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

Nat Microbiol. 2019 Mar;4(3):438-446. doi: 10.1038/s41564-018-0317-1. Epub 2018 Dec 10.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age Factors
  • Animals
  • Bunyaviridae Infections / immunology
  • Bunyaviridae Infections / physiopathology*
  • Disease Models, Animal*
  • Ferrets*
  • Gene Expression Profiling
  • Humans
  • Immunocompetence
  • Inflammation
  • Interferons / immunology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Phlebovirus / genetics
  • Phlebovirus / pathogenicity*
  • Thrombocytopenia / mortality
  • Thrombocytopenia / virology
  • Viral Load

Substances

  • Interferons