Severe fever with thrombocytopenia syndrome phlebovirus (SFTSV), listed in the most dangerous pathogens by the World Health Organization, has 12–30% fatality rates with a characteristic thrombocytopenia syndrome. With a majority of clinically diagnosed SFTSV patients older than ~50 years of age, age is a critical risk factor for SFTSV morbidity and mortality. Here, we report an age-dependent ferret model of SFTSV infection and pathogenesis that fully recapitulates the clinical manifestations of human infections. Whereas young adult ferrets (≤2 years of age) did not show any clinical symptoms and mortality, SFTSV-infected aged ferrets (≥4 years of age) demonstrated severe thrombocytopenia, reduced white blood cell counts and high fever with 93% mortality rate. Moreover, a significantly higher viral load was observed in aged ferrets. Transcriptome analysis of SFTSV-infected young ferrets revealed strong interferon-mediated anti-viral signalling, whereas inflammatory immune responses were markedly upregulated and persisted in aged ferrets. Thus, this immunocompetent age-dependent ferret model should be useful for anti-SFTSV therapy and vaccine development.
Subscribe to Journal
Get full journal access for 1 year
only $5.17 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
The data that support the findings of this study are available from the corresponding authors upon request. The RNA-seq data were deposited in the Gene Expression Omnibus (GEO) under the accession number GSE121911.
Wiwanitkit, S. & Wiwanitkit, V. Acute viral hemorrhage disease: a summary on new viruses. J. Acute Dis. 4, 277–279 (2015).
Adams, M. J. et al. Changes to taxonomy and the International Code of Virus Classification and Nomenclature ratified by the International Committee on Taxonomy of Viruses (2017). Arch. Virol. 162, 2505–2538 (2017).
Kim, K.-H. et al. Severe fever with thrombocytopenia syndrome, South Korea, 2012. Emerg. Infect. Dis. 19, 1892–1894 (2013).
Takahashi, T. et al. The first identification and retrospective study of severe fever with thrombocytopenia syndrome in Japan. J. Infect. Dis. 209, 816–827 (2013).
SFTSV Infection in Korea (KCDC, 2016); http://cdc.go.kr/CDC/mobile/notice/CdcKrIntro0201.jsp?menuIds=HOME001-MNU1154-MN&fid=21&q_type=&q_value=&cid=73941&pageNum=1
NIID. Severe fever with thrombocytopenia syndrome (SFTS) in Japan, as of February 2016. IASR 37, 39–40 (2016).
Zhan, J. et al. Current status of severe fever with thrombocytopenia syndrome in China. Virol. Sin. 32, 51–62 (2017).
Li, D. Severe fever with thrombocytopenia syndrome: a newly discovered emerging infectious disease. Clin. Microbiol. Infect. 21, 614–620 (2015).
Baba, M. et al. Establishment of an antiviral assay system and identification of severe fever with thrombocytopenia syndrome virus inhibitors. Antivir. Chem. Chemother. 25, 83–89 (2017).
Disease Web Statistics System (KCDC, 2017); http://www.cdc.go.kr/npt/biz/npp/ist/bass/bassDissStatsMain.do
Epidemiologic and Clinical Characteristics of Severe Fever with Thrombocytopenia Syndrome in the Republic of Korea (KCDC, 2016); http://cdc.go.kr/CDC/together/CdcKrTogether0302.jsp?menuIds=HOME001-MNU1154-MNU0005- MNU0088&fid=51&q_type=title&q_value=SFTS&cid=69842&pageNum=
Caution of SFTS Infection at Outdoor Activity (KCDC, 2018); http://www.cdc.go.kr/npt/biz/npp/portal/nppSumryMain.do?icdCd=D0018&icdgrpCd=04&icdSubgrpCd=
2018 Annual Review of Diseases Prioritized Under the Research and Development Blueprint. WHO Research and Development Blueprint (WHO, 2018).
Pepin, M., Bouloy, M., Bird, B. H., Kemp, A. & Paweska, J. Rift Valley fever virus (Bunyaviridae: Phlebovirus): an update on pathogenesis, molecular epidemiology, vectors, diagnostics and prevention. Vet. Res. 41, 61 (2010).
Swei, A. et al. The genome sequence of Lone Star virus, a highly divergent bunyavirus found in the Amblyomma americanum tick. PLoS ONE 8, e62083 (2013).
Liu, Y. et al. The pathogenesis of severe fever with thrombocytopenia syndrome virus infection in alpha/beta interferon knockout mice: insights into the pathologic mechanisms of a new viral hemorrhagic fever. J. Virol. 88, 1781–1786 (2014).
