{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T01:12:53Z","timestamp":1790298773352,"version":"4.1.0"},"reference-count":38,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2022,7,28]],"date-time":"2022-07-28T00:00:00Z","timestamp":1658966400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science (JSPS)","doi-asserted-by":"publisher","award":["JP18K14600"],"award-info":[{"award-number":["JP18K14600"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science (JSPS)","doi-asserted-by":"publisher","award":["JP19fk0108081"],"award-info":[{"award-number":["JP19fk0108081"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development (AMED)","doi-asserted-by":"publisher","award":["JP18K14600"],"award-info":[{"award-number":["JP18K14600"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development (AMED)","doi-asserted-by":"publisher","award":["JP19fk0108081"],"award-info":[{"award-number":["JP19fk0108081"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Heartland bandavirus (HRTV) is an emerging tick-borne virus that is distributed in the United States and that causes febrile illness with thrombocytopenia and leukocytopenia. It is genetically close to Dabie bandavirus, which is well known as severe fever with thrombocytopenia syndrome (SFTS) virus (SFTSV). The mortality rate of human HRTV infection is approximately 10%; however, neither approved anti-HRTV agents nor vaccines exist. An appropriate animal model should be developed to evaluate the efficacy of antiviral agents and vaccines against HRTV. The susceptibility of IFNAR\u2212\/\u2212 mice with HRTV infection was evaluated using subcutaneous, intraperitoneal, and retro-orbital inoculation routes. IFNAR\u2212\/\u2212 mice intraperitoneally infected with HRTV showed the most severe clinical signs, and the 50% lethal dose was 3.2 \u00d7 106 TCID50. Furthermore, to evaluate the utility of a novel lethal IFNAR\u2212\/\u2212 mice model, IFNAR\u2212\/\u2212 mice were orally administered favipiravir, ribavirin, or a solvent for 5 days immediately after a lethal dose of HRTV inoculation. The survival rates of the favipiravir-, ribavirin-, and solvent-administered mice were 100, 33, and 0%, respectively. The changes in bodyweights and HRTV RNA loads in the blood of favipiravir-treated IFNAR\u2212\/\u2212 mice were the lowest among the three groups, which suggests that favipiravir is a promising drug candidate for the treatment of patients with HRTV infection.<\/jats:p>","DOI":"10.3390\/v14081668","type":"journal-article","created":{"date-parts":[[2022,7,29]],"date-time":"2022-07-29T01:41:16Z","timestamp":1659058876000},"page":"1668","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Susceptibility of Type I Interferon Receptor Knock-Out Mice to Heartland Bandavirus (HRTV) Infection and Efficacy of Favipiravir and Ribavirin in the Treatment of the Mice Infected with HRTV"],"prefix":"10.3390","volume":"14","author":[{"given":"Hikaru","family":"Fujii","sequence":"first","affiliation":[{"name":"The Faculty of Veterinary Medicine, Okayama University of Science, 1-3 Ikoino-oka, Imabari 794-8555, Japan"},{"name":"Department of Virology I, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6309-277X","authenticated-orcid":false,"given":"Hideki","family":"Tani","sequence":"additional","affiliation":[{"name":"Department of Virology I, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan"},{"name":"Department of Virology, Toyama Institute of Health, 17-1 Nakataikouyama, Imizu-shi 939-0363, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazutaka","family":"Egawa","sequence":"additional","affiliation":[{"name":"Department of Virology I, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoshi","family":"Taniguchi","sequence":"additional","affiliation":[{"name":"Department of Virology I, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoki","family":"Yoshikawa","sequence":"additional","affiliation":[{"name":"Department of Virology I, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuetsu","family":"Fukushi","sequence":"additional","affiliation":[{"name":"Department of Virology I, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Souichi","family":"Yamada","sequence":"additional","affiliation":[{"name":"Department of Virology I, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shizuko","family":"Harada","sequence":"additional","affiliation":[{"name":"Department of Virology I, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takeshi","family":"Kurosu","sequence":"additional","affiliation":[{"name":"Department of Virology I, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5745-8413","authenticated-orcid":false,"given":"Masayuki","family":"Shimojima","sequence":"additional","affiliation":[{"name":"Department of Virology I, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takahiro","family":"Maeki","sequence":"additional","affiliation":[{"name":"Department of Virology I, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5823-8300","authenticated-orcid":false,"given":"Chang-Kweng","family":"Lim","sequence":"additional","affiliation":[{"name":"Department of Virology I, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3805-4165","authenticated-orcid":false,"given":"Mutsuyo","family":"Takayama-Ito","sequence":"additional","affiliation":[{"name":"Department of Virology I, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Komeno","sequence":"additional","affiliation":[{"name":"FUJIFILM Toyama Chemical Co., Ltd., 2-4-1 Shimookui, Toyama City 930-8508, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nozomi","family":"Nakajima","sequence":"additional","affiliation":[{"name":"FUJIFILM Toyama Chemical Co., Ltd., 2-4-1 Shimookui, Toyama City 930-8508, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yousuke","family":"Furuta","sequence":"additional","affiliation":[{"name":"FUJIFILM Toyama Chemical Co., Ltd., 2-4-1 Shimookui, Toyama City 930-8508, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akihiko","family":"Uda","sequence":"additional","affiliation":[{"name":"Department of Veterinary Science, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6249-6716","authenticated-orcid":false,"given":"Shigeru","family":"Morikawa","sequence":"additional","affiliation":[{"name":"The Faculty of Veterinary Medicine, Okayama University of Science, 1-3 Ikoino-oka, Imabari 794-8555, Japan"},{"name":"Department of Veterinary Science, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masayuki","family":"Saijo","sequence":"additional","affiliation":[{"name":"Department of Virology I, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan"},{"name":"Sapporo City Health & Welfare Bureau, Public Health Office, WEST 19, Chuo-ku West 19, Sapporo 060-0042, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,7,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3023","DOI":"10.1007\/s00705-020-04731-2","article-title":"2020 taxonomic update for phylum Negarnaviricota (Riboviria: Orthornavirae), including the large orders Bunyavirales and Mononegavirales","volume":"165","author":"Kuhn","year":"2020","journal-title":"Arch. Virol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1523","DOI":"10.1056\/NEJMoa1010095","article-title":"Fever with thrombocytopenia associated with a novel bunyavirus in China","volume":"364","author":"Yu","year":"2011","journal-title":"N. Engl. J. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"43","DOI":"10.7774\/cevr.2018.7.1.43","article-title":"Epidemiology of severe fever and thrombocytopenia syndrome virus infection and the need for therapeutics for the prevention","volume":"7","author":"Robles","year":"2018","journal-title":"Clin. Exp. Vaccine Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1892","DOI":"10.3201\/eid1911.130792","article-title":"Severe fever with thrombocytopenia syndrome, South Korea, 2012","volume":"19","author":"Kim","year":"2013","journal-title":"Emerg. Infect. Dis."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"816","DOI":"10.1093\/infdis\/jit603","article-title":"The first identification and retrospective study of Severe Fever with Thrombocytopenia Syndrome in Japan","volume":"209","author":"Takahashi","year":"2014","journal-title":"J. Infect. Dis."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Xu, B., Liu, L., Huang, X., Ma, H., Zhang, Y., Du, Y., Wang, P., Tang, X., Wang, H., and Kang, K. (2011). Metagenomic analysis of fever, thrombocytopenia and leukopenia syndrome (FTLS) in Henan Province, China: Discovery of a new bunyavirus. PLoS Pathog., 7.","DOI":"10.1371\/journal.ppat.1002369"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"929","DOI":"10.1007\/s10096-020-04098-x","article-title":"Epidemiological characteristics of severe fever with thrombocytopenia syndrome in Hefei of Anhui Province: A population-based surveillance study from 2011 to 2018","volume":"40","author":"You","year":"2021","journal-title":"Eur. J. Clin. Microbiol. Infect. Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1029","DOI":"10.3201\/eid2505.181463","article-title":"Endemic Severe Fever with Thrombocytopenia Syndrome, Vietnam","volume":"25","author":"Tran","year":"2019","journal-title":"Emerg. Infect. Dis."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1080\/22221751.2019.1710436","article-title":"The first discovery of severe fever with thrombocytopenia syndrome virus in Taiwan","volume":"9","author":"Lin","year":"2020","journal-title":"Emerg. Microbes Infect."},{"key":"ref_10","unstructured":"(2022, June 28). Available online: https:\/\/www.cdc.gov\/heartland-virus\/statistics\/index.html."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1056\/NEJMoa1203378","article-title":"A new phlebovirus associated with severe febrile illness in Missouri","volume":"367","author":"McMullan","year":"2012","journal-title":"N. Engl. J. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1093\/cid\/ciu434","article-title":"Heartland virus-associated death in tennessee","volume":"59","author":"Muehlenbachs","year":"2014","journal-title":"Clin. Infect. Dis."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"358","DOI":"10.3201\/eid2502.181288","article-title":"Seroprevalence of Heartland Virus Antibodies in Blood Donors, Northwestern Missouri, USA","volume":"25","author":"Lindsey","year":"2019","journal-title":"Emerg. Infect. Dis."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"992","DOI":"10.4269\/ajtmh.16-0967","article-title":"The Emergence of Severe Fever with Thrombocytopenia Syndrome Virus","volume":"97","author":"Silvas","year":"2017","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Brault, A.C., Savage, H.M., Duggal, N.K., Eisen, R.J., and Staples, J.E. (2018). Heartland Virus Epidemiology, Vector Association, and Disease Potential. Viruses, 10.","DOI":"10.3390\/v10090498"},{"key":"ref_16","first-page":"510","article-title":"Novel Clinical and Pathologic Findings in a Heartland Virus-Associated Death","volume":"64","author":"Fill","year":"2017","journal-title":"Clin. Infect. Dis."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1016\/j.antiviral.2013.09.015","article-title":"Favipiravir (T-705), a novel viral RNA polymerase inhibitor","volume":"100","author":"Furuta","year":"2013","journal-title":"Antiviral Res"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.coviro.2014.04.011","article-title":"Ribavirin: A drug active against many viruses with multiple effects on virus replication and propagation. Molecular basis of ribavirin resistance","volume":"8","author":"Beaucourt","year":"2014","journal-title":"Curr. Opin. Virol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"423","DOI":"10.7883\/yoken.67.423","article-title":"Effects of ribavirin on severe fever with thrombocytopenia syndrome virus in vitro","volume":"67","author":"Shimojima","year":"2014","journal-title":"Jpn. J. Infect. Dis."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1016\/j.virol.2017.08.004","article-title":"Heartland virus infection in hamsters deficient in type I interferon signaling: Protracted disease course ameliorated by favipiravir","volume":"511","author":"Westover","year":"2017","journal-title":"Virology"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e00061-15","DOI":"10.1128\/mSphere.00061-15","article-title":"Efficacy of T-705 (Favipiravir) in the Treatment of Infections with Lethal Severe Fever with Thrombocytopenia Syndrome Virus","volume":"1","author":"Tani","year":"2016","journal-title":"mSphere"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.virol.2015.03.010","article-title":"Therapeutic effect of post-exposure treatment with antiserum on severe fever with thrombocytopenia syndrome (SFTS) in a mouse model of SFTS virus infection","volume":"482","author":"Shimada","year":"2015","journal-title":"Virology"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Tani, H., Komeno, T., Fukuma, A., Fukushi, S., Taniguchi, S., Shimojima, M., Uda, A., Morikawa, S., Nakajima, N., and Furuta, Y. (2018). Therapeutic effects of favipiravir against severe fever with thrombocytopenia syndrome virus infection in a lethal mouse model: Dose-efficacy studies upon oral administration. PLoS ONE, 13.","DOI":"10.1101\/399899"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1781","DOI":"10.1128\/JVI.02277-13","article-title":"The pathogenesis of severe fever with thrombocytopenia syndrome virus infection in alpha\/beta interferon knockout