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

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

doi:10.1016/j.virs.2024.08.007

October 2024

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

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

Chongda Luo ^a,b,c ,
Xintong Yan ^a,b,c ,
Shaokang Yang ^c ,
Sichen Ren ^a,b,c ,
Yan Luo ^a,b,c ,
Jiazheng Li ^a,b,c ,
Ping Wang ^a,b,c ,
Yunfeng Shao ^a,b,c ,
Wei Li ^c ,
Song Li ^a,b,c ,
Jingjing Yang ^{a,b
,,} ,
Ruiyuan Cao ^{c
,,} ,
Wu Zhong ^{c
,,}

cstr: 32224.14.j.virs.2024.08.007

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

Corresponding author: Jingjing Yang, yangjingjing@hainanu.edu.cn
Ruiyuan Cao, 21cc@163.com
Wu Zhong, zhongwu@bmi.ac.cn
Received Date: 19 April 2024
Accepted Date: 15 August 2024
Available online: 20 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.
- Severe fever with thrombocytopenia syndrome virus (SFTSV)
- , Antiviral activity
- , Vitamin D derivatives
- , Drug combination

Electronic Supplementary Material

10.1016j.virs.2024.08.007-ESM.docx
References
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.
Proportional views