Serving the Society Since 1986
高级搜索
Volume 39 Issue 5
October 2024

    . doi: 10.1016/j.virs.2024.08.007
    Citation: Chongda Luo, Xintong Yan, Shaokang Yang, Sichen Ren, Yan Luo, Jiazheng Li, Ping Wang, Yunfeng Shao, Wei Li, Song Li, Jingjing Yang, Ruiyuan Cao, Wu Zhong. Antiviral activity of vitamin D derivatives against severe fever with thrombocytopenia syndrome virus in vitro and in vivo .VIROLOGICA SINICA, 2024, 39(5) : 802-811.  http://dx.doi.org/10.1016/j.virs.2024.08.007
    shu

    维生素D类似物在体外和体内对严重发热伴血小板减少综合征的抗病毒活性

    cstr: 32224.14.j.virs.2024.08.007

    • a. 海南大学药学院, 海口;

    • b. 海南大学李松院士工作站(药学院), 三亚;

    • c. 北京药理毒理研究所国家应急药物工程研究中心

    • 严重发热伴血小板减少综合征病毒（SFTSV）是一种蜱传病毒，可引起严重发热血小板减少综合征，该病主要表现为发热和出血，并可能伴有严重的神经系统症状。目前，尚无批准用于该适应症的特异性抗病毒药物。基于此，我们在本研究中主要关注维生素D类似物是否在体内外水平均可有效抑制SFTSV。体外研究表明，维生素D类似物能够以剂量依赖的方式抑制病毒RNA复制、空斑形成和蛋白质表达。体内研究表明，维生素D类似物度骨化醇和阿尔法骨化醇均可显著提高致死剂量SFTSV感染的ICR乳鼠的存活率，并降低BALB/c成鼠血液中的SFTSV载量。加药时序实验表明，维生素D类似物主要在SFTSV感染的进入后阶段发挥作用。然而，在RIG-I缺陷的Huh7.5细胞中，未观察到维生素D类似物对SFTSV感染引起的细胞病变具有保护作用，同时，服用维生素D类似物并未提高成年A129小鼠的存活率或降低其血液中的病毒载量。进一步，我们利用转录组测序对维生素D类似物的抗病毒机制解析，提示阿法骨化醇可能通过激活宿主天然免疫反应发挥抗病毒作用。为了拓展维生素D类似物的应用范围，我们开展了体内外水平的药物联用实验，结果表明维生素D类似物和T-705在细胞水平具有协同作用，且阿尔法骨化醇和T-705组合物在小鼠中疗效也显著增强。这项研究证实了维生素 D 类似物具有抗SFTSV潜力，并表明它们可能与用于治疗SFTSV感染的其他化合物具有协同作用。

    Antiviral activity of vitamin D derivatives against severe fever with thrombocytopenia syndrome virus in vitro and in vivo

    • a. School of Pharmaceutical Sciences, Hainan University, Haikou, 570228, China;

    • b. Song Li's Academician Workstation of Hainan University (School of Pharmaceutical Sciences), Yazhou Bay, Sanya, 572000, China;

    • c. National Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing, 100850, China

    • Severe fever with thrombocytopenia syndrome virus (SFTSV) is a tick-borne virus that causes the severe fever thrombocytopenia syndrome, which manifests as fever and haemorrhage, accompanied by severe neurological complications. To date, no specific antiviral drugs have been approved for this indication. Herein, we investigated whether vitamin D derivatives inhibit SFTSV both in vitro and in vivo. An in vitro study demonstrated that vitamin D derivatives significantly suppressed viral RNA replication, plaque formation, and protein expression in a dose-dependent manner. Subsequently, in vivo studies revealed that doxercalciferol and alfacalcidol were associated with increased survival and reduced viral RNA load in the blood. Time-of-addition assay suggested that vitamin D derivatives primarily acted during the post-entry phase of SFTSV infection. However, cytopathic effect protective activity was not observed in RIG-I immunodeficient cell line Huh7.5, and the administration of vitamin D derivatives did not improve the survival rates or reduce the blood viral loads in adult A129 mice. Further transcriptome exploration into the antiviral mechanism revealed that alfacalcidol stimulates host innate immunity to exert antiviral effects. To expand the application of vitamin D derivatives, in vitro and in vivo drug combination assays were performed, which highlighted the synergistic effects of vitamin D derivatives and T-705 on SFTSV. The combination of alfacalcidol and T-705 significantly enhanced the therapeutic effects in mice. This study highlights the potential of vitamin D derivatives against SFTSV and suggests that they may have synergistic effects with other compounds used in the treatment of SFTSV infection.
    • 加载中

      1. Ali, N., 2020. Role of vitamin D in preventing of COVID-19 infection, progression and severity. J. nfect.Public Health 13, 1373-1380.

