{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T23:52:30Z","timestamp":1784073150201,"version":"3.55.0"},"reference-count":37,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2020,7,16]],"date-time":"2020-07-16T00:00:00Z","timestamp":1594857600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["AI083409"],"award-info":[{"award-number":["AI083409"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["AI093580"],"award-info":[{"award-number":["AI093580"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["AI131586"],"award-info":[{"award-number":["AI131586"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pathogens"],"abstract":"<jats:p>Lassa virus (LASV) is a mammarenavirus (arenavirus) that causes zoonotic infection in humans that can lead to fatal hemorrhagic Lassa fever (LF) disease. Currently, there are no FDA-approved vaccines or therapeutics against LASV. Development of treatments against LF and other related arenavirus-induced hemorrhagic fevers (AHFs) requires relevant animal models that can recapitulate clinical and pathological features of AHF diseases in humans. Laboratory mice are generally resistant to LASV infection, and non-human primates, while being a good animal model for LF, are limited by their high cost. Here, we describe a small, affordable, and convenient animal model that is based on outbred Hartley guinea pigs infected with Pichinde virus (PICV), a mammarenavirus that is non-pathogenic in humans, for use as a surrogate model of human LF. We conducted a detailed analysis of tissue histopathology and immunohistochemical analysis of different organs of outbred Hartley guinea pigs infected with different PICV strains that show differential disease phenotypes and pathologies. Comparing to infection with the avirulent PICV strain (P2 or rP2), animals infected with the virulent strain (P18 or rP18) show extensive pathological changes in different organs that sustain high levels of virus replication. The similarity of tissue pathology and viral antigen distribution between the virulent PICV\u2013guinea pig model and lethal human LASV infection supports a role of this small animal model as a surrogate model of studying human LF in order to understand its pathogenesis and for evaluating potential preventative and therapeutic options against AHFs.<\/jats:p>","DOI":"10.3390\/pathogens9070579","type":"journal-article","created":{"date-parts":[[2020,7,17]],"date-time":"2020-07-17T10:22:02Z","timestamp":1594981322000},"page":"579","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Pichinde Virus Infection of Outbred Hartley Guinea Pigs as a Surrogate Animal Model for Human Lassa Fever: Histopathological and Immunohistochemical Analyses"],"prefix":"10.3390","volume":"9","author":[{"given":"Wun-Ju","family":"Shieh","sequence":"first","affiliation":[{"name":"Infectious Disease Pathology Branch, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuiyun","family":"Lan","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA 30322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sherif R.","family":"Zaki","sequence":"additional","affiliation":[{"name":"Infectious Disease Pathology Branch, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hinh","family":"Ly","sequence":"additional","affiliation":[{"name":"Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, St Paul, MN 55108, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuying","family":"Liang","sequence":"additional","affiliation":[{"name":"Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, St Paul, MN 55108, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,7,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"(1972). Lassa fever. Br. Med. J., 4, 253\u2013254.","DOI":"10.1136\/bmj.4.5835.253"},{"key":"ref_2","unstructured":"CDC (2020, February 03). Lassa Fever, Available online: https:\/\/www.cdc.gov\/vhf\/lassa\/index.html."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1007\/s00405-010-1370-4","article-title":"Early-onset sensorineural hearing loss in Lassa fever","volume":"268","author":"Ibekwe","year":"2010","journal-title":"Eur. Arch. Oto-Rhino-Laryngology"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Sattler, R.A., Paessler, S., Ly, H., and Huang, C. (2020). Animal models of lassa fever. Pathogens, 9.","DOI":"10.3390\/pathogens9030197"},{"key":"ref_5","first-page":"523","article-title":"Comparative pathology of Lassa virus infection in monkeys, guinea-pigs, and Mastomys natalensis*","volume":"52","author":"Walker","year":"1975","journal-title":"Bull. World Heal. Organ."