Coupled small molecules target RNA interference and JAK/STAT signaling to reduce Zika virus infection in Aedes aegypti.
Coupled small molecules target RNA interference and JAK/STAT signaling to reduce Zika virus infection in Aedes aegypti.
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DOI：
10.1371/journal.ppat.1010411
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发表时间：
2022-04
期刊：
影响因子：
6.7
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中科院分区：
文献类型：
--
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最近的全球寨卡疫情暴露了蚊媒病毒所构成的重大威胁。目前尚无有效的疫苗或预防措施来预防寨卡病毒（ZIKV）感染。限制接触受感染的蚊子是减少疾病发病率的最佳方法。最近的研究重点是针对蚊子的繁殖和免疫反应，以减少传播。先前的工作评估了胰岛素信号传导对媒介蚊子中抗病毒 JAK/STAT 和 RNAi 的影响。具体来说，喂食胰岛素的蚊子在不依赖 RNAi、ERK 介导的 JAK/STAT 依赖机制中导致病毒复制减少。在这项工作中，我们证明通过重新利用小分子药物来靶向胰岛素信号传导会导致 RNAi 和 JAK/STAT 抗病毒途径的激活。感染 ZIKV 的埃及伊蚊被喂食含有去甲基星醌 B1 (DMAQ-B1)（一种有效的胰岛素模拟物）以及 AKT 抑制剂 VIII 的血液。这种协调反应的激活进一步降低了埃及伊蚊的 ZIKV 水平。这种效应包括相对于单途径激活而言，在摄入血粉后 11 天内，唾液腺 ZIKV 水平在数量上有更大程度的降低。总之，我们的研究表明，现场递送这些小分子有可能大幅减少病毒从蚊子传播到人类的可能性。随着寨卡病毒等感染变得越来越繁重和普遍，了解如何控制昆虫媒介中的该病毒家族是公共卫生中的一个重要问题。虫媒病毒对人类构成重大威胁，并且由于气候变化和媒介种群的扩大而日益受到关注。最近寨卡病毒的爆发表明，由病毒感染引起的蚊媒疾病仍然是一个突出且不断演变的威胁，必须积极应对。由于目前尚无针对寨卡病毒感染的暴露后治疗方法，减少传播以及感染的可能性将为高危人群带来相当大的好处。在这里，我们表明，现成的小分子可以重新利用，以有效减少病毒复制和临床相关寨卡病毒株在媒介蚊子中传播的可能性。此外，我们展示了如何在我们的药物治疗方案中同时激活两种胰岛素介导的经典抗病毒途径，以降低蚊子唾液中的病毒水平，病毒通过唾液传播给人类。我们共同证明了靶向胰岛素信号传导作为降低蚊子感染率和寨卡病毒传播的手段的可行性。
The recent global Zika epidemics have revealed the significant threat that mosquito-borne viruses pose. There are currently no effective vaccines or prophylactics to prevent Zika virus (ZIKV) infection. Limiting exposure to infected mosquitoes is the best way to reduce disease incidence. Recent studies have focused on targeting mosquito reproduction and immune responses to reduce transmission. Previous work has evaluated the effect of insulin signaling on antiviral JAK/STAT and RNAi in vector mosquitoes. Specifically, insulin-fed mosquitoes resulted in reduced virus replication in an RNAi-independent, ERK-mediated JAK/STAT-dependent mechanism. In this work, we demonstrate that targeting insulin signaling through the repurposing of small molecule drugs results in the activation of both RNAi and JAK/STAT antiviral pathways. ZIKV-infected Aedes aegypti were fed blood containing demethylasterriquinone B1 (DMAQ-B1), a potent insulin mimetic, in combination with AKT inhibitor VIII. Activation of this coordinated response additively reduced ZIKV levels in Aedes aegypti. This effect included a quantitatively greater reduction in salivary gland ZIKV levels up to 11 d post-bloodmeal ingestion, relative to single pathway activation. Together, our study indicates the potential for field delivery of these small molecules to substantially reduce virus transmission from mosquito to human. As infections like Zika virus are becoming more burdensome and prevalent, understanding how to control this family of viruses in the insect vector is an important issue in public health. Arboviruses pose a significant threat to humans and are an increasing concern as a result of climate change and expanding vector-competent populations. The recent Zika outbreaks demonstrate that mosquito-borne illnesses caused by viral infection remain a prominent and evolving threat that must be actively addressed. As there are currently no post-exposure therapeutics available for Zika virus infection, reducing transmission and, in turn, the likelihood of infection would provide sizeable benefit for human populations most at risk. Here, we show that readily available small molecules can be repurposed to effectively reduce viral replication and likelihood of transmission for a clinically relevant strain of Zika in vector competent mosquitoes. Furthermore, we show how two insulin-mediated canonical antiviral pathways are simultaneously activated in our drug treatment regimen to reduce virus levels in mosquito saliva, through which virus is transmitted to humans. Together, we demonstrate the viability of targeting insulin signaling as a means of reducing the rate of mosquito infection and decreased transmission of Zika virus.
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影响因子：
64.5
作者：
Brunet, A;Bonni, A;Greenberg, ME
通讯作者：
Greenberg, ME
DOI：
10.1016/j.jmii.2017.12.005
发表时间：
2020-02-01
影响因子：
7.4
作者：
Lee, Ing-Kit;Hsieh, Ching-Jung;Liu, Jien-Wei
通讯作者：
Liu, Jien-Wei
DOI：
10.3390/v13010108
发表时间：
2021-01-14
期刊：
Viruses
影响因子：
--
作者：
Dong S;Dimopoulos G
通讯作者：
Dimopoulos G
影响因子：
3.7
作者：
Ahlers LR;Bastos RG;Hiroyasu A;Goodman AG
通讯作者：
Goodman AG
影响因子：
3.8
作者：
Asad, Sultan;Parry, Rhys;Asgari, Sassan
通讯作者：
Asgari, Sassan