RIG-I, MDA5 and TLR3 synergistically play an important role in restriction of dengue virus infection.
RIG-I, MDA5 and TLR3 synergistically play an important role in restriction of dengue virus infection.
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DOI：
10.1371/journal.pntd.0000926
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发表时间：
2011-01-04
影响因子：
3.8
通讯作者：
Liu DX
中科院分区：
文献类型：
--
作者：
Nasirudeen AM;Wong HH;Thien P;Xu S;Lam KP;Liu DX
登革热病毒（DV）感染是世界上最常见的蚊媒病毒性疾病之一。先天免疫系统对于病毒的早期检测和采取一系列防御措施（包括产生 1 型干扰素 (IFN)）非常重要。因此，彻底了解 DV 感染期间的先天免疫反应对于我们了解 DV 发病机制至关重要。最近将该微阵列应用于 1 型登革热病毒 (DV1) 感染的肺癌细胞，结果显示细胞外和细胞质模式识别受体的表达均增加；视黄酸诱导基因-I (RIG-I)、黑色素瘤分化相关基因-5 (MDA-5) 和 Toll 样受体-3 (TLR3)。此前有报道称，这些细胞内 RNA 传感器能够感知不同细胞中的 DV 感染。在这项研究中，我们表明它们共同参与启动针对 DV 的有效 IFN 生产。这些基因沉默的细胞非常容易受到 DV 感染。 RIG-I和MDA5敲除的HUH-7细胞和TLR3敲除的巨噬细胞对DV感染高度敏感。当细胞仅沉默 RIG-I 和 MDA5（而非 TLR3）时，在病毒感染时观察到 IFN-β 的大量产生，反之亦然。对病毒感染的高敏感性导致 HUH-7 细胞内质网应激诱导细胞凋亡。总的来说，我们的研究表明，细胞内 RNA 病毒传感器（RIG-I、MDA5 和 TLR3）在 DV 感染后被激活，对于宿主防御病毒至关重要。由登革热病毒感染引起的登革热、登革出血热和登革休克综合征是世界许多地区尤其是东南亚的主要公共卫生问题。使用 DNA 微阵列技术研究宿主细胞响应病毒感染的转录变化一直是人们非常感兴趣的领域。在我们之前的研究中，我们使用微阵列技术来研究与登革热病毒感染相关的个体人类基因的表达。大多数上调的基因是1型干扰素相关基因。为了更好地了解对登革热病毒的先天免疫反应，我们敲低了 HUH-7 细胞中的 RIG-I、MDA5 和 TLR3 基因。使用 siRNA 技术沉默这些基因导致病毒复制显着增加。病毒载量的增加诱导内质网应激，导致细胞凋亡。这项研究证明了 RIG-I、MDA5 和 TLR3 在限制登革热病毒感染方面的协同作用。
Dengue virus (DV) infection is one of the most common mosquito-borne viral diseases in the world. The innate immune system is important for the early detection of virus and for mounting a cascade of defense measures which include the production of type 1 interferon (IFN). Hence, a thorough understanding of the innate immune response during DV infection would be essential for our understanding of the DV pathogenesis. A recent application of the microarray to dengue virus type 1 (DV1) infected lung carcinoma cells revealed the increased expression of both extracellular and cytoplasmic pattern recognition receptors; retinoic acid inducible gene-I (RIG-I), melanoma differentiation associated gene-5 (MDA-5) and Toll-like receptor-3 (TLR3). These intracellular RNA sensors were previously reported to sense DV infection in different cells. In this study, we show that they are collectively involved in initiating an effective IFN production against DV. Cells silenced for these genes were highly susceptible to DV infection. RIG-I and MDA5 knockdown HUH-7 cells and TLR3 knockout macrophages were highly susceptible to DV infection. When cells were silenced for only RIG-I and MDA5 (but not TLR3), substantial production of IFN-β was observed upon virus infection and vice versa. High susceptibility to virus infection led to ER-stress induced apoptosis in HUH-7 cells. Collectively, our studies demonstrate that the intracellular RNA virus sensors (RIG-I, MDA5 and TLR3) are activated upon DV infection and are essential for host defense against the virus. Dengue fever, dengue haemmorhagic fever and dengue shock syndrome, which are caused by dengue virus infection, are a major public health problem in many parts of the world, especially South East Asia. The investigation of host cell transcriptional changes in response to virus infection using DNA microarray technology has been an area of great interest. In our previous study, we used microarray technology to study expression of individual human genes in relation to dengue virus infection. Most of the genes that were upregulated were type 1 interferon related genes. To gain a better understanding of the innate immune response to dengue virus, we knocked down RIG-I, MDA5 and TLR3 genes in HUH-7 cells. Silencing these genes using siRNA technology resulted in significant increase in viral replication. This increase in viral load induced ER stress leading to apoptosis. This study demonstrates a synergistic role for RIG-I, MDA5 and TLR3 in restricting dengue virus infection.
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影响因子：
64.8
作者：
Alexopoulou, L;Holt, AC;Flavell, RA
通讯作者：
Flavell, RA
DOI：
10.1073/pnas.1934678100
发表时间：
2003-09-16
影响因子：
11.1
作者：
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通讯作者：
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影响因子：
30.5
作者：
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通讯作者：
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影响因子：
5.8
作者：
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通讯作者：
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影响因子：
5.3
作者：
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通讯作者：
Hiscott, J