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Peer-reviewedCC BYPLOS Pathogens

Integrated in vivo and transcriptomic analyses of lethal Oropouche virus infection reveal suppression of pathogenic host responses by antiviral therapy

  • Cássia Sousa Moraes1,2
  • Gabriel Gonzalez3
  • Akihiko Sato1,4,5,6
  • Shigeru Miki6
  • Atsuko Inoue1,7
  • Koshiro Tabata1
  • Joshua W Kranrod1,8
  • Chilekwa Frances Kabamba1,2
  • Aiko Ohnuma9
  • Keita Matsuno1,10,11,12
  • Rio Harada1,2
  • Shinji Saito1
6 more authors
  • Naoki Akimoto2,4
  • Michihito Sasaki1,4
  • Yasuko Orba1,4,11,12
  • William W Hall1,12,13,14
  • Hirofumi Sawa1,11,12,13
  • Yukari Itakura1
14 affiliations
  1. 1Division of Biological Response Analysis, Institute for Vaccine Research and Development, Hokkaido University, Sapporo, Hokkaido, Japan.
  2. 2Graduate School of Infectious Diseases, Hokkaido University, Sapporo, Hokkaido, Japan.
  3. 3Division of Research Support, Institute for Vaccine Research and Development, Hokkaido University, Sapporo, Hokkaido, Japan.
  4. 4Division of Molecular Pathobiology, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Hokkaido, Japan.
  5. 5Laboratory for Drug Discovery & Disease Research, Shionogi & Co., Ltd, Osaka, Japan.
  6. 6Division of Vaccinology for Clinical Development, Institute for Vaccine Research and Development, Hokkaido University, Sapporo, Hokkaido, Japan.
  7. 7Faculty of Pharmaceutical Science, Graduate School of Life Science, Hokkaido University, Sapporo, Hokkaido, Japan.
  8. 8Division of Molecular Psychoimmunology, Institute for Genetic Medicine, Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan.
  9. 9Technical Office, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Hokkaido, Japan.
  10. 10Division of Risk Analysis and Management, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Hokkaido, Japan.
  11. 11One Health Research Center, Hokkaido University, Sapporo, Hokkaido, Japan.
  12. 12International Collaboration Unit, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Hokkaido, Japan.
  13. 13Global Virus Network, Tampa, Florida, United States of America.
  14. 14National Virus Reference Laboratory, School of Medicine, University College Dublin, Dublin, Ireland.
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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.

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Cite

BibTeXRIS
BibTeX
@article{moraes2026integrated,
  title = {{Integrated in vivo and transcriptomic analyses of lethal Oropouche virus infection reveal suppression of pathogenic host responses by antiviral therapy}},
  author = {Cássia Sousa Moraes and Gabriel Gonzalez and Akihiko Sato and Shigeru Miki and Atsuko Inoue and Koshiro Tabata and Joshua W Kranrod and Chilekwa Frances Kabamba and Aiko Ohnuma and Keita Matsuno and Rio Harada and Shinji Saito and Naoki Akimoto and Michihito Sasaki and Yasuko Orba and William W Hall and Hirofumi Sawa and Yukari Itakura},
  journal = {PLOS Pathogens},
  year = {2026},
  month = oct,
  doi = {10.1371/journal.ppat.1014647},
  url = {https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014647},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Integrated in vivo and transcriptomic analyses of lethal Oropouche virus infection reveal suppression of pathogenic host responses by antiviral therapy
AU  - Cássia Sousa Moraes
AU  - Gabriel Gonzalez
AU  - Akihiko Sato
AU  - Shigeru Miki
AU  - Atsuko Inoue
AU  - Koshiro Tabata
AU  - Joshua W Kranrod
AU  - Chilekwa Frances Kabamba
AU  - Aiko Ohnuma
AU  - Keita Matsuno
AU  - Rio Harada
AU  - Shinji Saito
AU  - Naoki Akimoto
AU  - Michihito Sasaki
AU  - Yasuko Orba
AU  - William W Hall
AU  - Hirofumi Sawa
AU  - Yukari Itakura
PY  - 2026
DA  - 2026/10/07
JO  - PLOS Pathogens
DO  - 10.1371/journal.ppat.1014647
UR  - https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014647
AB  - 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.
SN  - 1553-7374
SN  - 1553-7366
ER  -