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 *Corresponding Author
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.
Credits: None available.
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