1887

Abstract

Ferrets are widely used for experimental modelling of viral infections. However, background disease in ferrets could potentially confound intended experimental interpretation. Here we report the detection of a subclinical infection of ferret hepatitis E virus (FRHEV) within a colony sub-group of female laboratory ferrets that had been enrolled on an experimental viral infection study (non-hepatitis). Lymphoplasmacytic cuffing of periportal spaces was identified on histopathology but was negative for the RNA and antigens of the administered virus. Follow-up viral metagenomic analysis conducted on liver specimens revealed sequences attributed to FRHEV and these were confirmed by reverse-transcriptase polymerase chain reaction. Further genomic analysis revealed contiguous sequences spanning 79–95 % of the FRHEV genome and that the sequences were closely related to those reported previously in Europe. Using hybridization by RNAScope, we confirmed the presence of HEV-specific RNA in hepatocytes. The HEV open reading frame 2 (ORF2) protein was also detected by immunohistochemistry in the hepatocytes and the biliary canaliculi. In conclusion, the results of our study provide evidence of background infection with FRHEV in laboratory ferrets. As this infection can be subclinical, we recommend routine monitoring of ferret populations using virological and liver function tests to avoid incorrect causal attribution of any liver disease detected in studies.

Funding
This study was supported by the:
  • USZ Innovations-Pool
    • Principle Award Recipient: AchimWeber
  • Uniscientia Stiftung
    • Principle Award Recipient: AchimWeber
  • Department for Environment, Food and Rural Affairs, UK Government (Award SE0558)
    • Principle Award Recipient: SharonM Brookes
  • This is an open-access article distributed under the terms of the Creative Commons Attribution License. This article was made open access via a Publish and Read agreement between the Microbiology Society and the corresponding author’s institution.
Loading

Article metrics loading...

/content/journal/jgv/10.1099/jgv.0.001803
2022-11-10
2024-10-11
Loading full text...

Full text loading...

/deliver/fulltext/jgv/103/11/jgv001803.html?itemId=/content/journal/jgv/10.1099/jgv.0.001803&mimeType=html&fmt=ahah

