Human liver-derived organoids recapitulate Oropouche virus infection and manifestation, enabling antiviral drug discovery

Jiajing Li; Xin Wang; Yibo Ding; Fang Qin; Shirlene T.S. de Lima; Lito Papamichail; Rick Schraauwen; Julia Forato; Ingra M. Claro; Xinyi Hua; Leda M. Simões Mello; Dewy Mae Offermans; Monique M.A. Verstegen; Marjan Boter; Maikel P. Peppelenbosch; Anna Barbiero; Elisabetta Pagani; Harry L.A. Janssen; José A. Telmos Silva; Magnun N.N. dos Santos; Eder C. Pincinato; José Luiz Proenca-Modena; Pengfei Li; Adam A. Anas; Luc J.W. van der Laan; Concetta Castilletti; Bas B. Oude Munnink; William M. de Souza; Wenshi Wang; Qiuwei Pan

doi:10.1016/j.xcrm.2026.102646

Human liver-derived organoids recapitulate Oropouche virus infection and manifestation, enabling antiviral drug discovery

Jiajing Li
, Xin Wang
, Yibo Ding
, Fang Qin
, Shirlene T.S. de Lima
, Lito Papamichail
, Rick Schraauwen
, Julia Forato
, Ingra M. Claro
, Xinyi Hua
, Leda M. Simões Mello
, Dewy Mae Offermans
, Monique M.A. Verstegen
, Marjan Boter
, Maikel P. Peppelenbosch
, Anna Barbiero
, Elisabetta Pagani
, Harry L.A. Janssen
, José A. Telmos Silva
, Magnun N.N. dos Santos

Eder C. Pincinato, José Luiz Proenca-Modena, Pengfei Li, Adam A. Anas, Luc J.W. van der Laan, Concetta Castilletti, Bas B. Oude Munnink, William M. de Souza, Wenshi Wang, Qiuwei Pan

Microbiology, Immunology, and Molecular Genetics

Research output: Contribution to journal › Article › peer-review

3 Scopus citations

Abstract

SummaryOropouche virus (OROV) is a neglected, re-emerging arbovirus that typically causes self-limiting febrile illness but can also lead to severe complications. With no approved vaccines or treatments available, we integrate clinical data with human liver-derived organoids to assess liver involvement in OROV infection and identify antiviral candidates through drug repurposing. Patient blood tests show elevated liver enzymes, indicating OROV-associated hepatic dysfunction. OROV isolates productively infect liver organoids and induce severe cellular damage. Transcriptomic profiling reveals strong virus-host interactions, including activation of interferon-stimulated genes and cell death pathways. Pharmacological inhibition of the interferon pathway enhances OROV replication, whereas treatment with therapeutic interferon-α suppresses the infection. Molnupiravir, a clinically approved antiviral drug targeting viral RNA-dependent RNA polymerase, markedly inhibits OROV replication and mitigates virus-induced cytopathology. Combining molnupiravir with interferon-α results in synergistic antiviral activity, indicating the complementarity of virus-targeted and host-directed strategies. These findings strengthen preparedness and response to OROV emergence.

Original language	English
Article number	102646
Number of pages	25
Journal	Cell Reports Medicine
Volume	7
Issue number	3
DOIs	https://doi.org/10.1016/j.xcrm.2026.102646
State	Published - Mar 17 2026

Bibliographical note

Publisher Copyright:
© 2026 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license. http://creativecommons.org/licenses/by/4.0/

Funding

Q.P. is supported by a VIDI personal grant (no. 91719300) from the Netherlands Organisation for Health Research and Development (ZonMw) . W.M.d.S. is sup-ported by Burroughs Wellcome Fund-Climate Change and Human Health Seed Grants (grant number 1022448) and a Wellcome Trust-Digital Technol-ogy Development Award in Climate Sensitive Infectious Disease Modeling (grant number 226075/Z/22/Z) . J.L.P.-M. is supported by the Sao Paulo Research Foundation (grant number 2022/10442-0) and National Council for Scientific and Technological Development (grant number 309971/2023-3) . We are grateful to the staff of the CASA clinics in Leiden and Rotterdam for collecting fetal tissues. We thank Dr. Ron Smits from the Department of Gastro-enterology and Hepatology, Erasmus MC, the Netherlands, for providing tech-nical assistance. We thank Dr. Sven Reiche from Federal Research Institute for Animal Health, Germany, for providing the anti-OROV Gc antibody and Dr. Chantal Reusken from the National Institute for Public Health and the Environ-ment, the Netherlands, for providing the OROV strain TRVL9760.