mice: Insights into the pathologic mechanisms of a new viral hemorrhagic fever","volume":"88","author":"Liu","year":"2014","journal-title":"J. Virol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"104","DOI":"10.3389\/fmicb.2017.00104","article-title":"Animal Models of Emerging Tick-Borne Phleboviruses: Determining Target Cells in a Lethal Model of SFTSV Infection","volume":"8","author":"Matsuno","year":"2017","journal-title":"Front. Microbiol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e02246-17","DOI":"10.1128\/JVI.02246-17","article-title":"RIG-I-Like Receptor and Toll-Like Receptor Signaling Pathways Cause Aberrant Production of Inflammatory Cytokines\/Chemokines in a Severe Fever with Thrombocytopenia Syndrome Virus Infection Mouse Model","volume":"92","author":"Yamada","year":"2018","journal-title":"J. Virol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2070","DOI":"10.3201\/eid2212.160472","article-title":"Vertebrate Host Susceptibility to Heartland Virus","volume":"22","author":"Calvert","year":"2016","journal-title":"Emerg. Infect. Dis."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e0004922","DOI":"10.1128\/jvi.00049-22","article-title":"Reverse Genetics System for Heartland Bandavirus: NSs Protein Contributes to Heartland Bandavirus Virulence","volume":"96","author":"Taniguchi","year":"2022","journal-title":"J. Virol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"445","DOI":"10.4269\/ajtmh.13-0209","article-title":"First detection of heartland virus (Bunyaviridae: Phlebovirus) from field collected arthropods","volume":"89","author":"Savage","year":"2013","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1038\/nri2802","article-title":"Immunity and immunopathology to viruses: What decides the outcome?","volume":"10","author":"Rouse","year":"2010","journal-title":"Nat. Rev. Immunol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"9503","DOI":"10.1074\/jbc.RA118.006563","article-title":"Heartland virus antagonizes type I and III interferon antiviral signaling by inhibiting phosphorylation and nuclear translocation of STAT2 and STAT1","volume":"294","author":"Feng","year":"2019","journal-title":"J. Biol. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1007\/5584_2016_135","article-title":"Syrian Hamsters as a Small Animal Model for Emerging Infectious Diseases: Advances in Immunologic Methods","volume":"972","author":"Warner","year":"2017","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2061","DOI":"10.3389\/fimmu.2018.02061","article-title":"The Dual Nature of Type I and Type II Interferons","volume":"9","author":"Lee","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1186\/1465-9921-6-135","article-title":"Proinflammatory cytokine responses induced by influenza A (H5N1) viruses in primary human alveolar and bronchial epithelial cells","volume":"6","author":"Chan","year":"2005","journal-title":"Respir. Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1016\/j.coi.2011.07.016","article-title":"The pathogenesis of influenza virus infections: The contributions of virus and host factors","volume":"23","author":"Fukuyama","year":"2011","journal-title":"Curr. Opin. Immunol."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Khalil, J., Kato, H., and Fujita, T. (2021). The Role of Non-Structural Protein NSs in the Pathogenesis of Severe Fever with Thrombocytopenia Syndrome. Viruses, 13.","DOI":"10.3390\/v13050876"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"893","DOI":"10.3201\/eid2405.171802","article-title":"Heartland Virus and Hemophagocytic Lymphohistiocytosis in Immunocompromised Patient, Missouri, USA","volume":"24","author":"Carlson","year":"2018","journal-title":"Emerg. Infect. Dis."},{"key":"ref_38","first-page":"270","article-title":"Prevention, Notes from the field: Heartland virus disease\u2014United States, 2012\u20132013","volume":"63","author":"Pastula","year":"2014","journal-title":"MMWR Morb. Mortal Wkly Rep."}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/14\/8\/1668\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:58:42Z","timestamp":1760140722000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/14\/8\/1668"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,28]]},"references-count":38,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2022,8]]}},"alternative-id":["v14081668"],"URL":"https:\/\/doi.org\/10.3390\/v14081668","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,7,28]]}}}