{ "abstract": "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 in vivo. 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 in vivo, 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. Author summary: Oropouche virus (OROV) is an emerging zoonotic arbovirus that causes large outbreaks of Oropouche fever across Central and South America. Although most infections are self-limiting, some progress to severe neurological manifestations, and recent reports of deaths and adverse pregnancy outcomes have heightened public health concern. Despite thousands of reported cases every year, no approved antiviral treatments or vaccines are available. In this study, we evaluated favipiravir, an antiviral drug licensed for use against influenza, as a potential treatment for OROV infection. Favipiravir strongly inhibited viral replication in vitro and completely protected hamsters from lethal infections, preventing viral invasion of the central nervous system and the development of neurological symptoms. Notably, treatment remained highly protective even when antiviral administration was initiated after infection had begun. Transcriptomic analyses further revealed that OROV infection triggers strong antiviral and inflammatory responses, together with disruption of tissue homeostasis in the liver and brain, which are largely prevented by favipiravir treatment. Consequently, our findings demonstrate that favipiravir effectively inhibits viral spread and mitigates tissue damage and severe disease outcomes by suppressing virus-driven host responses, highlighting its potential as a promising therapeutic option for OROV infection and providing new insight into host responses associated with disease progression.", "abstract_shown": true, "affiliations": [ "Division of Biological Response Analysis, Institute for Vaccine Research and Development, Hokkaido University, Sapporo, Hokkaido, Japan.", "Graduate School of Infectious Diseases, Hokkaido University, Sapporo, Hokkaido, Japan.", "Division of Research Support, Institute for Vaccine Research and Development, Hokkaido University, Sapporo, Hokkaido, Japan.", "Division of Molecular Pathobiology, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Hokkaido, Japan.", "Laboratory for Drug Discovery & Disease Research, Shionogi & Co., Ltd, Osaka, Japan.", "Division of Vaccinology for Clinical Development, Institute for Vaccine Research and Development, Hokkaido University, Sapporo, Hokkaido, Japan.", "Faculty of Pharmaceutical Science, Graduate School of Life Science, Hokkaido University, Sapporo, Hokkaido, Japan.", "Division of Molecular Psychoimmunology, Institute for Genetic Medicine, Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan.", "Technical Office, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Hokkaido, Japan.", "Division of Risk Analysis and Management, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Hokkaido, Japan.", "One Health Research Center, Hokkaido University, Sapporo, Hokkaido, Japan.", "International Collaboration Unit, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Hokkaido, Japan.", "Global Virus Network, Tampa, Florida, United States of America.", "National Virus Reference Laboratory, School of Medicine, University College Dublin, Dublin, Ireland." ], "article_type": "Research Article", "arxiv": null, "author_total": 18, "authors": [ { "affs": [ 0, 1 ], "name": "Cássia Sousa Moraes", "orcid": "0000-0002-1954-6455" }, { "affs": [ 2 ], "name": "Gabriel Gonzalez", "orcid": "0000-0002-2180-2120" }, { "affs": [ 0, 3, 4, 5 ], "name": "Akihiko Sato", "orcid": "0000-0001-6625-1679" }, { "affs": [ 5 ], "name": "Shigeru Miki" }, { "affs": [ 0, 6 ], "name": "Atsuko Inoue", "orcid": "0009-0009-3267-3908" }, { "affs": [ 0 ], "name": "Koshiro Tabata", "orcid": "0000-0002-0227-2515" }, { "affs": [ 0, 7 ], "name": "Joshua W Kranrod", "orcid": "0000-0001-8596-3153" }, { "affs": [ 0, 1 ], "name": "Chilekwa Frances Kabamba", "orcid": "0009-0005-1326-5272" }, { "affs": [ 8 ], "name": "Aiko Ohnuma" }, { "affs": [ 0, 9, 10, 11 ], "name": "Keita Matsuno", "orcid": "0000-0002-4205-6526" }, { "affs": [ 0, 1 ], "name": "Rio Harada", "orcid": "0009-0009-3738-9658" }, { "affs": [ 