Funders	Funder number
VIDI personal from the Netherlands Organisation for Health Research and Development (ZonMw)	91719300
Burroughs Wellcome Fund-Climate Change and Human Health Seed Grants	1022448
Wellcome Trust-Digital Technology Development Award in Climate Sensitive Infectious Disease Modeling	226075/Z/22/Z
National Council for Scientific and Technological Development	309971/2023-3
Sao Paulo Research Foundation	2022/10442-0

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Oropouche emergence
liver
organoids
therapeutic discovery

ASJC Scopus subject areas

General Medicine
General Biochemistry, Genetics and Molecular Biology

Access to Document

10.1016/j.xcrm.2026.102646

Cite this

Li, J., Wang, X., Ding, Y., Qin, F., de Lima, S. T. S., Papamichail, L., Schraauwen, R., Forato, J., Claro, I. M., Hua, X., Simões Mello, L. M., Offermans, D. M., Verstegen, M. M. A., Boter, M., Peppelenbosch, M. P., Barbiero, A., Pagani, E., Janssen, H. L. A., Telmos Silva, J. A., ... Pan, Q. (2026). Human liver-derived organoids recapitulate Oropouche virus infection and manifestation, enabling antiviral drug discovery. Cell Reports Medicine, 7(3), Article 102646. https://doi.org/10.1016/j.xcrm.2026.102646

@article{0926e856a4e649e0a08ddd96d90fd153,

title = "Human liver-derived organoids recapitulate Oropouche virus infection and manifestation, enabling antiviral drug discovery",

abstract = "SummaryOropouche virus (OROV) is a neglected, re-emerging arbovirus that typically causes self-limiting febrile illness but can also lead to severe complications. With no approved vaccines or treatments available, we integrate clinical data with human liver-derived organoids to assess liver involvement in OROV infection and identify antiviral candidates through drug repurposing. Patient blood tests show elevated liver enzymes, indicating OROV-associated hepatic dysfunction. OROV isolates productively infect liver organoids and induce severe cellular damage. Transcriptomic profiling reveals strong virus-host interactions, including activation of interferon-stimulated genes and cell death pathways. Pharmacological inhibition of the interferon pathway enhances OROV replication, whereas treatment with therapeutic interferon-α suppresses the infection. Molnupiravir, a clinically approved antiviral drug targeting viral RNA-dependent RNA polymerase, markedly inhibits OROV replication and mitigates virus-induced cytopathology. Combining molnupiravir with interferon-α results in synergistic antiviral activity, indicating the complementarity of virus-targeted and host-directed strategies. These findings strengthen preparedness and response to OROV emergence.",

keywords = "Oropouche emergence, liver, organoids, therapeutic discovery",

author = "Jiajing Li and Xin Wang and Yibo Ding and Fang Qin and \{de Lima\}, \{Shirlene T.S.\} and Lito Papamichail and Rick Schraauwen and Julia Forato and Claro, \{Ingra M.\} and Xinyi Hua and \{Sim{\~o}es Mello\}, \{Leda M.\} and Offermans, \{Dewy Mae\} and Verstegen, \{Monique M.A.\} and Marjan Boter and Peppelenbosch, \{Maikel P.\} and Anna Barbiero and Elisabetta Pagani and Janssen, \{Harry L.A.\} and \{Telmos Silva\}, \{Jos{\'e} A.\} and \{dos Santos\}, \{Magnun N.N.\} and Pincinato, \{Eder C.\} and Proenca-Modena, \{Jos{\'e} Luiz\} and Pengfei Li and Anas, \{Adam A.\} and \{van der Laan\}, \{Luc J.W.\} and Concetta Castilletti and \{Oude Munnink\}, \{Bas B.\} and \{de Souza\}, \{William M.\} and Wenshi Wang and Qiuwei Pan",

note = "Publisher Copyright: {\textcopyright} 2026 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license. http://creativecommons.org/licenses/by/4.0/",

year = "2026",

month = mar,

day = "17",

doi = "10.1016/j.xcrm.2026.102646",

language = "English",

volume = "7",

journal = "Cell Reports Medicine",

issn = "2666-3791",

publisher = "Cell Press",

number = "3",

}

Li, J, Wang, X, Ding, Y, Qin, F, de Lima, STS, Papamichail, L, Schraauwen, R, Forato, J, Claro, IM, Hua, X, Simões Mello, LM, Offermans, DM, Verstegen, MMA, Boter, M, Peppelenbosch, MP, Barbiero, A, Pagani, E, Janssen, HLA, Telmos Silva, JA, dos Santos, MNN, Pincinato, EC, Proenca-Modena, JL, Li, P, Anas, AA, van der Laan, LJW, Castilletti, C, Oude Munnink, BB, de Souza, WM, Wang, W & Pan, Q 2026, 'Human liver-derived organoids recapitulate Oropouche virus infection and manifestation, enabling antiviral drug discovery', Cell Reports Medicine, vol. 7, no. 3, 102646. https://doi.org/10.1016/j.xcrm.2026.102646

TY - JOUR

T1 - Human liver-derived organoids recapitulate Oropouche virus infection and manifestation, enabling antiviral drug discovery

AU - Li, Jiajing

AU - Wang, Xin

AU - Ding, Yibo

AU - Qin, Fang

AU - de Lima, Shirlene T.S.