      2. Baba, M., Okamoto, M., Toyama, M., Sakakibara, N., Shimojima, M., Saijo, M., Niwa, T. and Yagi, Y., 2023. Amodiaquine derivatives as inhibitors of severe fever with thrombocytopenia syndrome virus (SFTSV) replication. Antivir. Res. 210, 105479.

      3. Bopp, N.E., Kaiser, J.A., Strother, A.E., Barrett, A.D.T., Beasley, D.W.C., Benassi, V., Milligan, G.N., Preziosi, M.-P. and Reece, L.M., 2020. Baseline mapping of severe fever with thrombocytopenia syndrome virology, epidemiology and vaccine research and development. npj Vaccines 5, 111.

      4. Brown, A.J., 2001. Therapeutic uses of vitamin D analogues. Am. J. Kidney Dis. 38, S3-S19.

      5. Brown, A.J. and Slatopolsky, E., 2008. Vitamin D analogs: therapeutic applications and mechanisms for selectivity. Mol. Aspect. Med. 29, 433-452.

      6. Chen, J., Tang, Z., Slominski, A., Li, W., Zmijewski, M., Liu, Y. and Chen, J.J.E.j.o.m.c., 2020. Vitamin D and its analogs as anticancer and anti-inflammatory agents. 207, 112738.

      7. Christakos, S., Li, S., De La Cruz, J. and Bikle, D.D., 2019. New developments in our understanding of vitamin D metabolism, action and treatment. Metabolism 98, 112-120.

      8. Costa, B., Becker, J., Krammer, T., Mulenge, F., Duran, V., Pavlou, A., Gern, O.L., Chu, X., Li, Y., Cicin-Sain, L., Eiz-Vesper, B., Messerle, M., Dolken, L., Saliba, A.-E., Erhard, F. and Kalinke, U., 2024. Human cytomegalovirus exploits STING signaling and counteracts IFN/ISG induction to facilitate infection of dendritic cells. Nat. Commun. 15, 1745.

      9. Fernandez, G.J., Ramirez-Mejia, J.M., Castillo, J.A. and Urcuqui-Inchima, S., 2023. Vitamin D modulates expression of antimicrobial peptides and proinflammatory cytokines to restrict Zika virus infection in macrophages. Int. Immunopharm. 119, 110232.

      10. Furuta, Y., Gowen, B.B., Takahashi, K., Shiraki, K., Smee, D.F. and Barnard, D.L., 2013. Favipiravir (T-705), a novel viral RNA polymerase inhibitor. Antivir. Res. 100, 446-454.

      11. Gao, Y., Cao, J., Xing, P., Altmeyer, R. and Zhang, Y., 2021. Evaluation of small molecule combinations against respiratory syncytial virus in vitro. Molecules 26, 2607.

      12. Ismailova, A. and White, J.H., 2021. Vitamin D, infections and immunity. Rev. Endocr. Metab. Disord. 23, 265-277.

      13. Janousek, J., Pilarova, V., Macakova, K., Nomura, A., Veiga-Matos, J., Silva, D.D.d., Remiao, F., Saso, L., Mala-Ladova, K., Maly, J., Novakova, L. and Mladenka, P., 2022. Vitamin D: sources, physiological role, biokinetics, deficiency, therapeutic use, toxicity, and overview of analytical methods for detection of vitamin D and its metabolites. Crit. Rev. Clin. Lab Sci. 59, 517-554.

      14. Jaratsittisin, J., Xu, B., Sornjai, W., Weng, Z., Kuadkitkan, A., Li, F., Zhou, G.-C. and Smith, D.R., 2020. Activity of vitamin D receptor agonists against dengue virus. Sci. Rep. 10, 10835.

      15. Jimenez-Sousa, M.A., Martinez, I., Medrano, L.M., Fernandez-Rodriguez, A. and Resino, S., 2018. Vitamin D in human immunodeficiency virus infection: influence on immunity and disease. Front. Immunol. 9, 458.