0 ], "name": "Shinji Saito" }, { "affs": [ 1, 3 ], "name": "Naoki Akimoto" }, { "affs": [ 0, 3 ], "name": "Michihito Sasaki", "orcid": "0000-0003-1607-2175" }, { "affs": [ 0, 3, 10, 11 ], "name": "Yasuko Orba", "orcid": "0000-0001-9910-3912" }, { "affs": [ 0, 11, 12, 13 ], "name": "William W Hall" }, { "affs": [ 0, 10, 11, 12 ], "name": "Hirofumi Sawa", "orcid": "0000-0003-2569-2755" }, { "affs": [ 0 ], "name": "Yukari Itakura", "orcid": "0000-0002-3463-1834" } ], "bibtex": "https://research.draconitic.com/paper/3ha1rff2418qg.bib", "cited_by": 0, "doi": "10.1371/journal.ppat.1014647", "fulltext_url": "https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014647", "id": "3ha1rff2418qg", "issns": [ "1553-7374", "1553-7366" ], "landing_url": "https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014647", "language": "eng", "licence": "CC-BY", "licence_label": "CC BY", "licence_source": "article", "licence_url": "https://creativecommons.org/licenses/by/4.0/", "metadata_licence": null, "native_subjects": [ [ "openalex", "2725|Viral Infections and Vectors" ], [ "plos", "/Biology and life sciences/Computational biology/Genome analysis/Transcriptome analysis" ], [ "plos", "/Biology and life sciences/Genetics/Gene expression/Viral gene expression" ], [ "plos", "/Biology and life sciences/Genetics/Genomics/Genome analysis/Transcriptome analysis" ], [ "plos", "/Biology and life sciences/Genetics/Microbial genetics/Viral genetics/Viral gene expression" ], [ "plos", "/Biology and life sciences/Immunology/Immune response/Inflammation" ], [ "plos", "/Biology and life sciences/Immunology/Vaccination and immunization/Antiviral therapy" ], [ "plos", "/Biology and life sciences/Microbiology/Animal models of infection" ], [ "plos", "/Biology and life sciences/Microbiology/Virology/Viral genetics/Viral gene expression" ], [ "plos", "/Biology and life sciences/Microbiology/Virology/Viral replication" ], [ "plos", "/Biology and life sciences/Microbiology/Virology/Virus effects on host gene expression" ], [ "plos", "/Biology and life sciences/Organisms/Eukaryota/Animals/Vertebrates/Amniotes/Mammals/Rodents/Hamsters" ], [ "plos", "/Biology and life sciences/Zoology/Animals/Vertebrates/Amniotes/Mammals/Rodents/Hamsters" ], [ "plos", "/Medicine and health sciences/Clinical medicine/Signs and symptoms/Inflammation" ], [ "plos", "/Medicine and health sciences/Immunology/Immune response/Inflammation" ], [ "plos", "/Medicine and health sciences/Immunology/Vaccination and immunization/Antiviral therapy" ], [ "plos", "/Medicine and health sciences/Public and occupational health/Preventive medicine/Vaccination and immunization/Antiviral therapy" ], [ "plos", "/Research and analysis methods/Animal studies/Animal models of disease/Animal models of infection" ] ], "openalex": "W7220851649", "pdf_url": "https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1014647&type=printable", "pmcid": "PMC13657405", "pmid": "42842618", "published": "2026-10-07", "publisher": "Public Library of Science", "ris": "https://research.draconitic.com/paper/3ha1rff2418qg.ris", "sources": [ { "first_seen": "2026-10-30T12:17:30Z", "native_id": "10.1371/journal.ppat.1014647", "source": "plos", "url": "https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014647" }, { "first_seen": "2026-10-30T12:18:02Z", "native_id": "MED:42842618", "source": "europepmc", "url": "https://europepmc.org/article/MED/42842618" } ], "subjects": [ { "field": "biology", "origin": "plos:genomics", "subfield": "genetics-genomics" }, { "field": "biology", "origin": "plos:immunology", "subfield": "immunology" }, { "field": "biology", "origin": "plos:microbiology", "subfield": "microbiology" } ], "title": "Integrated in vivo and transcriptomic analyses of lethal Oropouche virus infection reveal suppression of pathogenic host responses by antiviral therapy", "title_text": "Integrated in vivo and transcriptomic analyses of lethal Oropouche virus infection reveal suppression of pathogenic host responses by antiviral therapy", "type": "peer-reviewed", "updated_at": "2026-10-30T12:18:02Z", "url": "https://research.draconitic.com/paper/3ha1rff2418qg", "venue": "PLOS Pathogens", "versions": [] }