{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T15:22:37Z","timestamp":1785252157249,"version":"3.55.0"},"reference-count":46,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2022,10,13]],"date-time":"2022-10-13T00:00:00Z","timestamp":1665619200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"The Japanese Society for the Promotion of Science (JSPS)","award":["19K10595"],"award-info":[{"award-number":["19K10595"]}]},{"name":"The Japanese Society for the Promotion of Science (JSPS)","award":["16K08801"],"award-info":[{"award-number":["16K08801"]}]},{"name":"The Japanese Society for the Promotion of Science (JSPS)","award":["20K07510"],"award-info":[{"award-number":["20K07510"]}]},{"name":"The Japanese Society for the Promotion of Science (JSPS)","award":["JP22jm0110019"],"award-info":[{"award-number":["JP22jm0110019"]}]},{"name":"Science and Technology Research Partnership for Sustainable Development","award":["19K10595"],"award-info":[{"award-number":["19K10595"]}]},{"name":"Science and Technology Research Partnership for Sustainable Development","award":["16K08801"],"award-info":[{"award-number":["16K08801"]}]},{"name":"Science and Technology Research Partnership for Sustainable Development","award":["20K07510"],"award-info":[{"award-number":["20K07510"]}]},{"name":"Science and Technology Research Partnership for Sustainable Development","award":["JP22jm0110019"],"award-info":[{"award-number":["JP22jm0110019"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Hantaan virus is the causative agent of hemorrhagic fever with renal syndrome (HFRS). The Hantaan virus strain, Korean hemorrhagic fever virus clone-5 (KHF5), causes weight loss and renal hemorrhage in laboratory mice. Clone-4 (KHF4), which has a single E417K amino acid change in its glycoprotein, is an avirulent variant. In this study, KHF4 and KHF5 were compared to evaluate pathological differences in mice in vitro and in vivo. The characteristics of the two glycoproteins were not significantly different in vitro. However, the virulent KHF5 strain targeted the lungs and caused pneumonia and edema in vivo. Both strains induced high infectivity levels in the liver and caused hepatitis; however, petechial hemorrhage and glycogen storage reduction were observed in KHF5-infected mice alone. Renal hemorrhage was observed using viral antigens in the tubular region of KHF5-infected mice. In addition, an increase in white blood cell levels and neutrophilia were found in KHF5-infected mice. Microarray analysis of liver cells showed that CD8+ T cell activation, acute-phase protein production, and neutrophil activation was induced by KHF5 infection. KHF5 infectivity was significantly increased in vivo and the histological and clinicopathological findings were similar to those in patients with HFRS.<\/jats:p>","DOI":"10.3390\/v14102247","type":"journal-article","created":{"date-parts":[[2022,10,14]],"date-time":"2022-10-14T01:44:13Z","timestamp":1665711853000},"page":"2247","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Pathological Studies on Hantaan Virus-Infected Mice Simulating Severe Hemorrhagic Fever with Renal Syndrome"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4232-3177","authenticated-orcid":false,"given":"Zhouoxing","family":"Wei","sequence":"first","affiliation":[{"name":"Graduate School of Infectious Diseases, Hokkaido University, Sapporo 060-0815, Japan"},{"name":"Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3825-7018","authenticated-orcid":false,"given":"Kenta","family":"Shimizu","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases and Host Defense, Graduate School of Medicine, Gunma University, Maebashi 371-8511, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2600-8134","authenticated-orcid":false,"given":"Rakiiya S.","family":"Sarii","sequence":"additional","affiliation":[{"name":"Graduate School of Infectious Diseases, Hokkaido University, Sapporo 060-0815, Japan"},{"name":"Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5137-2408","authenticated-orcid":false,"given":"Devinda S.","family":"Muthusinghe","sequence":"additional","affiliation":[{"name":"Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan"},{"name":"WISE Program for One Health Frontier Graduate School of Excellence, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sithumini M. W.","family":"Lokupathirage","sequence":"additional","affiliation":[{"name":"Graduate School of Infectious Diseases, Hokkaido University, Sapporo 060-0815, Japan"},{"name":"Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junko","family":"Nio-Kobayashi","sequence":"additional","affiliation":[{"name":"Laboratory of Histology and Cytology, Department of Anatomy, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0062-2753","authenticated-orcid":false,"given":"Kumiko","family":"Yoshimatsu","sequence":"additional","affiliation":[{"name":"Graduate School of Infectious Diseases, Hokkaido University, Sapporo 060-0815, Japan"},{"name":"Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,13]]},"reference":[{"key":"ref_1","unstructured":"(2022, September 14). ICTV Virus Taxonomy: 2021 Release. Available online: https:\/\/talk.ictvonline.org\/taxonomy\/."