      16. Kim, E. and Park, S.J.M., 2023. Dabie bandavirusEmerging tick-borne: virology, Epidemiol. Pre. 11, 2309.

      17. Kim, K.-H., Yi, J., Kim, G., Choi, S.J., Jun, K.I., Kim, N.-H., Choe, P.G., Kim, N.-J., Lee, J.-K. and Oh, M.-d., 2013. Severe fever with thrombocytopenia syndrome, South Korea, 2012. Emerg. Infect. Dis. 19, 1892-1894.

      18. Kubodera, N., 2009. A new look at the most successful prodrugs for active vitamin D (D hormone): alfacalcidol and doxercalciferol. Molecules 14, 3869-3880.

      19. Kuhn, J.H., Adkins, S., Alioto, D., Alkhovsky, S.V., Amarasinghe, G.K., Anthony, S.J., Avsic-Zupanc, T., Ayllon, M.A., Bahl, J., Balkema-Buschmann, A., Ballinger, M.J., Bartonicka, T., Basler, C., Bavari, S., Beer, M., Bente, D.A., Bergeron, E., et al., 2020. 2020 taxonomic update for phylum Negarnaviricota (Riboviria: orthornavirae), including the large orders Bunyavirales and Mononegavirales. Arch. Virol. 165, 3023-3072.

      20. Li, H., Jiang, X.-M., Cui, N., Yuan, C., Zhang, S.-F., Lu, Q.-B., Yang, Z.-D., Xin, Q.-L., Song, Y.-B., Zhang, X.-A., Liu, H.-Z., Du, J., Fan, X.-J., Yuan, L., Yuan, Y.-M., Wang, Z., Wang, J., Zhang, L., Zhang, D.-N., Wang, Z.-B., Dai, K., Bai, J.-Y., Hao, Z.-N., Fan, H., Fang, L.-Q., Xiao, G., Yang, Y., Peng, K., Wang, H.-Q., Li, J.-X., Zhang, L.-K. and Liu, W., 2021. Clinical effect and antiviral mechanism of T-705 in treating severe fever with thrombocytopenia syndrome. Signal Transduct. Targeted Ther. 6, 145.

      21. Li, Y., Liu, M., Yan, Y., Wang, Z., Dai, Q., Yang, X., Guo, X., Li, W., Chen, X., Cao, R. and Zhong, W., 2022. Molnupiravir and its active form, EIDD-1931, show potent antiviral activity against enterovirus infections in vitro and in vivo. Viruses 14, 1142.

      22. Liu, Q., He, B., Huang, S.Y., Wei, F. and Zhu, X.Q., 2014. Severe fever with thrombocytopenia syndrome, an emerging tick-borne zoonosis. Lancet Infect. Dis. 14, 763-772.

      23. Liu, W., Lu, Q.B., Cui, N., Li, H., Wang, L.Y., Liu, K., Yang, Z.D., Wang, B.J., Wang, H.Y., Zhang, Y.Y., Zhuang, L., Hu, C.Y., Yuan, C., Fan, X.J., Wang, Z., Zhang, L., Zhang, X.A., Walker, D.H. and Cao, W.C., 2013. Case-fatality ratio and effectiveness of ribavirin therapy among hospitalized patients in China who had severe fever with thrombocytopenia syndrome. Clin. Infect. Dis. 57, 1292-1299.

      24. Lu, Q.B., Zhang, S.Y., Cui, N., Hu, J.G., Fan, Y.D., Guo, C.T., Qin, S.L., Yang, Z.D., Wang, L.Y., Wang, H.Y., Zhang, X.A., Liu, W. and Cao, W.C., 2015. Common adverse events associated with ribavirin therapy for Severe Fever with Thrombocytopenia Syndrome. Antivir. Res. 119, 19-22.

      25. Ma, J., Zhang, X., Soloveva, V., Warren, T., Guo, F., Wu, S., Lu, H., Guo, J., Su, Q., Shen, H., Solon, E., Comunale, M.A., Mehta, A., Guo, J.-T., Bavari, S., Du, Y., Block, T.M. and Chang, J., 2018. Enhancing the antiviral potency of ER α-glucosidase inhibitor IHVR-19029 against hemorrhagic fever viruses in vitro and in vivo. Antivir. Res. 150, 112-122.

      26. MN Prichard and C.Shipman, 1990. A three-dimensional model to analyze drug-drug interactions. Antivir. Res. 14:181-205.

