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Ferret animal model of severe fever with thrombocytopenia syndrome phlebovirus for human lethal infection and pathogenesis

Nature Microbiology volume 4, pages 438–446 (2019)Cite this article

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Abstract

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.

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Fig. 1: Survival and body weight of young adult and aged ferrets following inoculation with SFTSV.
Fig. 2: Haematological analysis of SFTSV-inoculated ferrets (n = 21 per group).
Fig. 3: Concentration of liver enzymes in the blood of SFTSV-inoculated ferrets (n = 21 per group).
Fig. 4: Distribution of the number of viral RNA copies in tissues and blood of SFTSV-infected ferrets.
Fig. 5: Immunohistochemistry of tissues from aged ferret infected with SFTSV.
Fig. 6: Overview of RNA-seq data from PBMCs of young adult and aged ferrets infected with SFTSV and control ferrets at 2 and 4 dpi (n = 2 for control and 2 dpi of young adult ferrets and n = 3 for 4 dpi of young adult ferrets and aged ferrets).

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Data availability

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.

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Acknowledgements

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.

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  1. These authors contributed equally: Su-Jin Park, Young-Il Kim.

Authors and Affiliations

  1. Department of Microbiology, College of Medicine and Medical Research Institute, Chungbuk National University, Cheongju, Republic of Korea

    Su-Jin Park, Young-Il Kim, Hyeok-Il Kwon, Eun-Ha Kim, Young-Jae Si, Min-Suk Song & Young Ki Choi

  2. Zoonotic Infectious Diseases Research Center, Chungbuk National University, Cheongju, Republic of Korea

    Su-Jin Park, Young-Il Kim, Hyeok-Il Kwon, Eun-Ha Kim, Young-Jae Si, Min-Suk Song & Young Ki Choi

  3. Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    Angela Park, Kyle Jung, Woo-Jin Shin, Jianxiong Zeng, Younho Choi & Jae U. Jung

  4. Laboratory Animal Center, Korea Research Institute of Bioscience and Biotechnology, University of Science and Technology, Daejeon, Republic of Korea

    Chul-Ho Lee

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Contributions

S.-J.P., Y.-I.K. and Y.K.C. conceptualized the study. S.-J.P., Y.-I.K., H.-I.K., E.-H.K., Y.-J.S., C.-H.L., A.P., K.J., W.-J.S., M.-S.S., Y.C. and J.Z. conducted the investigation. S.-J.P., J.U.J. and Y.K.C. wrote the paper.

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Correspondence to Jae U. Jung or Young Ki Choi.

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Park, SJ., Kim, YI., 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

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