References

  1. Yin X, Ambardekar C, Lu Y, Feng Z. Distinct entry mechanisms for nonenveloped and quasi-enveloped hepatitis E viruses. J Virol 2016; 90:4232–4242 [View Article] [PubMed]
    [Google Scholar]
  2. Purdy MA, Drexler JF, Meng X-J, Norder H, Okamoto H et al. ICTV virus taxonomy profile: Hepeviridae 2022. J Gen Virol 2022; 103: [View Article] [PubMed]
    [Google Scholar]
  3. W.H.O Hepatitis e fact sheet; 2021 https://www.who.int/news-room/fact-sheets/detail/hepatitis-e accessed 9 November 2022
  4. Thiry D, Mauroy A, Pavio N, Purdy MA, Rose N et al. Hepatitis E virus and related viruses in animals. Transbound Emerg Dis 2017; 64:37–52 [View Article] [PubMed]
    [Google Scholar]
  5. Debing Y, Moradpour D, Neyts J, Gouttenoire J. Update on hepatitis E virology: implications for clinical practice. J Hepatol 2016; 65:200–212 [View Article] [PubMed]
    [Google Scholar]
  6. Schlosser J, Eiden M, Vina-Rodriguez A, Fast C, Dremsek P et al. Natural and experimental hepatitis E virus genotype 3-infection in European wild boar is transmissible to domestic pigs. Vet Res 2014; 45:121 [View Article] [PubMed]
    [Google Scholar]
  7. Li T-C, Yonemitsu K, Terada Y, Takeda N, Takaji W et al. Ferret hepatitis E virus infection in Japan. Jpn J Infect Dis 2015; 68:60–62 [View Article] [PubMed]
    [Google Scholar]
  8. Lenggenhager D, Pawel S, Honcharova-Biletska H, Evert K, Wenzel JJ et al. The histologic presentation of hepatitis E reflects patients’ immune status and pre-existing liver condition. Mod Pathol 2021; 34:233–248 [View Article] [PubMed]
    [Google Scholar]
  9. Murphy EG, Williams NJ, Jennings D, Chantrey J, Verin R et al. First detection of Hepatitis E virus (Orthohepevirus C) in wild brown rats (Rattus norvegicus) from Great Britain. Zoonoses Public Health 2019; 66:686–694 [View Article] [PubMed]
    [Google Scholar]
  10. Li T-C, Yang T, Yoshizaki S, Ami Y, Suzaki Y et al. Ferret hepatitis E virus infection induces acute hepatitis and persistent infection in ferrets. Vet Microbiol 2016; 183:30–36 [View Article] [PubMed]
    [Google Scholar]
  11. Raj VS, Smits SL, Pas SD, Provacia LBV, Moorman-Roest H et al. Novel hepatitis E virus in ferrets, the Netherlands. Emerg Infect Dis 2012; 18:1369–1370 [View Article] [PubMed]
    [Google Scholar]
  12. Li T-C, Yoshizaki S, Kataoka M, Ami Y, Suzaki Y et al. Genetic and physicochemical analyses of a novel ferret hepatitis E virus, and clinical signs of infection after birth. Infect Genet Evol 2017; 51:153–159 [View Article] [PubMed]
    [Google Scholar]
  13. Wang L, Gong W, Fu H, Li M, Zhang Y et al. Hepatitis E virus detected from Chinese laboratory ferrets and farmed mink. Transbound Emerg Dis 2018; 65:e219–e223 [View Article] [PubMed]
    [Google Scholar]
  14. Lewandowski K, Xu Y, Pullan ST, Lumley SF, Foster D et al. Metagenomic nanopore sequencing of influenza virus direct from clinical respiratory samples. J Clin Microbiol 2019; 58:e00963-19 [View Article] [PubMed]
    [Google Scholar]
  15. Li Y, Wang H, Nie K, Zhang C, Zhang Y et al. VIP: an integrated pipeline for metagenomics of virus identification and discovery. Sci Rep 2016; 6:23774 [View Article] [PubMed]
    [Google Scholar]
  16. Sridhar S, Teng JLL, Chiu TH, Lau SKP, Woo PCY. Hepatitis E virus genotypes and evolution: emergence of camel hepatitis E variants. Int J Mol Sci 2017; 18:E869 [View Article] [PubMed]
    [Google Scholar]
  17. Pickett BE, Sadat EL, Zhang Y, Noronha JM, Squires RB et al. ViPR: an open bioinformatics database and analysis resource for virology research. Nucleic Acids Res 2012; 40:D593–8 [View Article] [PubMed]
    [Google Scholar]
  18. Katoh K, Standley DM. MAFFT multiple sequence alignment software version 7: improvements in performance and usability. Mol Biol Evol 2013; 30:772–780 [View Article] [PubMed]
    [Google Scholar]
  19. Nguyen L-T, Schmidt HA, von Haeseler A, Minh BQ. Iq-tree: a fast and effective stochastic algorithm for estimating maximum-likelihood phylogenies. Mol Biol Evol 2015; 32:268–274 [View Article] [PubMed]
    [Google Scholar]
