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- Title
The antiparasitic drug niclosamide inhibits dengue virus infection by interfering with endosomal acidification independent of mTOR.
- Authors
Kao, Jo-Chi; HuangFu, Wei-Chun; Tsai, Tsung-Ting; Ho, Min-Ru; Jhan, Ming-Kai; Shen, Ting-Jing; Tseng, Po-Chun; Wang, Yung-Ting; Lin, Chiou-Feng
- Abstract
Background: The antiparasitic agent niclosamide has been demonstrated to inhibit the arthropod-borne Zika virus. Here, we investigated the antiviral capacity of niclosamide against dengue virus (DENV) serotype 2 infection in vitro and in vivo. Principle Finding: Niclosamide effectively retarded DENV-induced infection in vitro in human adenocarcinoma cells (A549), mouse neuroblastoma cells (Neuro-2a), and baby hamster kidney fibroblasts (BHK-21). Treatment with niclosamide did not retard the endocytosis of DENV while niclosamide was unable to enhance the antiviral type I interferon response. Furthermore, niclosamide did not cause a direct effect on viral replicon-based expression. Niclosamide has been reported to competitively inhibit the mTOR (mammalian target of rapamycin), STAT3 (signal transducer and activator of transcription 3), and NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) signaling pathways; however, selective inhibitors of those pathways did not reduce DENV infection. Similar to the vacuolar-type H+-ATPase inhibitor bafilomycin A1, both niclosamide and other protonophores, such as CCCP (carbonyl cyanide m-chlorophenyl hydrazone), and FCCP (carbonyl cyanide-p-trifluoromethoxyphenylhydrazone), effectively reduced endosomal acidification and viral dsRNA replication. Co-administration of a single dose of niclosamide partially decreased viral replication, viral encephalitis, and mortality in DENV-infected ICR suckling mice. Significance: These results demonstrate that niclosamide diminishes viral infection by hindering endosomal acidification.
- Subjects
DOUBLE-stranded RNA; DENGUE; ADENOCARCINOMA; NEUROBLASTOMA; VIROLOGY; RAPAMYCIN
- Publication
PLoS Neglected Tropical Diseases, 2018, Vol 12, Issue 8, p1
- ISSN
1935-2727
- Publication type
Article
- DOI
10.1371/journal.pntd.0006715