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

Ethnopharmacological relevance and aim of the study: Triptetygium 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. Methods: A 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. Results: Celastrol 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 mu M, respectively. This antiviral effect of celastrol was associated with celastrol-induced interferon -alpha (IFN-alpha) expression and was attenuated by a specific inhibitor of the JAK STAT signaling pathway downstream of IFN-alpha or specific shRNA. Furthermore, celastrol protected ICR suckling mice against life-threatening DENV infection. Conclusion: Celastrol represents a potential anti-DENV agent that induces IFN-alpha expression and stimulates a downstream antiviral response, making the therapy a promising drug or dietary supplement for the treatment of DENV-infected patients. (C) 2016 Elsevier B.V. All rights reserved.