Celastrol inhibits dengue virus replication via up-regulating type I interferon and downstream interferon-stimulated responses

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• 作者：Jung-Sheng Yu^a ; ^b ; ¹ ; Chin-Kai Tseng^c ; ^d ; ¹ ; Chun-Kuang Lin^e ; Yao-Chin Hsu^a ; Yu-Hsuan Wu^c ; ^d ; Ching-Liang Hsieh^b ; ^f ; ^g ; ^{clhsieh@mail.cmuh.org.tw} ; Jin-Ching Lee^h ; ⁱ ; ^j ; ^{jclee@kmu.edu.tw}
• 关键词：Dengue virus ; Celastrol ; Antiviral interferon response
• 刊名：Antiviral Research
• 出版年：2017
• 出版时间：January 2017
• 年：2017
• 卷：137
• 期：Complete
• 页码：49-57
• 全文大小：1592 K
• 卷排序：137

文摘

Tripterygium wilfordii (lei gong teng; Thunder of God Vine), a member of the Celastraceae family, is a medicinal plant used to treat a range of illnesses. Celastrol is a quinone methide triterpene and the most abundant bioactive constituent isolated from the root extracts of T. wilfordii. Previous studies have shown that celastrol exhibits antiviral activity against HIV and SARS-CoV. To date, no investigations of the anti-DENV activity of celastrol have been reported. This work aimed to investigate the anti-DENV effect and possible mechanism of celastrol in vitro and in vivo.MethodsA four-serotype DENV infection system was performed to determine the anti-DENV effect of celastrol by detecting DENV RNA replication and protein synthesis. The precise anti-DENV replication mechanism of celastrol was clarified using specific RNA silencing and specific inhibitor. In addition, the therapeutic efficacy of celastrol was evaluated by monitoring survival rates and clinical scores in a DENV-infected Institute of Cancer Research (ICR) suckling mouse model.ResultsCelastrol inhibited DENV-1, -2, -3, and -4 RNA replication with EC50 values of 0.19 ± 0.09, 0.12 ± 0.11, 0.16 ± 0.14, and 0.17 ± 0.08 μM, respectively. This antiviral effect of celastrol was associated with celastrol-induced interferon-α (IFN-α) expression and was attenuated by a specific inhibitor of the JAK–STAT signaling pathway downstream of IFN-α or specific shRNA. Furthermore, celastrol protected ICR suckling mice against life-threatening DENV infection.ConclusionCelastrol represents a potential anti-DENV agent that induces IFN-α expression and stimulates a downstream antiviral response, making the therapy a promising drug or dietary supplement for the treatment of DENV-infected patients.