title: Animal Models of Emerging Tick-Borne Phleboviruses: Determining Target Cells in a Lethal Model of SFTSV Infection.
abstract: The pathogenesis of clinical manifestations caused by newly emerging tick-borne phleboviruses [i.e., Severe fever with thrombocytopenia syndrome virus (SFTSV) and Heartland virus (HRTV)], such as severe thrombocytopenia and lymphocytopenia, are not yet fully understood. In the present study, to establish an animal model mimicking the profile of fatal human cases, we examined the susceptibilities of adult mice from 12 strains, aged mice from two strains, and cynomolgus macaques to SFTSV and/or HRTV infections. However, none of these immunocompetent animals developed lethal diseases after infection with SFTSV or HRTV. Thus, we tested a lethal animal model of SFTSV infection using interferon-α/β receptor knock-out (IFNAR-/-) mice to identify the target cell(s) of virus infection, as well as lesions that are potentially associated with hematological changes. IbaI-positive macrophages and Pax5-positive immature B cells overlapped with SFTSV-positive cells in the spleen and lymph nodes of IFNAR-/-mice, and IbaI-SFTSV-double positive cells were also observed in the liver and kidney, thereby suggesting crucial roles for macrophages in the pathogenesis of SFTSV infection in mice. In the mandibular lymph nodes and spleens of infected mice, we observed extensive necrosis comprising B220-positive B cells, which may be associated with severe lymphocytopenia. The results of this study suggest a resemblance between the IFNAR-/-mouse model and lethal infections in humans, as well as roles for multiple cells during pathogenesis in mice.
authors.affiliation: Molecular Virology and Host-Pathogen Interaction Unit, Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rocky Mountain Laboratories, HamiltonMT, USA; Laboratory of Microbiology, Graduate School of Veterinary Medicine, Hokkaido UniversitySapporo, Japan; Global Station for Zoonosis Control, Global Institution for Collaborative Research and Education, Hokkaido UniversitySapporo, Japan.
authors.forename: Keita
authors.initials: K
authors.lastname: Matsuno
authors.affiliation: Division of Molecular Pathobiology, Research Center for Zoonosis Control, Hokkaido University Sapporo, Japan.
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Orba
authors.affiliation: Rocky Mountain Veterinary Branch, Rocky Mountain Laboratories, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton MT, USA.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Maede-White
authors.affiliation: Rocky Mountain Veterinary Branch, Rocky Mountain Laboratories, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton MT, USA.
authors.forename: Dana
authors.initials: D
authors.lastname: Scott
authors.affiliation: Rocky Mountain Veterinary Branch, Rocky Mountain Laboratories, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton MT, USA.
authors.forename: Friederike
authors.initials: F
authors.lastname: Feldmann
authors.affiliation: NHFPC Key Laboratory for Medical Virology, National Institute for Viral Disease Control and Prevention, China CDC Beijing, China.
authors.forename: Mifang
authors.initials: M
authors.lastname: Liang
authors.affiliation: Molecular Virology and Host-Pathogen Interaction Unit, Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rocky Mountain Laboratories, HamiltonMT, USA; Department of Molecular Medicine, Mayo Clinic, RochesterMN, USA.
authors.forename: Hideki
authors.initials: H
authors.lastname: Ebihara
keywords: aged mouse; disease modeling; heartland virus; immunocompromised mouse; mouse; nonhuman primate; severe fever with thrombocytopenia syndrome virus