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

Identifieur interne : 000454 ( Main/Exploration ); précédent : 000453; suivant : 000455

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

Auteurs : Jo-Chi Kao [Taïwan] ; Wei-Chun Huangfu [Taïwan] ; Tsung-Ting Tsai [Taïwan] ; Min-Ru Ho [Taïwan] ; Ming-Kai Jhan [Taïwan] ; Ting-Jing Shen [Taïwan] ; Po-Chun Tseng [Taïwan] ; Yung-Ting Wang [Taïwan] ; Chiou-Feng Lin [Taïwan]

Source :

RBID : pubmed:30125275

Descripteurs français

English descriptors

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.


DOI: 10.1371/journal.pntd.0006715
PubMed: 30125275
PubMed Central: PMC6117097


Affiliations:


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<div type="abstract" xml:lang="en">
<p>
<b>BACKGROUND</b>
</p>
<p>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.</p>
</div>
<div type="abstract" xml:lang="en">
<p>
<b>PRINCIPLE FINDING</b>
</p>
<p>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.</p>
</div>
<div type="abstract" xml:lang="en">
<p>
<b>SIGNIFICANCE</b>
</p>
<p>These results demonstrate that niclosamide diminishes viral infection by hindering endosomal acidification.</p>
</div>
</front>
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<Year>2018</Year>
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<Issue>8</Issue>
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<Month>08</Month>
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<Title>PLoS neglected tropical diseases</Title>
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<AbstractText Label="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.</AbstractText>
<AbstractText Label="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.</AbstractText>
<AbstractText Label="SIGNIFICANCE">These results demonstrate that niclosamide diminishes viral infection by hindering endosomal acidification.</AbstractText>
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<ForeName>Jo-Chi</ForeName>
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<Affiliation>Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.</Affiliation>
</AffiliationInfo>
<AffiliationInfo>
<Affiliation>Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.</Affiliation>
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<LastName>HuangFu</LastName>
<ForeName>Wei-Chun</ForeName>
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<Affiliation>Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.</Affiliation>
</AffiliationInfo>
<AffiliationInfo>
<Affiliation>Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.</Affiliation>
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<ForeName>Tsung-Ting</ForeName>
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<Affiliation>Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.</Affiliation>
</AffiliationInfo>
<AffiliationInfo>
<Affiliation>Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.</Affiliation>
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<ForeName>Min-Ru</ForeName>
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<AffiliationInfo>
<Affiliation>Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.</Affiliation>
</AffiliationInfo>
<AffiliationInfo>
<Affiliation>Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.</Affiliation>
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<ForeName>Ming-Kai</ForeName>
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<Affiliation>Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.</Affiliation>
</AffiliationInfo>
<AffiliationInfo>
<Affiliation>Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.</Affiliation>
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<ForeName>Ting-Jing</ForeName>
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</AffiliationInfo>
<AffiliationInfo>
<Affiliation>Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.</Affiliation>
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<ForeName>Po-Chun</ForeName>
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<Affiliation>Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.</Affiliation>
</AffiliationInfo>
<AffiliationInfo>
<Affiliation>Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.</Affiliation>
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<Affiliation>Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.</Affiliation>
</AffiliationInfo>
<AffiliationInfo>
<Affiliation>Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.</Affiliation>
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<ForeName>Chiou-Feng</ForeName>
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<AffiliationInfo>
<Affiliation>Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.</Affiliation>
</AffiliationInfo>
<AffiliationInfo>
<Affiliation>Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.</Affiliation>
</AffiliationInfo>
</Author>
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<Language>eng</Language>
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<PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType>
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<Year>2018</Year>
<Month>08</Month>
<Day>20</Day>
</ArticleDate>
</Article>
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<Country>United States</Country>
<MedlineTA>PLoS Negl Trop Dis</MedlineTA>
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<ISSNLinking>1935-2727</ISSNLinking>
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<MeshHeading>
<DescriptorName UI="D000818" MajorTopicYN="N">Animals</DescriptorName>
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<MeshHeading>
<DescriptorName UI="D000833" MajorTopicYN="N">Animals, Suckling</DescriptorName>
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<MeshHeading>
<DescriptorName UI="D000977" MajorTopicYN="N">Antiparasitic Agents</DescriptorName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D000998" MajorTopicYN="N">Antiviral Agents</DescriptorName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D002460" MajorTopicYN="N">Cell Line</DescriptorName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D006224" MajorTopicYN="N">Cricetinae</DescriptorName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D003716" MajorTopicYN="N">Dengue Virus</DescriptorName>
<QualifierName UI="Q000502" MajorTopicYN="Y">physiology</QualifierName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D004705" MajorTopicYN="N">Endocytosis</DescriptorName>
<QualifierName UI="Q000187" MajorTopicYN="Y">drug effects</QualifierName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D011992" MajorTopicYN="N">Endosomes</DescriptorName>
<QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName>
<QualifierName UI="Q000187" MajorTopicYN="Y">drug effects</QualifierName>
</MeshHeading>
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<MeshHeading>
<DescriptorName UI="D006863" MajorTopicYN="N">Hydrogen-Ion Concentration</DescriptorName>
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<MeshHeading>
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<MeshHeading>
<DescriptorName UI="D008813" MajorTopicYN="N">Mice, Inbred ICR</DescriptorName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D009534" MajorTopicYN="N">Niclosamide</DescriptorName>
<QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName>
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<MeshHeading>
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<CoiStatement>The authors have declared that no competing interests exist.</CoiStatement>
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