Human cathelicidin peptide LL-37 as a therapeutic antiviral targeting Venezuelan equine encephalitis virus infections
Human cathelicidin peptide LL-37 as a therapeutic antiviral targeting Venezuelan equine encephalitis virus infections
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DOI：
10.1016/j.antiviral.2019.02.002
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发表时间：
2019-04-01
影响因子：
7.6
通讯作者：
Narayanan, Aarthi
中科院分区：
文献类型：
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作者：
Ahmed, Aslaa;Siman-Tov, Gavriella;Narayanan, Aarthi
委内瑞拉马脑炎病毒（VEEV）是一种属于披膜病毒科的新世界甲病毒，会引起人类和马的周期性疾病爆发，并具有很高的死亡率和发病率。 VEEV 通过气溶胶途径具有高度传染性，因此已被开发为生物武器（Hawley 和 Eitzen，2001）。尽管目前将其归类为 B 类选择药物，但尚无 FDA 批准的疫苗或疗法来对抗 VEEV 感染。在这里，我们利用天然存在的宿主防御肽 LL-37 作为抑制受感染细胞中 VEEV 增殖的治疗策略。 LL-37 此前已通过与病毒颗粒直接相互作用以及通过在宿主细胞中建立抗病毒状态间接地证明了对多种病毒的活性。我们发现 LL-37 通过抑制病毒复制而表现出针对 VEEV 的有效抗病毒活性。与未处理的对照相比，VEEV TC-83 株的基因组 RNA 拷贝和病毒滴度显着降低。 LL-37 还可以抑制 VEEV 的毒性特立尼达驴 (TrD) 株。进入分析显示，在 TC-83 感染的早期阶段，病毒 RNA 拷贝大幅减少。细胞与 LL-37 和 TC-83 预孵育会产生强烈的抑制反应，表明 LL-37 影响感染过程的早期阶段。共聚焦和电子显微镜图像证实了病毒颗粒的聚集，这可能有助于预防进入，从而减少病毒感染。 LL-37 治疗还调节受感染细胞中 I 型干扰素 (IFN) 的表达。 LL-37 处理以时间依赖性方式显着增加处理细胞中 IFN beta 1 的表达。我们的结果表明 LL-37 是治疗 VEEV 感染的一种相关且新颖的潜在治疗策略。
Venezuelan equine encephalitis virus (VEEV), a new world alphavirus belonging to the Togaviridae family, causes periodic disease outbreaks in humans and equines with high associated mortality and morbidity. VEEV is highly infectious via the aerosol route and so has been developed as a biological weapon (Hawley and Eitzen, 2001). Despite its current classification as a category B select agent, there are no FDA approved vaccines or therapeutics to counter VEEV infections. Here we utilize a naturally occurring host defense peptide, LL-37, as a therapeutic strategy to inhibit VEEV multiplication in infected cells. LL-37 has previously demonstrated activity against several viruses by directly interacting with viral particles and indirectly by establishing an antiviral state in the host cell. We show that LL-37 exhibited potent antiviral activity against VEEV by inhibiting viral replication. Genomic RNA copies of the TC-83 strain of VEEV and viral titers were significantly reduced compared to non-treated controls. LL-37 also inhibited the virulent Trinidad Donkey (TrD) strain of VEEV. Entry assays revealed a robust reduction of viral RNA copies at the early stages of TC-83 infection. Pre-incubation of cells with LL-37 and TC-83 resulted in a strong inhibitory response, indicating that LL-37 impacts early stages of the infectious process. Confocal and electron microscopy images confirmed the aggregation of viral particles, which potentially accounts for entry prevention and hence reduced viral infection. LL-37 treatment also modulated type I interferon (IFN) expression in infected cells. LL-37 treatment dramatically increased IFN beta 1 expression in treated cells in a time-dependent manner. Our results establish LL-37 as a relevant and novel potential therapeutic strategy for the treatment of VEEV infections.