Antiviral Activity of Selective Estrogen Receptor Modulators against Severe Fever with Thrombocytopenia Syndrome Virus In Vitro and In Vivo
Abstract
:1. Introduction
2. Materials and Methods
2.1. Cell Culture and Virus Propagation
2.2. Compounds
2.3. Cytopathic Effect Inhibition Assay
2.4. Quantitative Real-Time PCR (qRT-PCR)
2.5. Plaque Assay (Plaque-Forming Unit [PFU] Assay)
2.6. Mouse Experiments
2.7. Ethics Statement
2.8. Time-of-Addition Assays
2.9. Transcriptome Analysis
2.10. Statistical Analysis
3. Results
3.1. Effect of SERMs on SFTSV Infection In Vitro
3.2. SERMs Inhibit SFTSV RNA Replication and Infectious Virus Proliferation at Nontoxic Dose
3.3. Anti-SFTSV Effect of BZA In Vivo
3.4. BZA Acted on the Post-Enter Stage of SFTSV Infection
3.5. Transcriptome Analysis of BZA against SFTSV
4. Discussion
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- Kuhn, J.H.; Adkins, S.; Alioto, D.; Alkhovsky, S.V.; Amarasinghe, G.K.; Anthony, S.J.; Avšič-Županc, T.; Ayllón, M.A.; Bahl, J.; Balkema-Buschmann, A.; et al. 2020 taxonomic update for phylum Negarnaviricota (Riboviria: Orthornavirae), including the large orders Bunyavirales and Mononegavirales. Arch. Virol. 2020, 165, 3023–3072. [Google Scholar] [CrossRef] [PubMed]
- 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.; et al. Fever with thrombocytopenia associated with a novel bunyavirus in China. N. Engl. J. Med. 2011, 364, 1523–1532. [Google Scholar] [CrossRef] [PubMed]
- Li, J.C.; Wang, Y.N.; Zhao, J.; Li, H.; Liu, W. A review on the epidemiology of severe fever with thrombocytopenia syndrome. Zhonghua Liu Xing Bing Xue Za Zhi 2021, 42, 2226–2233. [Google Scholar] [PubMed]
- Chatterjee, S.; Kim, C.M.; Kim, D.M.; Seo, J.W.; Kim, D.Y.; Yun, N.R.; Jung, S.I.; Kim, U.J.; Kim, S.E.; Kim, H.A.; et al. Coinfection With Severe Fever With Thrombocytopenia Syndrome and Scrub Typhus in Korea. Open Forum. Infect. Dis. 2023, 10, ofad377. [Google Scholar] [CrossRef]
- Takahashi, T.; Maeda, K.; Suzuki, T.; Ishido, A.; Shigeoka, T.; Tominaga, T.; Kamei, T.; Honda, M.; Ninomiya, D.; Sakai, T.; et al. The first identification and retrospective study of Severe Fever with Thrombocytopenia Syndrome in Japan. J. Infect. Dis. 2014, 209, 816–827. [Google Scholar] [CrossRef]
- Tran, X.C.; Yun, Y.; Van An, L.; Kim, S.H.; Thao, N.T.P.; Man, P.K.C.; Yoo, J.R.; Heo, S.T.; Cho, N.H.; Lee, K.H. Endemic Severe Fever with Thrombocytopenia Syndrome, Vietnam. Emerg. Infect. Dis. 2019, 25, 1029–1031. [Google Scholar] [CrossRef]
- McMullan, L.K.; Folk, S.M.; Kelly, A.J.; MacNeil, A.; Goldsmith, C.S.; Metcalfe, M.G.; Batten, B.C.; Albariño, C.G.; Zaki, S.R.; Rollin, P.E.; et al. A new phlebovirus associated with severe febrile illness in Missouri. N. Engl. J. Med. 2012, 367, 834–841. [Google Scholar] [CrossRef] [PubMed]
- Lee, M.J.; Kim, K.H.; Yi, J.; Choi, S.J.; Choe, P.G.; Park, W.B.; Kim, N.J.; Oh, M.D. In vitro antiviral activity of ribavirin against severe fever with thrombocytopenia syndrome virus. Korean J. Intern. Med. 2017, 32, 731–737. [Google Scholar] [CrossRef]
- Shimojima, M.; Fukushi, S.; Tani, H.; Yoshikawa, T.; Fukuma, A.; Taniguchi, S.; Suda, Y.; Maeda, K.; Takahashi, T.; Morikawa, S.; et al. Effects of ribavirin on severe fever with thrombocytopenia syndrome virus in vitro. Jpn. J. Infect. Dis. 2014, 67, 423–427. [Google Scholar] [CrossRef]
- Shimojima, M.; Fukushi, S.; Tani, H.; Taniguchi, S.; Fukuma, A.; Saijo, M. Combination effects of ribavirin and interferons on severe fever with thrombocytopenia syndrome virus infection. Virol. J. 2015, 12, 181. [Google Scholar] [CrossRef]