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1093\/infdis\/137.3.298","article-title":"Isolation of the etiologic agent of Korean hemorrhagic fever","volume":"137","author":"Lee","year":"1978","journal-title":"J. Infect. Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"914","DOI":"10.1126\/science.8235615","article-title":"Genetic identification of a hantavirus associated with an outbreak of acute respiratory illness","volume":"262","author":"Nichol","year":"1993","journal-title":"Science"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"638","DOI":"10.1093\/infdis\/146.5.638","article-title":"Isolation of Hantaan virus, the etiologic agent of Korean hemorrhagic fever, from wild urban rats","volume":"146","author":"Lee","year":"1982","journal-title":"J. Infect. Dis."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"393","DOI":"10.4269\/ajtmh.1994.51.393","article-title":"Isolation of a strain of a Hantaan virus from a fatal case of hemorrhagic fever with renal syndrome in Slovenia","volume":"51","author":"Poljak","year":"1994","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1093\/infdis\/141.2.131","article-title":"Nephropathia epidemica: Detection of antigen in bank voles and serologic diagnosis of human infection","volume":"141","author":"Vaheri","year":"1980","journal-title":"J. Infect. Dis."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1417","DOI":"10.1093\/infdis\/jiy037","article-title":"Protective effectiveness of inactivated hantavirus vaccine against hemorrhagic fever with renal syndrome","volume":"217","author":"Jung","year":"2018","journal-title":"J. Infect. Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2989","DOI":"10.3389\/fmicb.2019.02989","article-title":"Vaccines and therapeutics against hantaviruses","volume":"10","author":"Liu","year":"2019","journal-title":"Front. Microbiol."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Hooper, J., Paolino, K.M., Mills, K., Kwilas, S., Josleyn, M., Cohen, M., Somerville, B., Wisniewski, M., Norris, S., and Hill, B. (2020). A Phase 2a randomized, double-blind, dose-optimizing study to evaluate the immunogenicity and safety of a bivalent DNA vaccine for hemorrhagic fever with renal syndrome delivered by intramuscular electroporation. Vaccines, 8.","DOI":"10.3390\/vaccines8030377"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"7405","DOI":"10.1128\/JVI.00576-10","article-title":"Pathogenic hantaviruses Andes virus and Hantaan virus induce adherens junction disassembly by directing vascular endothelial cadherin internalization in human endothelial cells","volume":"84","author":"Gorbunova","year":"2010","journal-title":"J. Virol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Taylor, S.L., Wahl-Jensen, V., Copeland, A.M., Jahrling, P.B., and Schmaljohn, C.S. (2013). Endothelial cell permeability during hantavirus infection involves factor XII-dependent increased activation of the kallikrein-kinin system. PLoS Pathog., 9.","DOI":"10.1371\/journal.ppat.1003470"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.antiviral.2014.08.007","article-title":"Pathophysiology of a severe case of Puumala hantavirus infection successfully treated with bradykinin receptor antagonist icatibant","volume":"111","author":"Vaheri","year":"2014","journal-title":"Antiviral Res."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Garanina, E., Martynova, E., Davidyuk, Y., Kabwe, E., Ivanov, K., Titova, A., Markelova, M., Zhuravleva, M., Cherepnev, G., and Shakirova, V.G. (2019). Cytokine storm combined with humoral immune response defect in fatal hemorrhagic fever with renal syndrome case, Tatarstan, Russia. Viruses, 11.","DOI":"10.3390\/v11070601"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1089\/vim.1995.8.75","article-title":"Serum levels of tumor necrosis factor-alpha, interleukin-1, and interleukin-6 in hemorrhagic fever with renal syndrome","volume":"8","author":"Krakauer","year":"1995","journal-title":"Viral Immunol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"567","DOI":"10.3389\/fimmu.2017.00567","article-title":"Serum cytokine profiles differentiating hemorrhagic fever with renal syndrome and hantavirus pulmonary syndrome","volume":"8","author":"Khaiboullina","year":"2017","journal-title":"Front. Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1182\/blood-2014-05-552729","article-title":"Current concepts in the diagnosis and management of cytokine release syndrome","volume":"124","author":"Lee","year":"2014","journal-title":"Blood"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2897","DOI":"10.1099\/0022-1317-70-11-2897","article-title":"Pathogenesis of hantaan virus in mice","volume":"70","author":"Tamura","year":"1989","journal-title":"J. Gen. Virol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1292\/jvms.59.863","article-title":"Hantavirus infection in SCID mice","volume":"59","author":"Yoshimatsu","year":"1997","journal-title":"J. Vet. Med. Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"7178","DOI":"10.1128\/JVI.00254-14","article-title":"Neutrophil depletion suppresses pulmonary vascular hyperpermeability and occurrence of pulmonary edema caused by hantavirus infection in C.B-17 SCID mice","volume":"88","author":"Koma","year":"2014","journal-title":"J. Virol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"692509","DOI":"10.3389\/fimmu.2021.692509","article-title":"Nlrc3 Knockout mice showed renal pathological changes after HTNV infection","volume":"12","author":"Ma","year":"2021","journal-title":"Front. Immunol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1186\/s12985-017-0686-8","article-title":"Appearance of renal hemorrhage in adult mice after inoculation of patient-derived hantavirus","volume":"14","author":"Shimizu","year":"2017","journal-title":"Virol. J."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1577","DOI":"10.1007\/s00705-018-3786-x","article-title":"Involvement of CD8(+) T cells in the development of renal hemorrhage in a mouse model of hemorrhagic fever with renal syndrome","volume":"163","author":"Shimizu","year":"2018","journal-title":"Arch. Virol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1099\/0022-1317-70-4-819","article-title":"Cross-reactive immunity among different serotypes of virus causing haemorrhagic fever with renal syndrome","volume":"70","author":"Asada","year":"1989","journal-title":"J. Gen. Virol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"8408","DOI":"10.1128\/JVI.77.15.8408-8417.2003","article-title":"Hantavirus-specific CD8+ T cell responses in newborn mice persistently infected with Hantaan virus","volume":"77","author":"Araki","year":"2003","journal-title":"J. Virol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1099\/0022-1317-70-3-615","article-title":"Characterization of Hantaan virus envelope glycoprotein antigenic determinants defined by monoclonal antibodies","volume":"70","author":"Arikawa","year":"1989","journal-title":"J. Gen. Virol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1007\/BF01309834","article-title":"Cell fusion by haemorrhagic fever with renal syndrome (HFRS) viruses and its application for titration of virus infectivity and neutralizing antibody","volume":"86","author":"Arikawa","year":"1985","journal-title":"Arch. Virol."},{"key":"ref_27","first-page":"154","article-title":"Use of vesicular stomatitis virus pseudotypes bearing hantaan or seoul virus envelope proteins in a rapid and safe neutralization test","volume":"10","author":"Ogino","year":"2003","journal-title":"Clin. Diagn. Lab. Immunol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"994","DOI":"10.4269\/ajtmh.2006.75.994","article-title":"Geographical distribution of hantaviruses in Thailand and potential human health significance of Thailand virus","volume":"75","author":"Pattamadilok","year":"2006","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1099\/0022-1317-77-4-695","article-title":"Characterization of the nucleocapsid protein of hantaan virus strain 76-118 using monoclonal antibodies","volume":"77","author":"Yoshimatsu","year":"1996","journal-title":"J. Gen. Virol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1070","DOI":"10.1016\/S0140-6736(81)92240-6","article-title":"Electron microscope appearance of Hantaan virus, the causative agent of Korean haemorrhagic fever","volume":"1","author":"Lee","year":"1981","journal-title":"Lancet"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1007\/BF01321121","article-title":"Antibody-dependent enhancement of hantavirus infection in macrophage cell lines","volume":"122","author":"Yao","year":"1992","journal-title":"Arch. Virol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1016\/j.humpath.2015.02.002","article-title":"Microvascular inflammation and acute tubular necrosis are major histologic features of hantavirus nephropathy","volume":"46","author":"Gnemmi","year":"2015","journal-title":"Hum. Pathol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.virusres.2013.12.036","article-title":"Hemorrhagic fever with renal syndrome in the New, and Hantavirus Pulmonary Syndrome in the old world: Paradi(se)gm lost or regained?","volume":"187","author":"Clement","year":"2014","journal-title":"Virus Res."