Inhibiting dengue virus infection by the antiparasitic drug niclosamide-mediated interference on endosomal acidification independent of mTOR
Chiou-Feng Lin1,2,*, Jo-Chi Kao1,2, Wei-Chun HuangFu3,4, Tsung-Ting Tsai1,2, Min-Ru Ho1,2, Ming-Kai Jhan1,2, Ting-Jing Shen1,2, Po-Chun Tseng1,2, Yung-Ting Wang1,2
1Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan; 2Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, Taiwan; 3Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan; 4Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan
Niclosamide, an antiparasitic agent, 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 DENV entry 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 reveal that niclosamide diminishes viral infection by impeding endosomal acidification.
Funding: This study was supported by grants from the Ministry of Science and Technology (MOST102-2628-B-038-011-MY3, 105-2321-B-038-002, 106-2321-B-038-002, and 107-2321-B-038-001) and the intramural funding 106TMU-CIT-01-2, Taipei, Taiwan.