- 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.; et al. Case-fatality ratio and effectiveness of ribavirin therapy among hospitalized patients in china who had severe fever with thrombocytopenia syndrome. Clin. Infect. Dis. 2013, 57, 1292–1299. [Google Scholar] [CrossRef]
- Tani, H.; Fukuma, A.; Fukushi, S.; Taniguchi, S.; Yoshikawa, T.; Iwata-Yoshikawa, N.; Sato, Y.; Suzuki, T.; Nagata, N.; Hasegawa, H.; et al. Efficacy of T-705 (Favipiravir) in the Treatment of Infections with Lethal Severe Fever with Thrombocytopenia Syndrome Virus. mSphere 2016, 1, e00061-15. [Google Scholar] [CrossRef] [PubMed]
- 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.; et al. Clinical effect and antiviral mechanism of T-705 in treating severe fever with thrombocytopenia syndrome. Signal Transduct. Target Ther. 2021, 6, 145. [Google Scholar] [CrossRef]
- Li, H.; Zhang, L.K.; Li, S.F.; Zhang, S.F.; Wan, W.W.; Zhang, Y.L.; Xin, Q.L.; Dai, K.; Hu, Y.Y.; Wang, Z.B.; et al. Calcium channel blockers reduce severe fever with thrombocytopenia syndrome virus (SFTSV) related fatality. Cell Res. 2019, 29, 739–753. [Google Scholar] [CrossRef] [PubMed]
- Dutertre, M.; Smith, C.L. Molecular mechanisms of selective estrogen receptor modulator (SERM) action. J. Pharmacol. Exp. Ther. 2000, 295, 431–437. [Google Scholar] [PubMed]
- Fuchs-Young, R.; Glasebrook, A.L.; Short, L.L.; Draper, M.W.; Rippy, M.K.; Cole, H.W.; Magee, D.E.; Termine, J.D.; Bryant, H.U. Raloxifene is a tissue-selective agonist/antagonist that functions through the estrogen receptor. Ann. N. Y. Acad. Sci. 1995, 761, 355–360. [Google Scholar] [CrossRef]
- Martinkovich, S.; Shah, D.; Planey, S.L.; Arnott, J.A. Selective estrogen receptor modulators: Tissue specificity and clinical utility. Clin. Interv. Aging 2014, 9, 1437–1452. [Google Scholar]
- Miao, G.; Peng, H.; Tang, H.; Liu, Y.; Zheng, X.; Liu, B.; Jiang, L.; Tang, W.; He, Y.; Liu, Y.; et al. Antiviral efficacy of selective estrogen receptor modulators against SARS-CoV-2 infection in vitro and in vivo reveals bazedoxifene acetate as an entry inhibitor. J. Med. Virol. 2022, 94, 4809–4819. [Google Scholar] [CrossRef]
- Johansen, L.M.; Brannan, J.M.; Delos, S.E.; Shoemaker, C.J.; Stossel, A.; Lear, C.; Hoffstrom, B.G.; Dewald, L.E.; Schornberg, K.L.; Scully, C.; et al. FDA-approved selective estrogen receptor modulators inhibit Ebola virus infection. Sci. Transl. Med. 2013, 5, 190ra179. [Google Scholar] [CrossRef]
- Zhao, Y.; Ren, J.; Harlos, K.; Jones, D.M.; Zeltina, A.; Bowden, T.A.; Padilla-Parra, S.; Fry, E.E.; Stuart, D.I. Toremifene interacts with and destabilizes the Ebola virus glycoprotein. Nature 2016, 535, 169–172. [Google Scholar] [CrossRef]
- Yang, J.; Yan, Y.; Dai, Q.; Yin, J.; Zhao, L.; Li, Y.; Li, W.; Zhong, W.; Cao, R.; Li, S. Tilorone confers robust in vitro and in vivo antiviral effects against severe fever with thrombocytopenia syndrome virus. Virol. Sin. 2022, 37, 145–148. [Google Scholar] [CrossRef]
- Yan, Y.; Yang, J.; Xiao, D.; Yin, J.; Song, M.; Xu, Y.; Zhao, L.; Dai, Q.; Li, Y.; Wang, C.; et al. Nafamostat mesylate as a broad-spectrum candidate for the treatment of flavivirus infections by targeting envelope proteins. Antivir. Res. 2022, 202, 105325. [Google Scholar] [CrossRef]
- Huynh, N.P.; Gloss, C.C.; Lorentz, J.; Tang, R.; Brunger, J.M.; McAlinden, A.; Zhang, B.; Guilak, F. Long non-coding RNA GRASLND enhances chondrogenesis via suppression of the interferon type II signaling pathway. Elife 2020, 9, e49558. [Google Scholar] [CrossRef]
