNA polymerase and hemagglutinin proteins (Orthomyxoviridae). All trees are midpoint-rooted for clarity and display bootstrap values for major branches. Different coloured dots represent viruses with different geographic origins. Colour shading represents different animal orders, and specific species are depicted with animal pictures. The scale bar represents the number of amino acid substitutions per site.

Extended Data Fig. 5 Phylogenetic tree of the Coronaviridae in farmed animals.

Phylogenetic tree of viruses in the Coronaviridae inferred from the amino acid sequences of the RNA-dependent RNA polymerase. The tree is midpoint-rooted for clarity and displays bootstrap values at the major branches. Different coloured dots represent viruses with different geographic origins. Colour shading represents different animal orders, and specific species are depicted with animal pictures. The scale bar represents the number of amino acid substitutions per site.

Extended Data Fig. 6 Inter-specific phylogenetic trees of four vertebrate-associated DNA virus families.

Phylogenetic trees were inferred for each DNA virus family based on the amino acid sequences of conserved viral proteins (DNA viruses = replication related protein, i.e., Anelloviridae: ORF1, Parvoviridae: NS1, Adenoviridae: DNA polymerase, and Circoviridae: Rep protein). All trees are midpoint-rooted for clarity and display bootstrap values for major branches. Coloured dots represent viruses with different host origins. The scale bar represents the number of amino acid substitutions per site.

Extended Data Fig. 7 Intra-specific phylogenetic diversity of multi-host infecting viruses identified in fur animals.

Phylogenetic trees were inferred for each virus species based on the nucleotide sequences of the key gene (i.e., Coronavirus: S1 gene, Paslahepevirus balayani: full genome, Japanese encephalitis virus: E gene, Mammalian orthoreovirus: S1 gene, Norwalk virus: VP1, Rotavirus A: VP7). All trees are midpoint-rooted for clarity and display bootstrap values for the major branches. Coloured dots represent different host sources.

Extended Data Fig. 8 Recombination and phylogenetic analysis of mink-derived Pipistrellus bat coronavirus HKU5.

(a) Maximum clade credibility (MCC) tree based on genome of mink-derived HKU5-like viruses. (b) Simplot was used to perform recombination scanning on the mink-derived HKU5-like sequences and related reference sequences. (c) Neighbour-Net reconstruction based on the complete genome sequences of mink HKU5 and Bat CoVs using Splitstree5, employing the HKY85 substitution model and 1000 bootstraps. (d) IQ-TREE (v2.1.4) was used to estimate maximum likelihood trees based on RdRp and S gene nucleotides, respectively.

Extended Data Fig. 9 Phylogenetic analysis of guinea pig-derived Influenza A virus H1N2.

Maximum clade credibility (MCC) trees based on the HA, MP, NA, NP, NS, PA, PB1, and PB2 gene sequences of H1N2 influenza virus. MCC trees were summarized from Bayesian phylodynamic inferences using BEAST (v1.10.5). Coloured lines and dots represent the host: human (red), rodent (green), and swine (light-blue).

Extended Data Fig. 10 Phylogenetic analysis of two mink-derived Influenza A virus H5N6.

Maximum clade credibility (MCC) trees based on the HA, MP, NA, NP, NS, PA, PB1, and PB2 gene sequences of H5N6. MCC trees were summarized from Bayesian phylodynamic inferences using BEAST (v1.10.5). Different virus clades are depicted in different colours. Blue dots denote the mink-derived H5N6 virus reported here.

Extended Data Fig. 11 Types and abundances of potentially high-risk viruses, along with their geographic and host origins.

(a) The radius of the bubbles indicates the abundance of each potentially high-risk virus, with larger bubbles representing greater abundance. Green bubbles indicate that the virus was identified for the first time in the corresponding host species, while red bubbles indicate previous identification in that host. (b) The relationship between potentially high-risk viruses and their hosts, tissue types, and geographical regions. The line thickness represents the frequency.

Supplementary information

Supplementary Fig. 1

The phylogeny of fur animal hosts, broadening the host range of the viruses identified here, the genome structure of rabbit coronavirus 1 and the phylogenetic tree of H6N2 influenza A virus. a, The phylogeny and taxonomic relationships of fur animal hosts surveyed and related representative mammalian species (data from TimeTree; https://timetree.org/). The dots indicate species that are involved in this study, with a star highlighting the phylogenetic position of humans. Owing to a lack of data for the species Notamacropus rufogriseus, the taxonomic relationships from the closely related Notamacropus parma were used. b, The heat map shows the expanded animal host range for 93 viruses, and the stacked bar chart on the right shows the number of expanded host for each virus. Different hosts are distinguished by colour. c, The genomic structure of the six rabbit CoV-1 sequences and the reference sequence of Pika coronavirus. d, The maximum likelihood tree and lineage classification of the HA gene of the H6N2 virus identified in muskrat.

Reporting Summary

Supplementary Table 1

Virus species demarcation criteria used in this study, related to the Methods.

Source data

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Zhao, J., Wan, W., Yu, K. et al. Farmed fur animals harbour viruses with zoonotic spillover potential. Nature 634, 228–233 (2024). https://doi.org/10.1038/s41586-024-07901-3

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