Dengue virus type 2 infections of Aedes aegypti are modulated by the mosquito's RNA interference pathway.
Dengue virus type 2 infections of Aedes aegypti are modulated by the mosquito's RNA interference pathway.
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DOI：
10.1371/journal.ppat.1000299
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发表时间：
2009-02
期刊：
影响因子：
6.7
通讯作者：
Blair, Carol D.
中科院分区：
文献类型：
--
作者：
Sanchez-Vargas, Irma;Scott, Jaclyn C.;Poole-Smith, B. Katherine;Franz, Alexander W. E.;Barbosa-Solomieu, Valerie;Wilusz, Jeffrey;Olson, Ken E.;Blair, Carol D.
大量研究表明，先天性和适应性免疫防御机制对登革病毒（DENV）感染的过程有很大影响，但对埃及伊蚊（Aedes aegypti）对虫媒病毒感染的先天性免疫应答知之甚少。我们在这里提出的证据表明，蚊子先天免疫反应的一个主要组成部分，RNA干扰（RNAi），是蚊子感染的一个重要的调制器。RNAi反应由双链RNA（dsRNA）触发，其作为正义RNA病毒感染的结果在细胞质中发生，导致产生小干扰RNA（siRNA）。这些siRNA有助于降解与dsRNA触发物具有序列同源性的病毒mRNA，从而抑制病毒复制。我们表明，虽然登革病毒2型（DENV 2）感染的Ae。埃及伊蚊培养的细胞和成年蚊子的口腔感染产生dsRNA和DENV 2特异性siRNA的产生，病毒复制和感染性病毒的释放持续存在，表明病毒规避RNAi。我们还表明，DENV 2并不完全逃避RNAi，因为通过沉默dcr 2，r2d2或ago 2（RNAi途径中编码重要传感器和效应蛋白的基因）的表达来损害该途径，增加了载体中的病毒复制，并减少了病毒传播所需的外源性孵育期。我们的研究结果表明RNAi作为Ae传播DENV的决定因素的主要作用。埃及人。登革病毒是全球最流行的虫媒病毒，通过持续感染的埃及伊蚊传播给人类。了解蚊子用来调节这些严重人类疾病病原体感染的机制，应该能让我们对导致传播的病毒-载体相互作用有重要的了解。RNA干扰（RNAi）是无脊椎动物用来抑制RNA病毒感染的先天防御机制;然而，对RNAi在蚊子中的抗病毒作用知之甚少。RNAi由双链RNA触发，导致与dsRNA触发物具有序列同源性的RNA降解。我们表明，登革病毒2型（DENV 2）感染的Ae。埃及伊蚊通过天然途径产生dsRNA和DENV 2特异性小干扰RNA，这是RNAi应答的标志;然而，蚊子的持续感染发生，表明DENV 2规避RNAi。我们还表明，DENV 2感染是由RNAi调节的，因为RNAi途径中编码重要传感器和效应蛋白的基因沉默表达的损伤增加了载体中的病毒复制，并减少了病毒传播前的潜伏期。我们的研究结果表明，RNAi在确定蚊子传播人类疾病的潜力方面发挥着重要作用。
A number of studies have shown that both innate and adaptive immune defense mechanisms greatly influence the course of human dengue virus (DENV) infections, but little is known about the innate immune response of the mosquito vector Aedes aegypti to arbovirus infection. We present evidence here that a major component of the mosquito innate immune response, RNA interference (RNAi), is an important modulator of mosquito infections. The RNAi response is triggered by double-stranded RNA (dsRNA), which occurs in the cytoplasm as a result of positive-sense RNA virus infection, leading to production of small interfering RNAs (siRNAs). These siRNAs are instrumental in degradation of viral mRNA with sequence homology to the dsRNA trigger and thereby inhibition of virus replication. We show that although dengue virus type 2 (DENV2) infection of Ae. aegypti cultured cells and oral infection of adult mosquitoes generated dsRNA and production of DENV2-specific siRNAs, virus replication and release of infectious virus persisted, suggesting viral circumvention of RNAi. We also show that DENV2 does not completely evade RNAi, since impairing the pathway by silencing expression of dcr2, r2d2, or ago2, genes encoding important sensor and effector proteins in the RNAi pathway, increased virus replication in the vector and decreased the extrinsic incubation period required for virus transmission. Our findings indicate a major role for RNAi as a determinant of DENV transmission by Ae. aegypti. Dengue viruses, globally the most prevalent arboviruses, are transmitted to humans by persistently infected Aedes aegypti mosquitoes. Understanding the mechanisms mosquitoes use to modulate infections by these agents of serious human diseases should give us critical insights into virus–vector interactions leading to transmission. RNA interference (RNAi) is an innate defense mechanism used by invertebrates to inhibit RNA virus infections; however, little is known about the antiviral role of RNAi in mosquitoes. RNAi is triggered by double-stranded RNA, leading to degradation of RNA with sequence homology to the dsRNA trigger. We show that dengue virus type 2 (DENV2) infection of Ae. aegypti by the natural route generates dsRNA and DENV2-specific small interfering RNAs, hallmarks of the RNAi response; nevertheless, persistent infection of mosquitoes occurs, suggesting that DENV2 circumvents RNAi. We also show that DENV2 infection is modulated by RNAi, since impairment by silencing expression of genes encoding important sensor and effector proteins in the RNAi pathway increases virus replication in the vector and decreases the incubation period before virus transmission. Our findings indicate a significant role for RNAi in determining the mosquito vector's potential for transmitting human diseases.
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