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Oestereich, L., L\u00fcdtke, A., Ruibal, P., Pallasch, E., Kerber, R., Rieger, T., Wurr, S., Bockholt, S., P\u00e9rez-Gir\u00f3n, J.V., and Krasemann, S. (2016). Chimeric mice with competent hematopoietic immunity reproduce key features of severe lassa fever. PLoS Pathog., 12.","DOI":"10.1371\/journal.ppat.1005656"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Rieger, T., Merkler, D., and G\u00fcnther, S. (2013). Infection of type I interferon receptor-deficient mice with Various Old World Arenaviruses: A model for studying virulence and host species barriers. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0072290"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3389","DOI":"10.1128\/JVI.06284-11","article-title":"Functional interferon system is required for clearance of Lassa Virus","volume":"86","author":"Yun","year":"2012","journal-title":"J. Virol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"10908","DOI":"10.1128\/JVI.01433-13","article-title":"Mice lacking functional STAT1 are highly susceptible to lethal infection with Lassa Virus","volume":"87","author":"Yun","year":"2013","journal-title":"J. Virol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2920","DOI":"10.1128\/JVI.02948-15","article-title":"Animal model of Sensorineural hearing loss associated with Lassa Virus infection","volume":"90","author":"Yun","year":"2015","journal-title":"J. Virol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"934","DOI":"10.1093\/infdis\/jiv522","article-title":"Efficacy of Favipiravir alone and in combination with ribavirin in a lethal, immunocompetent mouse model of Lassa Fever","volume":"213","author":"Oestereich","year":"2015","journal-title":"J. Infect. Dis."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Flatz, L., Rieger, T., Merkler, D., Bergthaler, A., Regen, T., Schedensack, M., Bestmann, L., Verschoor, A., Kreutzfeldt, M., and Bruck, W. (2010). T Cell-dependence of lassa fever pathogenesis. PLoS Pathog., 6.","DOI":"10.1371\/journal.ppat.1000836"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1177\/0300985816677153","article-title":"Temporal progression of lesions in guinea pigs infected with lassa virus","volume":"54","author":"Bell","year":"2016","journal-title":"Veter Pathol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/j.antiviral.2011.02.012","article-title":"Evaluation of Lassa antiviral compound ST-193 in a guinea pig model","volume":"90","author":"Cashman","year":"2011","journal-title":"Antivir. Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"865","DOI":"10.3201\/eid2505.181254","article-title":"Lassa Virus Targeting of Anterior Uvea and Endothelium of Cornea and Conjunctiva in Eye of Guinea Pig Model","volume":"25","author":"Gary","year":"2019","journal-title":"Emerg. Infect. Dis."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e00428-19","DOI":"10.1128\/mSphere.00428-19","article-title":"Lethal infection of lassa virus isolated from a human clinical sample in outbred guinea pigs without adaptation","volume":"4","author":"Maruyama","year":"2019","journal-title":"mSphere"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/j.antiviral.2011.07.015","article-title":"Lymphocytic choriomeningitis virus (LCMV) infection of macaques: A model for Lassa fever","volume":"92","author":"Zapata","year":"2011","journal-title":"Antivir. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1016\/j.chom.2017.07.008","article-title":"Interferon-\u03b3-Driven iNOS: A molecular pathway to terminal shock in Arenavirus Hemorrhagic Fever","volume":"22","author":"Remy","year":"2017","journal-title":"Cell Host Microbe"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"631","DOI":"10.4269\/ajtmh.1971.20.631","article-title":"Pichind\u00e9 virus, a new virus of the Tacaribe group from Colombia","volume":"20","author":"Trapido","year":"1971","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"ref_20","first-page":"228","article-title":"Pathological and virological features of arenavirus disease in guinea pigs. Comparison of two Pichinde virus strains","volume":"145","author":"Aronson","year":"1994","journal-title":"Am. J. Pathol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"10","DOI":"10.4269\/ajtmh.1993.49.10","article-title":"Pathogenesis of pichinde virus infection in strain 13 guinea Pigs: An immunocytochemical, virologic, and clinical chemistry study","volume":"49","author":"Connolly","year":"1993","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"872","DOI":"10.1128\/iai.32.2.872-880.1981","article-title":"Pathogenesis of a pichinde virus strain adapted to produce lethal infections in guinea pigs","volume":"32","author":"Jahrling","year":"1981","journal-title":"Infect. Immun."