The antiparasitic drug niclosamide inhibits dengue virus infection by interfering with endosomal acidification independent of mTOR

Jo Chi Kao, Wei Chun HuangFu, Tsung Ting Tsai, Min Ru Ho, Ming Kai Jhan, Ting Jing Shen, Po Chun Tseng, Yung Ting Wang, Chiou Feng Lin

Research output: Contribution to journalArticle

12 Citations (Scopus)

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.

Original languageEnglish
Article numbere0006715
JournalPLoS Neglected Tropical Diseases
Volume12
Issue number8
DOIs
Publication statusPublished - Aug 1 2018

ASJC Scopus subject areas

  • Public Health, Environmental and Occupational Health
  • Infectious Diseases

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