AU - Papamichail, Lito

AU - Schraauwen, Rick

AU - Forato, Julia

AU - Claro, Ingra M.

AU - Hua, Xinyi

AU - Simões Mello, Leda M.

AU - Offermans, Dewy Mae

AU - Verstegen, Monique M.A.

AU - Boter, Marjan

AU - Peppelenbosch, Maikel P.

AU - Barbiero, Anna

AU - Pagani, Elisabetta

AU - Janssen, Harry L.A.

AU - Telmos Silva, José A.

AU - dos Santos, Magnun N.N.

AU - Pincinato, Eder C.

AU - Proenca-Modena, José Luiz

AU - Li, Pengfei

AU - Anas, Adam A.

AU - van der Laan, Luc J.W.

AU - Castilletti, Concetta

AU - Oude Munnink, Bas B.

AU - de Souza, William M.

AU - Wang, Wenshi

AU - Pan, Qiuwei

PY - 2026/3/17

Y1 - 2026/3/17

N2 - SummaryOropouche virus (OROV) is a neglected, re-emerging arbovirus that typically causes self-limiting febrile illness but can also lead to severe complications. With no approved vaccines or treatments available, we integrate clinical data with human liver-derived organoids to assess liver involvement in OROV infection and identify antiviral candidates through drug repurposing. Patient blood tests show elevated liver enzymes, indicating OROV-associated hepatic dysfunction. OROV isolates productively infect liver organoids and induce severe cellular damage. Transcriptomic profiling reveals strong virus-host interactions, including activation of interferon-stimulated genes and cell death pathways. Pharmacological inhibition of the interferon pathway enhances OROV replication, whereas treatment with therapeutic interferon-α suppresses the infection. Molnupiravir, a clinically approved antiviral drug targeting viral RNA-dependent RNA polymerase, markedly inhibits OROV replication and mitigates virus-induced cytopathology. Combining molnupiravir with interferon-α results in synergistic antiviral activity, indicating the complementarity of virus-targeted and host-directed strategies. These findings strengthen preparedness and response to OROV emergence.

AB - SummaryOropouche virus (OROV) is a neglected, re-emerging arbovirus that typically causes self-limiting febrile illness but can also lead to severe complications. With no approved vaccines or treatments available, we integrate clinical data with human liver-derived organoids to assess liver involvement in OROV infection and identify antiviral candidates through drug repurposing. Patient blood tests show elevated liver enzymes, indicating OROV-associated hepatic dysfunction. OROV isolates productively infect liver organoids and induce severe cellular damage. Transcriptomic profiling reveals strong virus-host interactions, including activation of interferon-stimulated genes and cell death pathways. Pharmacological inhibition of the interferon pathway enhances OROV replication, whereas treatment with therapeutic interferon-α suppresses the infection. Molnupiravir, a clinically approved antiviral drug targeting viral RNA-dependent RNA polymerase, markedly inhibits OROV replication and mitigates virus-induced cytopathology. Combining molnupiravir with interferon-α results in synergistic antiviral activity, indicating the complementarity of virus-targeted and host-directed strategies. These findings strengthen preparedness and response to OROV emergence.

KW - Oropouche emergence

KW - liver

KW - organoids

KW - therapeutic discovery

UR - https://www.scopus.com/pages/publications/105033865155

UR - https://www.scopus.com/pages/publications/105033865155#tab=citedBy

U2 - 10.1016/j.xcrm.2026.102646

DO - 10.1016/j.xcrm.2026.102646

M3 - Article

C2 - 41806841

AN - SCOPUS:105033865155

SN - 2666-3791

VL - 7

JO - Cell Reports Medicine

JF - Cell Reports Medicine

IS - 3

M1 - 102646

ER -

Human liver-derived organoids recapitulate Oropouche virus infection and manifestation, enabling antiviral drug discovery

Abstract

Bibliographical note

Funding

UN SDGs

Keywords

ASJC Scopus subject areas

Access to Document

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