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

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).

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.

Author information

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.

Correspondence to Jae U. Jung or Young Ki Choi.

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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

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