- Zhao, L.; Yao, L.; Chen, R.; He, J.; Lin, T.; Qiu, S.; Chen, G.; Chen, H.; Qiu, S.X. Pinostrobin from plants and propolis against human coronavirus HCoV-OC43 by modulating host AHR/CYP1A1 pathway and lipid metabolism. Antivir. Res. 2023, 212, 105570. [Google Scholar] [CrossRef]
- Yan, F.; Yang, W.; Wang, X.; Gao, G. TMEΜ45B Interacts with Sindbis Virus Nsp1 and Nsp4 and Inhibits Viral Replication. J. Virol. 2022, 96, e0091922. [Google Scholar] [CrossRef]
- Pushparaj, S.; Zhu, Z.; Huang, C.; More, S.; Liang, Y.; Lin, K.; Vaddadi, K.; Liu, L. Regulation of influenza A virus infection by Lnc-PINK1-2:5. J. Cell. Mol. Med. 2022, 26, 2285–2298. [Google Scholar] [CrossRef] [PubMed]
- Ren, F.; Shen, S.; Wang, Q.; Wei, G.; Huang, C.; Wang, H.; Ning, Y.J.; Zhang, D.Y.; Deng, F. Recent Advances in Bunyavirus Reverse Genetics Research: Systems Development, Applications, and Future Perspectives. Front. Microbiol. 2021, 12, 771934. [Google Scholar] [CrossRef]
- Liu, K.; Zhou, H.; Sun, R.X.; Yao, H.W.; Li, Y.; Wang, L.P.; Di, M.; Li, X.L.; Yang, Y.; Gray, G.C.; et al. A national assessment of the epidemiology of severe fever with thrombocytopenia syndrome, China. Sci. Rep. 2015, 5, 9679. [Google Scholar] [CrossRef]
- 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.; et al. Common adverse events associated with ribavirin therapy for Severe Fever with Thrombocytopenia Syndrome. Antivir. Res. 2015, 119, 19–22. [Google Scholar] [CrossRef] [PubMed]
Functional Category | Compounds | EC50 a (μM) * | CC50 b (μM) | SI c |
---|---|---|---|---|
Positive drug | T-705 | 11.41 ± 7.83 | >100 | >8.76 |
Selective estrogen receptor modulators (SERMs) | Bazedoxifene acetate | 0.35 ± 0.09 | 3.81 ± 1.67 | 10.89 |
Raloxifene HCl | 0.50 ± 0.34 | 6.23 ± 2.71 | 12.46 | |
Pipendoxifene HCl | 0.33 ± 0.20 | 3.02 ± 0.39 | 9.15 | |
Arzoxifene HCl | 0.28 ± 0.16 | 2.17 ± 0.63 | 7.75 | |
Acolbifene HCl | 2.04 ± 0.69 | 7.48 ± 2.40 | 3.67 | |
Clomiphene citrate | 0.67 ± 0.61 | 2.54 ± 0.76 | 3.79 | |
Lasofoxifene tartrate | 1.00 ± 0.81 | 4.13 ± 0.75 | 4.13 | |
Tamoxifen citrate | 0.16 ± 0.12 | 3.49 ± 0.45 | 21.81 | |
Endoxifene HCl | >100 | 3.15 ± 0.55 | - | |
Ospemifene | >100 | 18.11 ± 5.48 | - | |
Cyclofenil | >100 | 19.37 ± 6.23 | - | |
Chlorotrianisene | >100 | >100 | - | |
Estrogen receptor degraders (ERDs) | Fulvestrant | >100 | >100 | - |
Amcenestrant | >100 | 7.67 ± 1.39 | - | |
Brilanestrant | >100 | 11.87 ± 0.95 | - | |
Camizestrant | >100 | 49.48 ± 9.61 | - | |
Estriol | >100 | 67.27 ± 20.11 | - | |
Estrogen receptor agonists (ERAs) | G-1 | >100 | 0.46 ± 0.21 | - |
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Yan, X.; Luo, C.; Yang, J.; Wang, Z.; Shao, Y.; Wang, P.; Yang, S.; Li, Y.; Dai, Q.; Li, W.; et al. Antiviral Activity of Selective Estrogen Receptor Modulators against Severe Fever with Thrombocytopenia Syndrome Virus In Vitro and In Vivo. Viruses 2024, 16, 1332. https://doi.org/10.3390/v16081332
Yan X, Luo C, Yang J, Wang Z, Shao Y, Wang P, Yang S, Li Y, Dai Q, Li W, et al. Antiviral Activity of Selective Estrogen Receptor Modulators against Severe Fever with Thrombocytopenia Syndrome Virus In Vitro and In Vivo. Viruses. 2024; 16(8):1332. https://doi.org/10.3390/v16081332
Chicago/Turabian StyleYan, Xintong, Chongda Luo, Jingjing Yang, Zhuang Wang, Yunfeng Shao, Ping Wang, Shaokang Yang, Yuexiang Li, Qingsong Dai, Wei Li, and et al. 2024. "Antiviral Activity of Selective Estrogen Receptor Modulators against Severe Fever with Thrombocytopenia Syndrome Virus In Vitro and In Vivo" Viruses 16, no. 8: 1332. https://doi.org/10.3390/v16081332