Chen, X.-P. et al. Infection and pathogenesis of Huaiyangshan virus (a novel tick-borne bunyavirus) in laboratory rodents. J. Gen. Virol. 93, 1288–1293 (2012).
Jin, C. et al. Pathogenesis of emerging severe fever with thrombocytopenia syndrome virus in C57/BL6 mouse model. Proc. Natl Acad. Sci. USA 109, 10053–10058 (2012).
Liu, S. et al. Systematic review of severe fever with thrombocytopenia syndrome: virology, epidemiology, and clinical characteristics. Rev. Med. Virol. 24, 90–102 (2014).
Jin, C. et al. SFTS virus infection in nonhuman primates. J. Infect. Dis. 211, 915–925 (2014).
Yun, S.-M. et al. Molecular genomic characterization of tick-and human-derived severe fever with thrombocytopenia syndrome virus isolates from South Korea. PLoS Negl. Trop. Dis. 11, e0005893 (2017).
Sun, J. et al. Factors associated with severe fever with thrombocytopenia syndrome infection and fatal outcome. Sci. Rep. 6, 33175 (2016).
Smith, S. A., Zimmerman, K. & Moore, D. M. Hematology of the domestic ferret (Mustela putorius furo). Vet. Clin. North Am. Exot. Anim. Prac. 18, 1–8 (2015).
Hein, J., Spreyer, F., Sauter-Louis, C. & Hartmann, K. Reference ranges for laboratory parameters in ferrets. Vet. Rec. 171, 218 (2012).
Li, S. et al. Multiple organ involvement in severe fever with thrombocytopenia syndrome: an immunohistochemical finding in a fatal case. Virol. J. 15, 97 (2018).
Hiraki, T. et al. Two autopsy cases of severe fever with thrombocytopenia syndrome (SFTS) in Japan: a pathognomonic histological feature and unique complication of SFTS. Pathol. Int. 64, 569–575 (2014).
Park, S.-J. et al. Dynamic changes in host gene expression associated with H5N8 avian influenza virus infection in mice. Sci. Rep. 5, 16512 (2015).
Shimada, S., Posadas-Herrera, G., Aoki, K., Morita, K. & Hayasaka, D. Therapeutic effect of post-exposure treatment with antiserum on severe fever with thrombocytopenia syndrome (SFTS) in a mouse model of SFTS virus infection. Virology 482, 19–27 (2015).
Kaneko, M. et al. A patient with severe fever with thrombocytopenia syndrome and hemophagocytic lymphohistiocytosis-associated involvement of the central nervous system. J. Infect. Chemother. 24, 292–297 (2018).
Deng, B. et al. Cytokine and chemokine levels in patients with severe fever with thrombocytopenia syndrome virus. PLoS ONE 7, e41365 (2012).
Liu, J. et al. Dynamic changes of laboratory parameters and peripheral blood lymphocyte subsets in severe fever with thrombocytopenia syndrome patients. Int. J. Infect. Dis. 58, 45–51 (2017).
This work was supported by the Korea Health Technology R&D Project, funded by the Ministry of Health & Welfare, Republic of Korea (HI15C2817), National Research Foundation of Korea (NRF-2017K2A9A1A01092932) to Y.K.C., National Institute of Health (AI129496, AI40718 and AI140705) to J.U.J. and the Ministry of Health & Welfare, Republic of Korea (HI15C2888) to M.-S.S. We thank I.-P. Mo and K.-S. Kim (College of Veterinary Medicine, Chungbuk National University) for their kind support in the immunohistochemistry assay and the haematoxylin and eosin histopathological study.
The authors declare no competing interests.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Park, S., Kim, Y., Park, A. et al. Ferret animal model of severe fever with thrombocytopenia syndrome phlebovirus for human lethal infection and pathogenesis. Nat Microbiol 4, 438–446 (2019). https://doi.org/10.1038/s41564-018-0317-1
Journal of Clinical Investigation (2020)
Genetic and pathogenic diversity of severe fever with thrombocytopenia syndrome virus (SFTSV) in South Korea
JCI Insight (2020)
Cross-genotype protection of live-attenuated vaccine candidate for severe fever with thrombocytopenia syndrome virus in a ferret model
Proceedings of the National Academy of Sciences (2019)
Severe Fever with Thrombocytopenia Syndrome Phlebovirus causes lethal viral hemorrhagic fever in cats
Scientific Reports (2019)
Severe fever and thrombocytopenia syndrome virus infection: Considerations for vaccine evaluation of a rare disease
Human Vaccines & Immunotherapeutics (2019)