Induction and Suppression of antiviral RNAi pathways by mosquito-specific and mosquito-borne viruses

蚊子特异性病毒和蚊媒病毒诱导和抑制抗病毒 RNAi 途径

• 批准号: 226337221
• 负责人: Professorin Dr. Sandra Junglen
• 金额: --
• 依托单位: Afdeling Medische Microbiologie
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2013
• 资助国家: 德国
• 起止时间: 2012-12-31 至 2019-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/226337221?language=en
• 关键词: Induction; Suppression; antiviral; RNAi; pathways

Background. Nearly one-fourth of emerging infectious diseases in humans is vector-borne and causes some of the most debilitating human diseases. Arthropod-borne viruses (arboviruses) are naturally maintained in an enzootic (sylvatic) cycle in which virus is transmitted during blood-feeding between arthropod vectors and amplifying vertebrate hosts. Human infections can be caused by spill-over infections or due to viral adaptation to new mosquito species and to human hosts. Especially flaviviruses are prone to escape their natural transmission cycles and to adapt to urban cycles where direct human-to-human transmission via mosquitoes occurs. For example, Dengue virus and Yellow fever virus emerged from enzootic cycles that involved non-human primates and forest-dwelling mosquitoes to epidemic cycles using the anthropophilic mosquitoes Aedes albopictus and Aedes aegypti as vectors and humans as amplifying hosts. With the increasing global spread of arboviruses, it is important to understand the factors that affect virus transmission by mosquitoes and to predict the potential of arboviruses to emerge into epidemic cycles. Previous research and preliminary observations. We and others have previously shown that RNA interference (RNAi) is an important antiviral defense mechanism in insects, including the major vector mosquito Aedes aegypti, and that RNAi plays a critical role in vector competence. More recently, we demonstrated that a related small RNA-based mechanism, the Piwi-associated RNA pathway, is also able to recognize and process arbovirus RNA in mosquitoes. Furthermore, we demonstrated that insect RNA viruses, including viruses with a tropism for mosquitoes, frequently suppress RNAi. Aim, approach and objectives. The overall aim of this project is to understand the role of antiviral RNAi and piRNA responses and viral counter-defense in establishing vector competence in mosquitoes. We will compare the induction and suppression of RNAi among representatives of the genus Flavivirus (Flaviviridae family) that differ in their mode of transmission, vector tropism, and sylvatic or epidemic origin. Specifically, we will i) profile viral small RNAs in different mosquito vectors; ii) compare RNAi suppressive activity among flaviviruses that differ in their vector competence; iii) elucidate the mechanism of the identified viral suppressors of RNAi. Importance. Arboviruses are an important group of human and animal pathogens and their emergence and re-emergence requires thorough understanding of vector transmission. This proposal will have a major impact on our understanding of vector competence. Furthermore, our results will contribute to our ability to predict the ability of arboviruses to cross the species barrier and the potential of known and novel sylvatic arboviruses to transfer into epidemic amplification cycles.

背景近四分之一的人类新发传染病是病媒传播的，并导致一些最严重的人类疾病。节肢动物传播的病毒（虫媒病毒）自然维持在一个地方性（森林）循环中，其中病毒在节肢动物载体和扩增脊椎动物宿主之间的吸血过程中传播。人类感染可能由溢出感染或由于病毒适应新的蚊子物种和人类宿主引起。特别是黄病毒易于逃离其自然传播周期，并适应通过蚊子发生直接人与人传播的城市周期。例如，登革热病毒和黄热病病毒是从涉及非人类灵长类动物和林栖蚊子的地方病循环到使用嗜中性蚊子白纹伊蚊和埃及伊蚊作为载体和人类作为扩增宿主的流行循环中出现的。随着虫媒病毒在全球范围内的传播，了解影响蚊子传播病毒的因素并预测虫媒病毒进入流行周期的可能性非常重要。以前的研究和初步观察。我们和其他人以前已经表明，RNA干扰（RNAi）是昆虫，包括主要的载体蚊子埃及伊蚊的一种重要的抗病毒防御机制，RNAi在载体能力中起着关键作用。最近，我们证明了一种相关的基于小RNA的机制，Piwi相关的RNA途径，也能够识别和处理蚊子中的虫媒病毒RNA。此外，我们证明了昆虫RNA病毒，包括对蚊子具有嗜性的病毒，经常抑制RNAi。宗旨、方法和目标。该项目的总体目标是了解抗病毒RNAi和皮尔纳反应以及病毒反防御在蚊子中建立载体能力的作用。我们将比较黄病毒属（黄病毒科）的代表之间的RNAi的诱导和抑制，不同的传播方式，载体嗜性，和森林或流行起源。具体而言，我们将i）分析不同蚊子载体中的病毒小RNA; ii）比较载体能力不同的黄病毒之间的RNAi抑制活性; iii）阐明所鉴定的RNAi病毒抑制子的机制。重要性虫媒病毒是人类和动物病原体的重要组成部分，其出现和重新出现需要对媒介传播的透彻理解。这一建议将对我们理解载体能力产生重大影响。此外，我们的研究结果将有助于我们预测虫媒病毒跨越物种屏障的能力，以及已知和新的森林虫媒病毒转移到流行性扩增循环的潜力。