Dataset Information

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

ABSTRACT:

Ethnopharmacological relevance and aim of the study

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.

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 ?M, respectively. This antiviral effect of celastrol was associated with celastrol-induced interferon-? (IFN-?) expression and was attenuated by a specific inhibitor of the JAK-STAT signaling pathway downstream of IFN-? 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-? expression and stimulates a downstream antiviral response, making the therapy a promising drug or dietary supplement for the treatment of DENV-infected patients.

SUBMITTER: Yu JS

PROVIDER: S-EPMC7113783 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Publications

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

Yu Jung-Sheng JS Tseng Chin-Kai CK Lin Chun-Kuang CK Hsu Yao-Chin YC Wu Yu-Hsuan YH Hsieh Ching-Liang CL Lee Jin-Ching JC

Antiviral research 20161112

<h4>Ethnopharmacological relevance and aim of the study</h4>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 ...[more]

PMID: 27847245

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Project description:Many viruses activate cellular autophagy in infected cells to facilitate their replication. Recently, we identified an interferon (IFN)-stimulated gene (ISG) Tudor domain containing 7 (TDRD7), which inhibits viral replication by blocking autophagy pathway. Here, we present a molecular mechanism for TDRD7 action and its relative contribution to protection against viral pathogenesis. TDRD7 inhibited the activation of adenosine monophosphate (AMP)-activated protein kinase (AMPK), a kinase required for initiating autophagy. Mechanistically, TDRD7 interacted directly with AMPK in the cytosolic compartment. Domain-mapping analyses revealed C-terminal Tudor domain of TDRD7 interacted with auto-inhibitory domain of AMPK. Deletion of Tudor domains abolished anti-AMPK and antiviral activities of TDRD7. We evaluated physiological relevance of TDRD7 function against viral replication using newly engineered TDRD7 knockout mice and the derived primary cells. TDRD7 knockout primary cells displayed increased AMPK activation, which led to a higher viral load. Subsequently, TDRD7 knockout mice showed enhanced susceptibility upon intranasal Sendai virus infection. Therefore, our study revealed a new antiviral function of IFN, mediated by TDRD7-AMPK, inhibiting viral replication and pathogenesis. IMPORTANCE Virus infection triggers induction of interferon (IFN)-stimulated genes (ISGs), which ironically inhibit viruses themselves. We identified Tudor domain-containing 7 (TDRD7) as a novel antiviral ISG, which inhibits viral replication by interfering with autophagy pathway. Here, we present a molecular basis for autophagy inhibitory function of TDRD7. TDRD7 interacted with adenosine monophosphate (AMP)-activated protein kinase (AMPK), the kinase that initiates autophagy, to inhibit its activation. We identified domains required for the interaction; deleting AMPK-interacting domain blocked antiAMPK and antiviral activities of TDRD7. We used primary cells and mice to evaluate the TDRD7-AMPK antiviral pathway. TDRD7-deficient primary mouse cells exhibited enhanced AMPK activation and viral replication. Finally, TDRD7 knockout mice showed increased susceptibility to respiratory virus infection. Therefore, our study revealed a new antiviral pathway of IFN and its contribution to host response. Our results have therapeutic potential; a TDRD7-derived peptide may be an effective AMPK inhibitor with application as antiviral agent.

Dataset Information

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

Ethnopharmacological relevance and aim of the study

Methods

Results

Conclusion

Publications

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

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