      27. Qu, M., Di, S., Zhang, S., Xia, Z. and Quan, G., 2017. Vitamin D receptor protects glioblastoma A172 cells against Coxsackievirus A16 infection induced cell death in the pathogenesis of hand, foot, and mouth disease. Biochem. Biophys. Res. Commun. 493, 952-956.

      28. Raabe, V.N., Kann, G., Ribner, B.S., Morales, A., Varkey, J.B., Mehta, A.K., Lyon, G.M., Vanairsdale, S., Faber, K., Becker, S., et al., 2017. Favipiravir and ribavirin treatment of epidemiologically linked cases of Lassa fever. Clin. Infect. Dis. 65, 855-859.

      29. Scharton, D., Bailey, K.W., Vest, Z., Westover, J.B., Kumaki, Y., Van Wettere, A., Furuta, Y. and Gowen, B.B., 2014. Favipiravir (T-705) protects against peracute Rift Valley fever virus infection and reduces delayed-onset neurologic disease observed with ribavirin treatment. Antivir. Res. 104, 84-92.

      30. Shimojima, M., Fukushi, S., Tani, H., Yoshikawa, T., Fukuma, A., Taniguchi, S., Suda, Y., Maeda, K., Takahashi, T., Morikawa, S. and Saijo, M., 2014. Effects of ribavirin on severe fever with thrombocytopenia syndrome virus in vitro. Jpn. J. Infect. Dis. 67, 423-427.

      31. Singh, S.K., Oestereich, L., Rieger, T., Neumann, M., Bernreuther, C., Lehmann, M., Krasemann, S., Wurr, S., Emmerich, P., De Lamballerie, X., Olschlager, S. and Gunther, S., 2014. Evaluation of antiviral efficacy of ribavirin, arbidol, and T-705 (favipiravir) in a mouse model for crimean-Congo hemorrhagic fever. PLoS Neglected Trop. Dis. 8, e2804.

      32. Sintov, A.C., Yarmolinsky, L., Dahan, A. and Ben-Shabat, S., 2014. Pharmacological effects of vitamin D and its analogs: recent developments. Drug Discov. Today 19, 1769-1774.

      33. Takahashi, T., Maeda, K., Suzuki, T., Ishido, A., Shigeoka, T., Tominaga, T., Kamei, T., Honda, M., Ninomiya, D., Sakai, T., Senba, T., et al., 2014. The first identification and retrospective study of severe fever with thrombocytopenia syndrome in Japan. J. Infect. Dis. 209, 816-827.

      34. Tani, H., Fukuma, A., Fukushi, S., Taniguchi, S., Yoshikawa, T., Iwata-Yoshikawa, N., Sato, Y., Suzuki, T., Nagata, N., Hasegawa, H., Kawai, Y., Uda, A., Morikawa, S., Shimojima, M., Watanabe, H. and Saijo, M., 2016. Efficacy of T-705 (Favipiravir) in the treatment of infections with lethal severe fever with thrombocytopenia syndrome virus. mSphere 1, : e00061-15.

      35. Tong, X., Smith, J., Bukreyeva, N., Koma, T., Manning, J.T., Kalkeri, R., Kwong, A.D. and Paessler, S., 2018. Merimepodib, an IMPDH inhibitor, suppresses replication of Zika virus and other emerging viral pathogens. Antivir. Res. 149, 34-40.

      36. Yan, Y.Z., Yang, J.J., Xiao, D., Yin, J.Y., Song, M.W., Xu, Y.J., Zhao, L., Dai, Q.S., Li, Y.X., Wang, C., Wang, Z., Ren, X.F., Yang, X.T., Ni, J., Liu, M.M., Guo, X.J., Li, W., Chen, X.J., Liu, Z.Q., Cao, R.Y. and Zhong, W., 2022. Nafamostat mesylate as a broad-spectrum candidate for the treatment of flavivirus infections by targeting envelope proteins. Antivir. Res. 202, 105325.

      37. Yang, J., Yan, Y., Dai, Q., Yin, J., Zhao, L., Li, Y., Li, W., Zhong, W., Cao, R. and Li, S., 2022. Tilorone confers robust in vitro and in vivo antiviral effects against severe fever with thrombocytopenia syndrome virus. Virol. Sin. 37, 145-148.