},{"key":"ref_34","first-page":"5555613","article-title":"Two atypical cases of hantavirus infection: Experience from a tertiary care unit in Sri Lanka","volume":"2021","author":"Rupasinghe","year":"2021","journal-title":"Case Rep. Infect. Dis."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1017\/S0950268817002904","article-title":"Population-based seroprevalence of Puumala hantavirus in Finland: Smoking as a risk factor","volume":"146","author":"Latronico","year":"2018","journal-title":"Epidemiol. Infect."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3947\/ic.2021.0148","article-title":"Hemorrhagic Fever with Renal syndrome: Literature review, epidemiology, clinical picture and pathogenesis","volume":"54","author":"Tariq","year":"2022","journal-title":"Infect. Chemother."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"399","DOI":"10.3389\/fcimb.2020.00399","article-title":"Orthohantavirus pathogenesis and cell tropism","volume":"10","author":"Noack","year":"2020","journal-title":"Front. Cell. Infect. Microbiol."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Krautkramer, E., Nusshag, C., Baumann, A., Schafer, J., Hofmann, J., Schnitzler, P., Klempa, B., Witkowski, P.T., Kruger, D.H., and Zeier, M. (2016). Clinical characterization of two severe cases of hemorrhagic fever with renal syndrome (HFRS) caused by hantaviruses Puumala and Dobrava-Belgrade genotype Sochi. BMC Infect. Dis., 16.","DOI":"10.1186\/s12879-016-2012-2"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2098","DOI":"10.3389\/fimmu.2018.02098","article-title":"Neutrophil activation in acute hemorrhagic fever with renal syndrome is mediated by hantavirus-infected microvascular endothelial cells","volume":"9","author":"Strandin","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1002\/hep.27447","article-title":"Liver is the major source of elevated serum lipocalin-2 levels after bacterial infection or partial hepatectomy: A critical role for IL-6\/STAT3","volume":"61","author":"Xu","year":"2015","journal-title":"Hepatology"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1046\/j.1523-1755.2002.00433.x","article-title":"Kidney Injury Molecule-1 (KIM-1): A novel biomarker for human renal proximal tubule injury","volume":"62","author":"Han","year":"2002","journal-title":"Kidney Int."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"van Leeuwen, L.P.M., de Jong, W., Doornekamp, L., van Gorp, E.C.M., Wismans, P.J., and Goeijenbier, M. (2022). Exotic viral hepatitis: A review on epidemiology, pathogenesis, and treatment. J. Hepatol., in press.","DOI":"10.1016\/j.jhep.2022.06.031"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"748232","DOI":"10.3389\/fvets.2021.748232","article-title":"Detection and genetic characterization of Seoul virus in liver tissue samples from Rattus norvegicus and Rattus tanezumi in urban areas of Southern China","volume":"8","author":"He","year":"2021","journal-title":"Front. Vet. Sci."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Maas, M., van Heteren, M., de Vries, A., Kuiken, T., Hoornweg, T., Veldhuis Kroeze, E., and Rockx, B. (2019). Seoul virus tropism and pathology in naturally infected feeder rats. Viruses, 11.","DOI":"10.3390\/v11060531"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1016\/j.virol.2004.01.030","article-title":"A new model of Hantaan virus persistence in mice: The balance between HTNV infection and CD8(+) T-cell responses","volume":"322","author":"Araki","year":"2004","journal-title":"Virology"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Yasuda, S.P., Shimizu, K., Koma, T., Hoa, N.T., Le, M.Q., Wei, Z., Muthusinghe, D.S., Lokupathirage, S.M.W., Hasebe, F., and Yamashiro, T. (2021). Immunological responses to Seoul orthohantavirus in experimentally and naturally infected brown rats (Rattus norvegicus). Viruses, 13.","DOI":"10.3390\/v13040665"}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/14\/10\/2247\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:53:38Z","timestamp":1760144018000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/14\/10\/2247"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,10,13]]},"references-count":46,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2022,10]]}},"alternative-id":["v14102247"],"URL":"https:\/\/doi.org\/10.3390\/v14102247","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,10,13]]}}}