{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T18:45:16Z","timestamp":1791830716446,"version":"4.3.4"},"update-to":[{"DOI":"10.1371\/journal.ppat.1014647","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T00:00:00Z","timestamp":1791763200000}}],"reference-count":41,"publisher":"Public Library of Science (PLoS)","issue":"10","license":[{"start":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T00:00:00Z","timestamp":1791331200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["25K18810"],"award-info":[{"award-number":["25K18810"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["25K09431"],"award-info":[{"award-number":["25K09431"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP223fa627005"],"award-info":[{"award-number":["JP223fa627005"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP24wm0225044"],"award-info":[{"award-number":["JP24wm0225044"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>\n                    Oropouche virus (OROV) is an emerging arbovirus responsible for large outbreaks of febrile illness in Central and South America, with increasing reports of severe neurological disease and fatal outcomes. Despite its growing public health impact, no approved antiviral therapies or vaccines are currently available. Here, we show that favipiravir, a broad-spectrum nucleoside analogue, robustly suppresses OROV replication and disease\n                    <jats:italic>in vivo<\/jats:italic>\n                    . In a lethal Syrian hamster model, favipiravir treatment provided complete protection against OROV infection, preventing viral dissemination to peripheral organs and the central nervous system, and remained highly effective when administration was initiated after infection. In contrast, insufficient antiviral control resulted in viral neuroinvasion and fatality. To define host responses associated with OROV pathogenesis and their modulation by antiviral therapy, we performed transcriptomic profiling of liver and brain tissues. OROV infection induced interferon-driven inflammatory programs accompanied by marked disruption of metabolic and tissue homeostatic pathways, whereas these transcriptional signatures were largely abrogated by favipiravir treatment. Together, our findings identify favipiravir as a potent antiviral candidate against OROV and provide the first\n                    <jats:italic>in vivo<\/jats:italic>\n                    , tissue-resolved transcriptomic framework of OROV infection, linking effective viral suppression with the prevention of neuroinvasion and pathogenic host responses. These results highlight antiviral intervention as a viable strategy to mitigate OROV-associated disease and mortality.\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1014647","type":"journal-article","created":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T17:48:55Z","timestamp":1791395335000},"page":"e1014647","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrated in vivo and transcriptomic analyses of lethal Oropouche virus infection reveal suppression of pathogenic host responses by antiviral therapy"],"prefix":"10.1371","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1954-6455","authenticated-orcid":true,"given":"C\u00e1ssia","family":"Sousa Moraes","sequence":"first","affiliation":[{"name":"Institute for Vaccine Research and Development, Hokkaido University","place":["Sapporo, Hokkaido, Japan"],"department":["Division of Biological Response 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Pathobiology"]},{"name":"Laboratory for Drug Discovery & Disease Research, Shionogi & Co., Ltd","place":["Osaka, Japan"]},{"name":"Institute for Vaccine Research and Development, Hokkaido University","place":["Sapporo, Hokkaido, Japan"],"department":["Division of Vaccinology for Clinical Development"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shigeru","family":"Miki","sequence":"additional","affiliation":[{"name":"Institute for Vaccine Research and Development, Hokkaido University","place":["Sapporo, Hokkaido, Japan"],"department":["Division of Vaccinology for Clinical Development"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-3267-3908","authenticated-orcid":true,"given":"Atsuko","family":"Inoue","sequence":"additional","affiliation":[{"name":"Institute for Vaccine Research and Development, Hokkaido University","place":["Sapporo, Hokkaido, Japan"],"department":["Division of Biological Response 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Hokkaido University","place":["Sapporo, Hokkaido, Japan"],"department":["Division of Molecular Psychoimmunology"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-1326-5272","authenticated-orcid":true,"given":"Chilekwa