A novel system for the launch of alphavirus RNA synthesis reveals a role for the Imd pathway in arthropod antiviral response.
A novel system for the launch of alphavirus RNA synthesis reveals a role for the Imd pathway in arthropod antiviral response.
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DOI：
10.1371/journal.ppat.1000582
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发表时间：
2009-09
期刊：
影响因子：
6.7
通讯作者：
Hardy RW
中科院分区：
文献类型：
--
作者：
Avadhanula V;Weasner BP;Hardy GG;Kumar JP;Hardy RW
甲病毒是通过节肢动物载体（主要是蚊子）在脊椎动物宿主之间传播的 RNA 病毒。节肢动物如何对抗甲病毒或病毒本身尚不清楚。黑腹果蝇是研究针对细菌和真菌感染的先天免疫的强大模型系统。在这项研究中，我们报告了使用一种新系统来分析果蝇基因组中表达辛德比斯病毒复制子 RNA 后辛德比斯病毒（甲病毒属的模式种）RNA 的复制。我们证明，免疫缺陷（Imd）途径的缺陷会增强病毒复制，而 Toll 途径的突变则不会影响病毒复制。通过胸腔内注射完整病毒观察到类似的结果，并在培养的蚊子细胞中得到证实。这些发现表明 Imd 途径介导对 Sindbis 病毒复制的抗病毒反应。据我们所知，这是首次证明 Imd 途径在昆虫中具有抗病毒作用。甲病毒是节肢动物传播的病毒，主要维持在蚊子和啮齿动物或鸟类之间的地方性循环中。传播给人类可能会导致多种症状，从亚临床脑炎到致命性脑炎。脊椎动物的感染会导致疾病，而蚊子的感染会导致终生持续感染。为了检查控制甲病毒感染的节肢动物宿主途径，我们采用了一种新的系统来控制果蝇基因组中辛德比斯病毒 RNA 复制的启动。我们提供的数据显示，使用 UAS-GAL4 错误表达系统在果蝇中进行细胞介导的转录后，辛德比斯病毒 RNA 会进行强劲复制。使用该系统，我们从遗传学角度证明，由于转录因子 Relish 的激活，免疫缺陷途径 (Imd) 会抑制病毒 RNA 复制。此外，我们还证实了 Relish 直系同源物的激活是辛德比斯病毒感染蚊子细胞的结果。我们的工作首次直接证明 Imd 通路在节肢动物抗病毒免疫中发挥作用。
Alphaviruses are RNA viruses transmitted between vertebrate hosts by arthropod vectors, primarily mosquitoes. How arthropods counteract alphaviruses or viruses per se is not very well understood. Drosophila melanogaster is a powerful model system for studying innate immunity against bacterial and fungal infections. In this study we report the use of a novel system to analyze replication of Sindbis virus (type species of the alphavirus genus) RNA following expression of a Sindbis virus replicon RNA from the fly genome. We demonstrate deficits in the immune deficiency (Imd) pathway enhance viral replication while mutations in the Toll pathway fail to affect replication. Similar results were observed with intrathoracic injections of whole virus and confirmed in cultured mosquito cells. These findings show that the Imd pathway mediates an antiviral response to Sindbis virus replication. To our knowledge, this is the first demonstration of an antiviral role for the Imd pathway in insects. Alphaviruses are arthropod-borne viruses maintained primarily in an endemic cycle between mosquitoes and rodents or birds. Transmission to humans may result in wide ranging symptoms from subclinical to fatal encephalitis. While infection of vertebrates causes disease, infection of mosquitoes results in a life-long, persistent infection. In order to examine arthropod host pathways involved in controlling alphavirus infections, we have employed a novel system for the controlled launch of Sindbis virus RNA replication from the genome of the fruit fly, Drosophila melanogaster. We present data showing robust replication of a Sindbis virus RNA following its cell-mediated transcription in flies using the UAS-GAL4 misexpression system. Using this system we have genetically demonstrated that the immune deficiency pathway (Imd) suppresses viral RNA replication as a consequence of the activation of the transcription factor Relish. Additionally, we confirmed the activation of the Relish ortholog as a consequence of Sindbis virus infection of mosquito cells. Our work is the first direct demonstration that the Imd pathway plays a role in arthropod antiviral immunity.
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