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"416","DOI":"10.4269\/ajtmh.1987.36.416","article-title":"Studies of the coagulation system in arenaviral hemorrhagic fever: Experimental infection of strain 13 Guinea Pigs with Pichinde Virus","volume":"36","author":"Cosgriff","year":"1987","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"6357","DOI":"10.1128\/JVI.00019-09","article-title":"Development of infectious clones for virulent and avirulent pichinde viruses: A model virus to study arenavirus-induced hemorrhagic fevers","volume":"83","author":"Lan","year":"2009","journal-title":"J. Virol."},{"key":"ref_25","first-page":"247","article-title":"Establishment of bisegmented and trisegmented reverse genetics systems to generate recombinant Pichind\u00e9 viruses","volume":"1604","author":"Dhanwani","year":"2018","journal-title":"Breast Cancer"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"E65","DOI":"10.1111\/j.1749-6632.2009.05051.x","article-title":"Molecular determinants of pichinde virus infection of guinea pigs-a small animal model system for arenaviral hemorrhagic fevers","volume":"1171","author":"Liang","year":"2009","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Lan, S., Shieh, W.J., Huang, Q., Zaki, S.R., Ly, H., and Liang, Y. (2020). Recombinant Pichinde virus infection of outbred Hartley guinea pigs as an improved surrogate small animal model for Lassa fever. Virulence, (submitted).","DOI":"10.3390\/pathogens9070579"},{"key":"ref_28","first-page":"349","article-title":"Pathologic and virologic study of fatal Lassa fever in man","volume":"107","author":"Walker","year":"1982","journal-title":"Am. J. Pathol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"6635","DOI":"10.1128\/JVI.00044-13","article-title":"Identification of Virulence Determinants within the L Genomic Segment of the Pichinde Arenavirus","volume":"87","author":"McLay","year":"2013","journal-title":"J. Virol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1128\/iai.37.2.771-778.1982","article-title":"Pathogenesis of Lassa virus infection in guinea pigs","volume":"37","author":"Jahrling","year":"1982","journal-title":"Infect. Immun."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Safronetz, D., Mire, C., Rosenke, K., Feldmann, F., Haddock, E., Geisbert, T., and Feldmann, H. (2015). A Recombinant vesicular stomatitis virus-based Lassa fever vaccine protects guinea pigs and macaques against challenge with geographically and genetically distinct Lassa Viruses. PLoS Neglected Trop. Dis., 9.","DOI":"10.1371\/journal.pntd.0003736"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1316","DOI":"10.1093\/infdis\/jit004","article-title":"A recently isolated Lassa virus from Mali demonstrates atypical clinical disease manifestations and decreased virulence in Cynomolgus macaques","volume":"207","author":"Safronetz","year":"2013","journal-title":"J. Infect. Dis."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1093\/infdis\/146.3.360","article-title":"Experimental infection of rhesus monkeys with Lassa virus and a closely related arenavirus, mozambique virus","volume":"146","author":"Walker","year":"1982","journal-title":"J. Infect. Dis."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1016\/j.antiviral.2016.08.012","article-title":"Treatment of Lassa virus infection in outbred guinea pigs with first-in-class human monoclonal antibodies","volume":"133","author":"Cross","year":"2016","journal-title":"Antivir. Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"14775","DOI":"10.1038\/srep14775","article-title":"The broad-spectrum antiviral favipiravir protects guinea pigs from lethal Lassa virus infection post-disease onset","volume":"5","author":"Safronetz","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41541-019-0104-x","article-title":"A recombinant vesicular stomatitis-based Lassa fever vaccine elicits rapid and long-term protection from lethal Lassa virus infection in guinea pigs","volume":"4","author":"Stein","year":"2019","journal-title":"npj Vaccines"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1097\/00019048-199505000-00011","article-title":"Hantavirus pulmonary syndrome","volume":"4","author":"Butler","year":"1995","journal-title":"Infect. Dis. Clin. Pr."}],"container-title":["Pathogens"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-0817\/9\/7\/579\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:49:10Z","timestamp":1760176150000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-0817\/9\/7\/579"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,7,16]]},"references-count":37,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2020,7]]}},"alternative-id":["pathogens9070579"],"URL":"https:\/\/doi.org\/10.3390\/pathogens9070579","relation":{},"ISSN":["2076-0817"],"issn-type":[{"value":"2076-0817","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,7,16]]}}}