Frances","family":"Kabamba","sequence":"additional","affiliation":[{"name":"Institute for Vaccine Research and Development, Hokkaido University","place":["Sapporo, Hokkaido, Japan"],"department":["Division of Biological Response Analysis"]},{"name":"Graduate School of Infectious Diseases, Hokkaido University","place":["Sapporo, Hokkaido, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aiko","family":"Ohnuma","sequence":"additional","affiliation":[{"name":"Technical Office, International Institute for Zoonosis Control, Hokkaido University","place":["Sapporo, Hokkaido, 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Oropouche virus in pregnancy","volume":"6","author":"DA Schwartz","year":"2025","journal-title":"Lancet Microbe"},{"issue":"6","key":"ppat.1014647.ref003","doi-asserted-by":"crossref","first-page":"738","DOI":"10.3390\/v17060738","article-title":"Oropouche Virus (OROV) and Breastfeeding Safety: Analysis of Related Orthobunyaviruses for Mother-Infant Vertical Transmission in Breast Milk","volume":"17","author":"DA Schwartz","year":"2025","journal-title":"Viruses"},{"issue":"21","key":"ppat.1014647.ref004","doi-asserted-by":"crossref","first-page":"2055","DOI":"10.1056\/NEJMc2412812","article-title":"A Case of Vertical Transmission of Oropouche Virus in Brazil","volume":"391","author":"CG Filho","year":"2024","journal-title":"New England Journal of Medicine"},{"issue":"9","key":"ppat.1014647.ref005","doi-asserted-by":"crossref","first-page":"1435","DOI":"10.3390\/v16091435","article-title":"Oropouche Virus (OROV) in Pregnancy: An Emerging Cause of Placental and Fetal Infection Associated with Stillbirth and Microcephaly following Vertical Transmission","volume":"16","author":"DA Schwartz","year":"2024","journal-title":"Viruses"},{"key":"ppat.1014647.ref006","first-page":"100896","article-title":"Oropouche fever fatalities and vertical transmission in South America: implications of a potential new mode of transmission","volume":"38","author":"R Sah","year":"2024","journal-title":"Lancet Reg Health Am"},{"key":"ppat.1014647.ref007","doi-asserted-by":"crossref","unstructured":"Bandeira AC, da Silva ACFN, Souza M, da Costa Saavedra R, Pereira FM, de Oliveira Santos SP. Clinical profile of Oropouche fever in Bahia, Brazil: unexpected fatal cases. 2024.","DOI":"10.1590\/SciELOPreprints.9342"},{"issue":"2","key":"ppat.1014647.ref008","doi-asserted-by":"crossref","first-page":"380","DOI":"10.3201\/eid2502.181189","article-title":"Oropouche virus\u2013associated aseptic meningoencephalitis, southeastern Brazil","volume":"25","author":"S Vernal","year":"2019","journal-title":"Emerging Infectious Diseases"},{"key":"ppat.1014647.ref009","article-title":"Oropouche Virus: An Emerging Neuroinvasive Arbovirus","author":"DM Pastula","year":"2024","journal-title":"Ann Neurol"},{"key":"ppat.1014647.ref010","unstructured":"Bhattacharyya S. Inflammation during virus infection: swings and roundabouts. 2023."},{"issue":"1","key":"ppat.1014647.ref011","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.virusres.2010.08.009","article-title":"Oropouche virus experimental infection in the golden hamster (Mesocrisetus auratus)","volume":"155","author":"AH Rodrigues","year":"2011","journal-title":"Virus Res"},{"key":"ppat.1014647.ref012","doi-asserted-by":"crossref","first-page":"107512","DOI":"10.1016\/j.pharmthera.2020.107512","article-title":"Favipiravir, an anti-influenza drug against life-threatening RNA virus infections","volume":"209","author":"K Shiraki","year":"2020","journal-title":"Pharmacol Ther"},{"issue":"3","key":"ppat.1014647.ref013","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.antiviral.2009.02.198","article-title":"T-705 (favipiravir) and related compounds: Novel broad-spectrum inhibitors of RNA viral infections","volume":"82","author":"Y Furuta","year":"2009","journal-title":"Antiviral Res"},{"key":"ppat.1014647.ref014","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1016\/j.ijid.2020.10.069","article-title":"Role of favipiravir in the treatment of COVID-19","volume":"102","author":"S Joshi","year":"2021","journal-title":"Int J Infect Dis"},{"issue":"1","key":"ppat.1014647.ref015","doi-asserted-by":"crossref","first-page":"1735","DOI":"10.1038\/s41467-021-21992-w","article-title":"Favipiravir antiviral efficacy against SARS-CoV-2 in a hamster model","volume":"12","author":"J-S Driouich","year":"2021","journal-title":"Nat Commun"},{"issue":"4","key":"ppat.1014647.ref016","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1016\/j.mjafi.2020.08.004","article-title":"Favipiravir: A new and emerging antiviral option in COVID-19","volume":"76","author":"U