title: Modeling Severe Fever with Thrombocytopenia Syndrome Virus Infection in Golden Syrian Hamsters: Importance of STAT2 in Preventing Disease and Effective Treatment with Favipiravir.
abstract: Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne disease endemic in parts of Asia. The etiologic agent, SFTS virus (SFTSV; family Bunyaviridae, genus Phlebovirus) has caused significant morbidity and mortality in China, South Korea, and Japan, with key features of disease being intense fever, thrombocytopenia, and leukopenia. Case fatality rates are estimated to be in the 30% range, and no antivirals or vaccines are approved for use for treatment and prevention of SFTS. There is evidence that in human cells, SFTSV sequesters STAT proteins in replication complexes, thereby inhibiting type I interferon signaling. Here, we demonstrate that hamsters devoid of functional STAT2 are highly susceptible to as few as 10 PFU of SFTSV, with animals generally succumbing within 5 to 6 days after subcutaneous challenge. The disease included marked thrombocytopenia and inflammatory disease characteristic of the condition in humans. Infectious virus titers were present in the blood and most tissues 3 days after virus challenge, and severe inflammatory lesions were found in the spleen and liver samples of SFTSV-infected hamsters. We also show that SFTSV infection in STAT2 knockout (KO) hamsters is responsive to favipiravir treatment, which protected all animals from lethal disease and reduced serum and tissue viral loads by 3 to 6 orders of magnitude. Taken together, our results provide additional insights into the pathogenesis of SFTSV infection and support the use of the newly described STAT2 KO hamster model for evaluation of promising antiviral therapies.
  
  
  OBJECTIVE
  Severe fever with thrombocytopenia syndrome (SFTS) is an emerging viral disease for which there are currently no therapeutic options or available vaccines. The causative agent, SFTS virus (SFTSV), is present in China, South Korea, and Japan, and infections requiring medical attention result in death in as many as 30% of the cases. Here, we describe a novel model of SFTS in hamsters genetically engineered to be deficient in a protein that helps protect humans and animals against viral infections. These hamsters were found to be susceptible to SFTSV and share disease features associated with the disease in humans. Importantly, we also show that SFTSV infection in hamsters can be effectively treated with a broad-spectrum antiviral drug approved for use in Japan. Our findings suggest that the new SFTS model will be an excellent resource to better understand SFTSV infection and disease as well as a valuable tool for evaluating promising antiviral drugs.
authors.affiliation: Department of Animal, Dairy, and Veterinary Sciences, Utah State University, Logan, Utah, USA brian.gowen@usu.edu.
authors.forename: Brian B
authors.initials: BB
authors.lastname: Gowen
authors.affiliation: Department of Animal, Dairy, and Veterinary Sciences, Utah State University, Logan, Utah, USA.
authors.forename: Jonna B
authors.initials: JB
authors.lastname: Westover
authors.affiliation: Department of Animal, Dairy, and Veterinary Sciences, Utah State University, Logan, Utah, USA.|Department of Pathology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, People's Republic of China.
authors.forename: Jinxin
authors.initials: J
authors.lastname: Miao
authors.affiliation: Department of Animal, Dairy, and Veterinary Sciences, Utah State University, Logan, Utah, USA.|Utah Veterinary Diagnostic Laboratory, Logan, Utah, USA.
authors.forename: Arnaud J
authors.initials: AJ
authors.lastname: Van Wettere
authors.affiliation: Department of Animal, Dairy, and Veterinary Sciences, Utah State University, Logan, Utah, USA.|Utah Veterinary Diagnostic Laboratory, Logan, Utah, USA.
authors.forename: Johanna D
authors.initials: JD
authors.lastname: Rigas
authors.affiliation: Department of Animal, Dairy, and Veterinary Sciences, Utah State University, Logan, Utah, USA.
authors.forename: Brady T
authors.initials: BT
authors.lastname: Hickerson
authors.affiliation: Department of Animal, Dairy, and Veterinary Sciences, Utah State University, Logan, Utah, USA.
authors.forename: Kie-Hoon
authors.initials: KH
authors.lastname: Jung
authors.affiliation: Department of Animal, Dairy, and Veterinary Sciences, Utah State University, Logan, Utah, USA.
authors.forename: Rong
authors.initials: R
authors.lastname: Li
authors.affiliation: Utah Veterinary Diagnostic Laboratory, Logan, Utah, USA.
authors.forename: Bettina L
authors.initials: BL
authors.lastname: Conrad
authors.affiliation: Department of Animal, Dairy, and Veterinary Sciences, Utah State University, Logan, Utah, USA.
authors.forename: Skot
authors.initials: S
authors.lastname: Nielson
authors.affiliation: Research Laboratories, Toyama Chemical Co., Ltd., Toyama, Japan.
authors.forename: Yousuke
authors.initials: Y
authors.lastname: Furuta
authors.affiliation: Department of Animal, Dairy, and Veterinary Sciences, Utah State University, Logan, Utah, USA.
authors.forename: Zhongde
authors.initials: Z
authors.lastname: Wang
mesh_terms: D000577:Amides / Q000494:pharmacology; D000818:Animals; D030801:Animals, Genetically Modified; D000998:Antiviral Agents / Q000494:pharmacology; D002044:Bunyaviridae Infections / Q000188:drug therapy / Q000235:genetics / Q000401:mortality / Q000821:virology*; D006224:Cricetinae; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D005838:Genotype; D006801:Humans; D008954:Models, Biological; D010641:Phenotype; D016856:Phlebovirus / Q000502:physiology*; D011719:Pyrazines / Q000494:pharmacology; D050795:STAT2 Transcription Factor / Q000235:genetics
chemical_list: D000577:Amides; D000998:Antiviral Agents; D011719:Pyrazines; D050795:STAT2 Transcription Factor; C462182:favipiravir
keywords: STAT2; animal model; antiviral; favipiravir; phlebovirus; severe fever with thrombocytopenia syndrome virus