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

• Published in: PLoS neglected tropical diseases Vol. 12; no. 8; p. e0006715
• Main 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
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.08.2018; Public Library of Science (PLoS)
• Subjects: Acidification; Adenocarcinoma; Adenosine triphosphatase; Animals; Animals, Suckling; Antiparasitic Agents; Antiviral Agents; Autophagy; Biology and Life Sciences; Carbonyl compounds; Carbonyls; Cell Line; Cells; Cricetinae; Cyanides; Dengue; Dengue fever; Dengue Virus - physiology; Dosage and administration; Double-stranded RNA; Drug therapy; Encephalitis; Endocytosis; Endocytosis - drug effects; Endosomes - chemistry; Endosomes - drug effects; Fibroblasts; Genomes; H+-transporting ATPase; Human diseases; Humans; Hydrazones; Hydrogen-Ion Concentration; Immunology; Infections; Interferon; Kidneys; Lymphocytes B; Medicine; Medicine and Health Sciences; Mice; Mice, Inbred ICR; Neuroblastoma; Neuroblastoma cells; Neuroblasts; NF-κB protein; Niclosamide; Niclosamide - pharmacology; Protein kinases; Proteins; Rapamycin; Replication; Research and Analysis Methods; Severe acute respiratory syndrome; Stat3 protein; Suckling behavior; TOR protein; Transcription; Transducers; Tropical diseases; Vector-borne diseases; Viral diseases; Viral infections; Viral Plaque Assay; Viral replication; Viruses; Zika virus; Taiwan
• ISSN: 1935-2735; 1935-2727; 1935-2735
• DOI: 10.1371/journal.pntd.0006715

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. 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. These results demonstrate that niclosamide diminishes viral infection by hindering endosomal acidification.