      38. Yu, X.J., Liang, M.F., Zhang, S.Y., Liu, Y., Li, J.D., Sun, Y.L., Zhang, L., Zhang, Q.F., Popov, V.L., Li, C., Qu, J., Li, Q., Zhang, Y.P., Hai, R., Wu, W., Wang, Q., Zhan, F.X., Wang, X.J., Kan, B., Wang, S.W., Wan, K.L., Jing, H.Q., Lu, J.X., Yin, W.W., Zhou, H., Guan, X.H., Liu, J.F., Bi, Z.Q., Liu, G.H., Ren, J., Wang, H., Zhao, Z., Song, J.D., He, J.R., Wan, T., Zhang, J.S., Fu, X.P., Sun, L.N., Dong, X.P., Feng, Z.J., Yang, W.Z., Hong, T., Zhang, Y., Walker, D.H., Wang, Y. and Li, D.X., 2011. Fever with thrombocytopenia associated with a novel bunyavirus in China. N. Engl. J. Med. 364, 1523-1532.

      39. Zhao, L., Yan, Y.Z., Dai, Q.S., Wang, Z.H., Yin, J.Y., Xu, Y.J., Wang, Z., Guo, X.J., Li, W., Cao, R.Y. and Zhong, W., 2022. The CDK1 inhibitor, Ro-3306, is a potential antiviral candidate against influenza virus infection. Antivir. Res. 201, 105296.

    • 加载中

    • Electronic Supplementary Material

      10.1016j.virs.2024.08.007-ESM.docx

    Figures(1)

    PDF

    Article Metrics

    Article views(581) PDF downloads(10) Cited by(0)

    Related
    Proportional views
      通讯作者: 陈斌, bchen63@163.com
      • 1. 

        沈阳化工大学材料科学与工程学院 沈阳 110142

      1. 本站搜索
      2. 百度学术搜索
      3. 万方数据库搜索
      4. CNKI搜索

      Antiviral activity of vitamin D derivatives against severe fever with thrombocytopenia syndrome virus in vitro and in vivo

        Corresponding author: Jingjing Yang, yangjingjing@hainanu.edu.cn
        Corresponding author: Ruiyuan Cao, 21cc@163.com
        Corresponding author: Wu Zhong, zhongwu@bmi.ac.cn
      • a. School of Pharmaceutical Sciences, Hainan University, Haikou, 570228, China;
      • b. Song Li's Academician Workstation of Hainan University (School of Pharmaceutical Sciences), Yazhou Bay, Sanya, 572000, China;
      • c. National Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing, 100850, China
      • Received Date: 19 April 2024
      • Accepted Date: 15 August 2024

      Abstract: Severe fever with thrombocytopenia syndrome virus (SFTSV) is a tick-borne virus that causes the severe fever thrombocytopenia syndrome, which manifests as fever and haemorrhage, accompanied by severe neurological complications. To date, no specific antiviral drugs have been approved for this indication. Herein, we investigated whether vitamin D derivatives inhibit SFTSV both in vitro and in vivo. An in vitro study demonstrated that vitamin D derivatives significantly suppressed viral RNA replication, plaque formation, and protein expression in a dose-dependent manner. Subsequently, in vivo studies revealed that doxercalciferol and alfacalcidol were associated with increased survival and reduced viral RNA load in the blood. Time-of-addition assay suggested that vitamin D derivatives primarily acted during the post-entry phase of SFTSV infection. However, cytopathic effect protective activity was not observed in RIG-I immunodeficient cell line Huh7.5, and the administration of vitamin D derivatives did not improve the survival rates or reduce the blood viral loads in adult A129 mice. Further transcriptome exploration into the antiviral mechanism revealed that alfacalcidol stimulates host innate immunity to exert antiviral effects. To expand the application of vitamin D derivatives, in vitro and in vivo drug combination assays were performed, which highlighted the synergistic effects of vitamin D derivatives and T-705 on SFTSV. The combination of alfacalcidol and T-705 significantly enhanced the therapeutic effects in mice. This study highlights the potential of vitamin D derivatives against SFTSV and suggests that they may have synergistic effects with other compounds used in the treatment of SFTSV infection.

        HTML

      Figure (1)  Reference (39) Relative (20)

      目录

      鄂ICP备05001977号

         

      鄂公网安备 42010602003674号

      Copyright © 2019 Virologica Sinica. All rights reserved

      /

      DownLoad:  Full-Size Img  PowerPoint
      Return
      Return