Citation: Jiajing Li, Marieke Alzeer, Xin Wang, Amber Hof, Debbie L.C. van den Berg, Qiuwei Pan. Human brain organoids and neural progenitor cells model oropouche virus infection and reveal varied responses to antiviral therapies .VIROLOGICA SINICA, 2026, 41(5) : 1256-1260.  http://dx.doi.org/10.1016/j.virs.2026.09.011

Human brain organoids and neural progenitor cells model oropouche virus infection and reveal varied responses to antiviral therapies

  • Highlights
    1 Human brain organoids and neural progenitor cells are susceptible to OROV infection.
    2 NHC (the active form of molnupiravir) shows suboptimal antiviral efficacy against OROV in neural models.
    3 IFN-α strongly inhibits OROV in NPCs but shows limited antiviral potency in brain organoids.
    4 Discrepancies between 2D and 3D platforms highlight the indispensable role of organoids in antiviral drug discovery.

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    1. Almeida, G.M., Souza, J.P., Mendes, N.D., Pontelli, M.C., Pinheiro, N.R., Nogueira, G.O., Cardoso, R.S., Paiva, I.M., Ferrari, G.D., Veras, F.P., Cunha, F.Q., Horta-Junior, J.A.C., Alberici, L.C., Cunha, T.M., Podolsky-Gondim, G.G., Neder, L., Arruda, E., Sebollela, A., 2021. Neural Infection by Oropouche Virus in Adult Human Brain Slices Induces an Inflammatory and Toxic Response. Front Neurosci 15, 674576.

    2. Bastos Mde, S., Figueiredo, L.T., Naveca, F.G., Monte, R.L., Lessa, N., Pinto de Figueiredo, R.M., Gimaque, J.B., Pivoto Joao, G., Ramasawmy, R., Mourao, M.P., 2012. Identification of Oropouche Orthobunyavirus in the cerebrospinal fluid of three patients in the Amazonas, Brazil. Am J Trop Med Hyg 86, 732-735.

    3. Chang, C.H., Peng, W.Y., Lee, W.H., Yang, L., Lin, T.Y., Yang, M.H., Tsai, T.H., 2023. Transporter modulation of molnupiravir and its metabolite beta-D-N4-hydroxycytidine across the blood-brain barrier in a rat. Commun Med (Lond) 3, 150.

    4. Connors, K.A., Pedlow, M.R., Frey, Z.D., Cornejo Pontelli, M., Whelan, S.P.J., Duprex, W.P., D'Aiuto, L., Wills, Z.P., Hartman, A.L., 2026. Neural cells are susceptible to historic and recently emerged Oropouche virus strains. PLoS Pathog 22, e1013933.

    5. Eigenhuis, K.N., Somsen, H.B., van der Kroeg, M., Smeenk, H., Korporaal, A.L., Kushner, S.A., de Vrij, F.M.S., van den Berg, D.L.C., 2023. A simplified protocol for the generation of cortical brain organoids. Front Cell Neurosci 17, 1114420.

    6. Guagliardo, S.A.J., Connelly, C.R., Lyons, S., Martin, S.W., Sutter, R., Hughes, H.R., Brault, A.C., Lambert, A.J., Gould, C.V., Staples, J.E., 2024. Reemergence of Oropouche Virus in the Americas and Risk for Spread in the United States and Its Territories, 2024. Emerg Infect Dis 30, 2241-2249.

    7. Jurado, K., Bannerman, C., Philip, D., Miller-Ensminger, T., Kennedy, E., Liu, S., Walsh, K., Ming, G.L., 2025. Oropouche virus disrupts neurodevelopment and is vertically transmitted. Res Sq. [Preprint]. doi:10.21203/rs.3.rs-7512609/v1.

    8. Kreit, M., Paul, S., Knoops, L., De Cock, A., Sorgeloos, F., Michiels, T., 2014. Inefficient type I interferon-mediated antiviral protection of primary mouse neurons is associated with the lack of apolipoprotein l9 expression. J Virol 88, 3874-3884.

    9. Lang, R., Li, H., Luo, X., Liu, C., Zhang, Y., Guo, S., Xu, J., Bao, C., Dong, W., Yu, Y., 2022. Expression and mechanisms of interferon-stimulated genes in viral infection of the central nervous system (CNS) and neurological diseases. Front Immunol 13, 1008072.

    10. Li, J., Wang, X., Ding, Y., Qin, F., de Lima, S.T.S., Papamichail, L., Schraauwen, R., Forato, J., Claro, I.M., Hua, X., Simoes 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., Dos Santos, M.N.N., Pincinato, E.C., Proenca-Modena, J.L., Li, P., Anas, A.A., van der Laan, L.J.W., Castilletti, C., Oude Munnink, B.B., de Souza, W.M., Wang, W., Pan, Q., 2026. Human liver-derived organoids recapitulate Oropouche virus infection and manifestation, enabling antiviral drug discovery. Cell Rep Med 7, 102646.

    11. Nakamura, K., Fujimoto, K., Hasegawa, C., Aoki, I., Yoshitsugu, H., Ugai, H., Yatsuzuka, N., Tanaka, Y., Furihata, K., Maas, B.M., Wickremasingha, P.K., Duncan, K.E., Iwamoto, M., Stoch, S.A., Uemura, N., 2022. A phase I, randomized, placebo-controlled study of molnupiravir in healthy Japanese to support special approval in Japan to treat COVID-19. Clin Transl Sci 15, 2697-2708.

    12. D.M., Pastula, J.D., Beckham, K.L., Tyler, Oropouche Virus: An Emerging Neuroinvasive Arbovirus, Ann. Neurol., 97, 2025, 28, 33.

    13. Wang, X., Ding, Y., Duarte-Neto, A.N., Al-Tawfiq, J.A., Wang, W., Pan, Q., Li, J., 2026a. Comprehensive analysis of epidemiological and clinical features of Oropouche virus infection (1975 to 2025): a systematic review. New Microbes New Infect 70, 101725.

    14. Wang, X., Li, J., Biharie, A., de Vries, A.C., Bijvelds, M.J.C., Janssen, H.L.A., Wang, W., Souza, W., Pan, Q., 2026b. Oropouche virus infects primary human intestinal organoids and is inhibited by type I and III interferon treatment. mBio 17, e0300325.

    15. Winkler, C.W., Woods, T.A., Groveman, B.R., Carmody, A.B., Speranza, E.E., Martens, C.A., Best, S.M., Haigh, C.L., Peterson, K.E., 2019. Neuronal maturation reduces the type I IFN response to orthobunyavirus infection and leads to increased apoptosis of human neurons. J Neuroinflammation 16, 229.

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    Human brain organoids and neural progenitor cells model oropouche virus infection and reveal varied responses to antiviral therapies

      Corresponding author: Debbie L.C. van den Berg, d.vandenberg@erasmusmc.nl
      Corresponding author: Qiuwei Pan, q.pan@erasmusmc.nl
    • a. Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, 3015 GD, the Netherlands;
    • b. Department of Developmental Biology, Erasmus MC-University Medical Center, Rotterdam, 3015 GD, the Netherlands

    Abstract: Highlights
    1 Human brain organoids and neural progenitor cells are susceptible to OROV infection.
    2 NHC (the active form of molnupiravir) shows suboptimal antiviral efficacy against OROV in neural models.
    3 IFN-α strongly inhibits OROV in NPCs but shows limited antiviral potency in brain organoids.
    4 Discrepancies between 2D and 3D platforms highlight the indispensable role of organoids in antiviral drug discovery.

    Figure (1)  Reference (15) Relative (20)

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