Agrawal","year":"2020","journal-title":"Med J Armed Forces India"},{"issue":"1","key":"ppat.1014647.ref017","doi-asserted-by":"crossref","first-page":"7604","DOI":"10.1038\/s41598-018-25780-3","article-title":"Favipiravir (T-705) protects against Nipah virus infection in the hamster model","volume":"8","author":"BE Dawes","year":"2018","journal-title":"Scientific Reports"},{"key":"ppat.1014647.ref018","doi-asserted-by":"crossref","first-page":"199680","DOI":"10.1016\/j.virusres.2025.199680","article-title":"Remdesivir as a potent antiviral against prototype and current epidemic Oropouche virus strains (BeAn19991 and PE-IAM4637)","volume":"363","author":"R Yoshikawa","year":"2026","journal-title":"Virus Res"},{"key":"ppat.1014647.ref019","doi-asserted-by":"crossref","first-page":"106171","DOI":"10.1016\/j.antiviral.2025.106171","article-title":"Lysergol exerts potent antiviral activity against the emerging Oropouche virus in vitro","volume":"238","author":"LD Coimbra","year":"2025","journal-title":"Antiviral Res"},{"key":"ppat.1014647.ref020","first-page":"100217","article-title":"Acridones as promising drug candidates against Oropouche virus","volume":"6","author":"MV Saivish","year":"2023","journal-title":"Curr Res Microb Sci"},{"issue":"10","key":"ppat.1014647.ref021","doi-asserted-by":"crossref","DOI":"10.1128\/mbio.01467-25","article-title":"Effective treatment of advanced Oropouche virus, Rift Valley fever virus, and Dabie bandavirus infections with 4\u2019-fluorouridine","volume":"16","author":"JB Westover","year":"2025","journal-title":"mBio"},{"issue":"1","key":"ppat.1014647.ref022","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1007\/s11908-025-00862-2","article-title":"Oropouche Virus, A New Emerging Threat","volume":"27","author":"N Labiod","year":"2025","journal-title":"Current Infectious Disease Reports"},{"key":"ppat.1014647.ref023","first-page":"100406","article-title":"Re-emergence of Oropouche virus as a novel global threat","volume":"8","author":"RS Salvato","year":"2025","journal-title":"Curr Res Microb Sci"},{"issue":"4","key":"ppat.1014647.ref024","doi-asserted-by":"crossref","first-page":"175","DOI":"10.3390\/v10040175","article-title":"Oropouche Fever: A Review","volume":"10","author":"H Sakkas","year":"2018","journal-title":"Viruses"},{"key":"ppat.1014647.ref025","doi-asserted-by":"crossref","first-page":"101596","DOI":"10.1016\/j.nmni.2025.101596","article-title":"The emergence of oropouche fever: A potential new threat?","author":"S Srivastava","year":"2025","journal-title":"New Microbes and New Infections"},{"key":"ppat.1014647.ref026","unstructured":"Control CfD, Prevention. Clinical overview of Oropouche virus disease. 2024."},{"issue":"4","key":"ppat.1014647.ref027","doi-asserted-by":"crossref","first-page":"732","DOI":"10.4269\/ajtmh.2012.11-0485","article-title":"Identification of Oropouche Orthobunyavirus in the cerebrospinal fluid of three patients in the Amazonas, Brazil","volume":"86","author":"M de Souza Bastos","year":"2012","journal-title":"The American Journal of Tropical Medicine and Hygiene"},{"issue":"3","key":"ppat.1014647.ref028","doi-asserted-by":"crossref","first-page":"102646","DOI":"10.1016\/j.xcrm.2026.102646","article-title":"Human liver-derived organoids recapitulate Oropouche virus infection and manifestation, enabling antiviral drug discovery","volume":"7","author":"J Li","year":"2026","journal-title":"Cell Rep Med"},{"issue":"7","key":"ppat.1014647.ref029","doi-asserted-by":"crossref","DOI":"10.1128\/jvi.00611-26","article-title":"Oropouche virus causes acute hepatitis in mice controlled by type I 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Oropouche virus replication in mice and confers protection against virus-induced disease","volume":"2025","author":"M Ferri\u00e9","year":"2025","journal-title":"bioRxiv"},{"key":"ppat.1014647.ref034","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1016\/j.antiviral.2015.07.003","article-title":"Alterations in favipiravir (T-705) pharmacokinetics and biodistribution in a hamster model of viral hemorrhagic fever","volume":"121","author":"BB Gowen","year":"2015","journal-title":"Antiviral Res"},{"key":"ppat.1014647.ref035","doi-asserted-by":"crossref","first-page":"107213","DOI":"10.1016\/j.ntt.2023.107213","article-title":"Pregnancy outcomes following maternal favipiravir exposure: A case series","volume":"98","author":"B Karadas","year":"2023","journal-title":"Neurotoxicology and Teratology"},{"key":"ppat.1014647.ref036","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1016\/j.ijid.2021.12.324","article-title":"Baseline uric acid levels and steady-state favipiravir 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