  20. Kalyaanamoorthy S, Minh BQ, Wong TKF, von Haeseler A, Jermiin LS. ModelFinder: fast model selection for accurate phylogenetic estimates. Nat Methods 2017; 14:587–589 [View Article] [PubMed]
    [Google Scholar]
  21. Hoang DT, Chernomor O, von Haeseler A, Minh BQ, Vinh LS. UFBoot2: improving the ultrafast bootstrap approximation. Mol Biol Evol 2018; 35:518–522 [View Article] [PubMed]
    [Google Scholar]
  22. Charif D, Lobry JR. Seqinr 1.0-2: A contributed package to the r project for statistical computing devoted to biological sequences retrieval and analysis. In Bastolla U, Porto M, Roman HE, Vendruscolo M. eds Structural Approaches to Sequence Evolution: Molecules, Networks, Populations Berlin, Heidelberg: Springer; 2007 pp 207–232
    [Google Scholar]
  23. Smits SL, Raj VS, Oduber MD, Schapendonk CME, Bodewes R et al. Metagenomic analysis of the ferret fecal viral flora. PLoS One 2013; 8:e71595 [View Article] [PubMed]
    [Google Scholar]
  24. Carolan LA, Butler J, Rockman S, Guarnaccia T, Hurt AC et al. TaqMan real time RT-PCR assays for detecting ferret innate and adaptive immune responses. J Virol Methods 2014; 205:38–52 [View Article] [PubMed]
    [Google Scholar]
  25. Lenggenhager D, Gouttenoire J, Malehmir M, Bawohl M, Honcharova-Biletska H et al. Visualization of hepatitis E virus RNA and proteins in the human liver. J Hepatol 2017; 67:471–479 [View Article] [PubMed]
    [Google Scholar]
  26. Aranday-Cortes E, Bull NC, Villarreal-Ramos B, Gough J, Hicks D et al. Upregulation of IL-17A, CXCL9 and CXCL10 in early-stage granulomas induced by Mycobacterium bovis in cattle. Transbound Emerg Dis 2013; 60:525–537 [View Article] [PubMed]
    [Google Scholar]
  27. Everett HE, Lean FZX, Byrne AMP, van Diemen PM, Rhodes S et al. Intranasal infection of ferrets with SARS-CoV-2 as a model for asymptomatic human infection. Viruses 2021; 13:113 [View Article] [PubMed]
    [Google Scholar]
  28. Huynh M, Laloi F. Diagnosis of liver disease in domestic ferrets (Mustela putorius). Vet Clin North Am Exot Anim Pract 2013; 16:121–144 [View Article] [PubMed]
    [Google Scholar]
  29. Ryan KA, Bewley KR, Fotheringham SA, Slack GS, Brown P et al. Dose-dependent response to infection with SARS-CoV-2 in the ferret model and evidence of protective immunity. Nat Commun 2021; 12:81 [View Article] [PubMed]
    [Google Scholar]
  30. Lean FZX, Lamers MM, Smith SP, Shipley R, Schipper D et al. Development of immunohistochemistry and in situ hybridisation for the detection of SARS-CoV and SARS-CoV-2 in formalin-fixed paraffin-embedded specimens. Sci Rep 2020; 10:21894 [View Article] [PubMed]
    [Google Scholar]
  31. García A, Erdman SE, Xu S, Feng Y, Rogers AB et al. Hepatobiliary inflammation, neoplasia, and argyrophilic bacteria in a ferret colony. Vet Pathol 2002; 39:173–179 [View Article] [PubMed]
    [Google Scholar]
  32. Bhat S, James J, Sadeyen J-R, Mahmood S, Everest HJ et al. Coinfection of chickens with H9N2 and H7N9 avian influenza viruses leads to emergence of reassortant H9N9 virus with increased fitness for poultry and a zoonotic potential. J Virol 2022; 96:e0185621 [View Article] [PubMed]
    [Google Scholar]
  33. Weingartl H, Czub M, Czub S, Neufeld J, Marszal P et al. Immunization with modified vaccinia virus Ankara-based recombinant vaccine against severe acute respiratory syndrome is associated with enhanced hepatitis in ferrets. J Virol 2004; 78:12672–12676 [View Article] [PubMed]
    [Google Scholar]
  34. Smith JH, Nagy T, Driskell E, Brooks P, Tompkins SM et al. Comparative pathology in ferrets infected with H1N1 influenza A viruses isolated from different hosts. J Virol 2011; 85:7572–7581 [View Article] [PubMed]
    [Google Scholar]
  35. Ciurkiewicz M, Armando F, Schreiner T, de Buhr N, Pilchová V et al. Ferrets are valuable models for SARS-CoV-2 research. Vet Pathol 2022; 59:661–672 [View Article] [PubMed]
    [Google Scholar]
  36. Une Y, Wakimoto Y, Nakano Y, Konishi M, Nomura Y. Spontaneous Aleutian disease in a ferret. J Vet Med Sci 2000; 62:553–555 [View Article] [PubMed]
    [Google Scholar]
