抗寄生蟲藥物氯硝柳胺抗登革病毒感染的分子機制

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Title:	抗寄生蟲藥物氯硝柳胺抗登革病毒感染的分子機制 Molecular Mechanism of Antiparasitic Niclosamide against Dengue Virus Infection
Authors:	高若綺 Kao, Jo-Chi
Keywords:	登革病毒;氯硝柳胺;內吞小體酸化作用;哺乳動物雷帕黴素靶蛋白;複製 Dengue virus;Niclosamide;Endosomal acidification;mTOR;Replication
Date:	2018
Issue Date:	2019-01-02 12:18:05 (UTC+8)
Abstract:	抗寄生蟲藥物氯硝柳胺被證實能抑制由蚊蟲媒介茲卡病毒的感染。本研究中，我們利用體外細胞及體內動物模式探討氯硝柳胺對抗登革病毒感染的效果。氯硝柳胺可有效地阻擋登革病毒感染人類肺腺癌細胞 (A549)、小鼠神經母細胞瘤細胞 (Neuro-2a) 以及幼倉鼠腎臟纖維母細胞 (BHK-21)。初步結果顯示氯硝柳胺不影響病毒感染進入細胞、宿主細胞因應感染生成第一型干擾素反應以及不直接影響病毒轉錄體的轉譯作用。氯硝柳胺已知可抑制mTOR、STAT3以及NF-κB訊息路徑，但利用各自的選擇性抑制劑卻無法降低登革病毒感染，故而推測氯硝柳胺應藉由其他方式抑制登革病毒感染。如同vacuolar ATPase的抑制劑巴佛洛霉素A1，氯硝柳胺以及其他的質子載體 (例如 CCCP以及FCCP) 皆能有效地抑制細胞內吞小體的酸化並減少病毒核糖核酸複製以達到降低登革病毒感染之作用。利用腦內合併腹腔注射登革病毒感染出生七天大的ICR-哺乳期小鼠，結果顯示單一劑量的氯硝柳胺能部份降低小鼠腦內的病毒量、病毒性腦炎以及小鼠死亡率。本研究結果證實氯硝柳胺透過阻擋細胞內吞小體的酸化作用進而降低登革病毒的感染。 Antiparasitic niclosamide has been demonstrated to inhibit the arthropod-borne Zika virus. Here we investigated the antiviral ability of niclosamide against dengue virus (DENV) serotype 2 infection in vitro and in vivo. Administration of niclosamide effectively retarded DENV-induced infection in vitro in human lung adenocarcinoma cells (A549), mouse neuroblastoma cells (Neuro-2a), and baby hamster kidney fibroblasts (BHK-21). Treatment of niclosamide did not retard the endocytosis of DENV or 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 single dose of niclosamide partly decreased viral replication, viral encephalitis, and mortality in DENV-infected ICR suckling mice. These results demonstrate that niclosamide diminishes DENV infection by hindering endosomal acidification.
Description:	碩士指導教授：林秋烽
Data Type:	thesis
Appears in Collections:	[Graduate Institute of Medical Sciences] Dissertation/Thesis

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