Open AccessThe antiparasitic drug niclosamide inhibits dengue virus infection by interfering with endosomal acidification independent of mTOR
Author(s) -
Jo Chi Kao,
Wei Chun HuangFu,
Tsung-Cheng Tsai,
Min Ru Ho,
Ming Kai Jhan,
TingJing Shen,
Po Chun Tseng,
Yung Ting Wang,
Chiou Feng Lin
Publication year - 2018
Publication title -
plos neglected tropical diseases
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.99
H-Index - 135
eISSN - 1935-2735
pISSN - 1935-2727
DOI - 10.1371/journal.pntd.0006715
Subject(s) - niclosamide , biology , panobinostat , virology , sindbis virus , dengue virus , microbiology and biotechnology , pharmacology , virus , biochemistry , ecology , rna , histone deacetylase , gene , histone
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.