  37. Yang T, Kataoka M, Ami Y, Suzaki Y, Kishida N et al. Characterization of self-assembled virus-like particles of ferret hepatitis E virus generated by recombinant baculoviruses. J Gen Virol 2013; 94:2647–2656 [View Article] [PubMed]
    [Google Scholar]
  38. Smith DB, Simmonds P, Jameel S, Emerson SU. Members Of The International Committee On The Taxonomy Of Viruses Hepeviridae Study Group et al. Consensus proposals for classification of the family hepeviridae. J Gen Virol 2015; 96:1191–1192 [View Article]
    [Google Scholar]
  39. Purdy MA, Harrison TJ, Jameel S, Meng X-J, Okamoto H et al. ICTV virus taxonomy profile: hepeviridae. J Gen Virol 2017; 98:2645–2646 [View Article] [PubMed]
    [Google Scholar]
  40. Berto A, Grierson S, Hakze-van der Honing R, Martelli F, Johne R et al. Hepatitis E virus in pork liver sausage, France. Emerg Infect Dis 2013; 19:264–266 [View Article] [PubMed]
    [Google Scholar]
  41. Sridhar S, Yip CC-Y, Wu S, Chew NF-S, Leung K-H et al. Transmission of rat hepatitis E virus infection to humans in Hong Kong: a clinical and epidemiological analysis. Hepatology 2021; 73:10–22 [View Article] [PubMed]
    [Google Scholar]
  42. Gustafson KD, Hawkins MG, Drazenovich TL, Church R, Brown SA et al. Founder events, isolation, and inbreeding: intercontinental genetic structure of the domestic ferret. Evol Appl 2018; 11:694–704 [View Article] [PubMed]
    [Google Scholar]
  43. Andonov A, Robbins M, Borlang J, Cao J, Hatchette T et al. Rat hepatitis E Virus linked to severe acute hepatitis in an immunocompetent patient. J Infect Dis 2019; 220:951–955 [View Article] [PubMed]
    [Google Scholar]
  44. Li T-C, Yoshizaki S, Ami Y, Suzaki Y, Yang T et al. Monkeys and rats are not susceptible to ferret hepatitis E virus infection. Intervirology 2015; 58:139–142 [View Article] [PubMed]
    [Google Scholar]
  45. Vidaña B, Brookes SM, Everett HE, Garcon F, Nuñez A et al. Inactivated pandemic 2009 H1N1 influenza A virus human vaccines have different efficacy after homologous challenge in the ferret model. Influenza Other Respir Viruses 2021; 15:142–153 [View Article] [PubMed]
    [Google Scholar]
  46. van den Brand JMA, Haagmans BL, Leijten L, van Riel D, Martina BEE et al. Pathology of experimental SARS coronavirus infection in cats and ferrets. Vet Pathol 2008; 45:551–562 [View Article] [PubMed]
    [Google Scholar]
  47. Darnell MER, Plant EP, Watanabe H, Byrum R, St Claire M et al. Severe acute respiratory syndrome coronavirus infection in vaccinated ferrets. J Infect Dis 2007; 196:1329–1338 [View Article] [PubMed]
    [Google Scholar]
  48. Allweiss L, Gass S, Giersch K, Groth A, Kah J et al. Human liver chimeric mice as a new model of chronic hepatitis E virus infection and preclinical drug evaluation. J Hepatol 2016; 64:1033–1040 [View Article] [PubMed]
    [Google Scholar]
  49. Ankavay M, Montpellier C, Sayed IM, Saliou J-M, Wychowski C et al. New insights into the ORF2 capsid protein, a key player of the hepatitis E virus lifecycle. Sci Rep 2019; 9:6243 [View Article] [PubMed]
    [Google Scholar]
  50. Risalde MA, Rivero-Juárez A, Romero-Palomo F, Frías M, López-López P et al. Persistence of hepatitis E virus in the liver of non-viremic naturally infected wild boar. PLoS One 2017; 12:e0186858 [View Article] [PubMed]
    [Google Scholar]
  51. Jung S, Seo DJ, Yeo D, Wang Z, Min A et al. Experimental infection of hepatitis E virus induces pancreatic necroptosis in miniature pigs. Sci Rep 2020; 10:12022 [View Article] [PubMed]
    [Google Scholar]
  52. Liang C, Zhao C, Liu T, Liu B, Liu Z et al. Characterization of chronic hepatitis E Virus infection in immunocompetent rabbits. Viruses 2022; 14:1252 [View Article] [PubMed]
    [Google Scholar]
  53. Sridhar S, Wu S, Situ J, Shun EH-K, Li Z et al. A small animal model of chronic hepatitis E infection using immunocompromised rats. JHEP Rep 2022; 4:100546 [View Article] [PubMed]
    [Google Scholar]
/content/journal/jgv/10.1099/jgv.0.001803
Loading
/content/journal/jgv/10.1099/jgv.0.001803
Loading

Data & Media loading...

Supplements

Supplementary material 1

PDF
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error