Aedes antiviral RNAi pathway

伊蚊抗病毒RNAi途径

• 批准号: 10289713
• 负责人: George Dimopoulos
• 金额: $ 75.6万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-11-20 至 2024-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10289713
• 关键词: Address; Aedes; Animal Model; Antiviral Response; Arbovirus Infections; Arboviruses; Area; Bioinformatics; Biology; Chikungunya virus; Complement; Culicidae; Dengue; Development; Disease Vectors; Drosophila melanogaster; Epidemic; Gene Silencing; Gene Transfer Techniques; Genes; Genetic; Goals; Immune; Immune signaling; Immune system; Immunity; Infection; Knowledge; Laboratories; Lacrosse; Mediating; Methods; Midgut; Molecular; Molecular Genetics; Molecular Virology; Movement; Natural Immunity; Ovary; Pathway interactions; Population Replacements; Proteins; Public Health; RNA Interference; RNA Interference Pathway; Regulation; Research; Resistance; Resources; Role; Salivary Glands; Signal Transduction; Sindbis Virus; Small Interfering RNA; Small RNA; Specificity; System; Testing; Tissues; Transgenic Organisms; Vertical Disease Transmission; Viral; Virus; Work; Yellow Fever; ZIKA; Zika Virus; antiviral immunity; combinatorial; design; disorder control; human pathogen; innate immune pathways; interdisciplinary approach; loss of function; mutant; next generation sequencing; novel; novel strategies; overexpression; pathogen; pathogenic virus; response; spatiotemporal; tool; tool development; transgene expression; transmission process; vector

SUMMARY Arboviruses remain an immense public health threat, causing yearly large epidemics. The overarching aim of this research is to better understand the role of the Aedes aegypti RNA interference (RNAi) pathway in antiviral defense and innate immunity, and to generate knowledge and tools for the development of new methods to control arbovirus transmission. Population replacement of wild-type with genetically modified mosquitoes incapable of pathogen transmission is emerging as a promising complement to other disease control methods. Because Ae. aegypti transmits multiple arbovirus pathogens that are frequently sympatric, it is important for a transgenic mosquito to be resistant to multiple pathogens. The siRNA pathway-mediated antiviral defense system is known to act against a broad range of viruses. However, despite the RNAi pathway's emergence as the major pan-antiviral defense system it remains understudied in mosquitoes. Our research plan is designed to test the overarching hypothesis that the A. aegypti proteins, Dicer-2 (Dcr-2), R2D2 and Argonaute-2 (Ago-2), are key components mediating an RNA silencing response that is broadly protective against arbovirus infections. We will use of siRNA-deficient loss-of-function mutants and transgenic mosquitoes over-expressing Dcr-2, Ago-2 and R2D2 that will be generated in Aim 1. With these genetic tools we will clarify the temporal and spatial specificity of the antiviral response in Aim 2, and investigate possible inter-tissue signaling and regulation of vertical transmission in Aim 3. In Aim 4 we will address interactions between the RNAi pathway and other innate immunity defense systems. This project utilizes the complementary expertise of Drs Dimopoulos and Myles with the arbovirus infection systems, mosquito transgenesis, mosquito innate immunity and RNAi/small RNA biology. Our proposed project will also generate powerful tools for studying other aspects of the RNAi pathway in Ae. aegypti biology.

总结 虫媒病毒仍然是一个巨大的公共卫生威胁，每年造成大规模流行病。首要目标 这项研究的目的是更好地了解埃及伊蚊RNA干扰（RNAi）途径在 抗病毒防御和先天免疫，并产生知识和工具，为发展新的 控制虫媒病毒传播的方法。用基因修饰的野生型替代群体 不能传播病原体的蚊子正在成为其他疾病的一种有希望的补充 控制方法因为爱埃及伊蚊传播多种虫媒病毒病原体， 对转基因蚊子抵抗多种病原体是重要的。siRNA通路介导的 已知抗病毒防御系统对多种病毒起作用。然而，尽管RNAi 尽管该途径作为主要的泛抗病毒防御系统的出现，但它在蚊子中的研究仍然不足。我们 研究计划的目的是测试的总体假设，即A。埃及伊蚊蛋白，Dicer-2（Dcr-2），R2D2 和Argonaute-2（Ago-2）是介导RNA沉默反应的关键组分， 对抗虫媒病毒感染。我们将使用siRNA缺陷的功能丧失突变体和转基因 过表达Dcr-2、Ago-2和R2D2的蚊子，其将在目标1中产生。有了这些基因工具 我们将阐明Aim 2中抗病毒反应的时间和空间特异性，并研究可能的 组织间信号传导和Aim 3中垂直传输的调节。在目标4中，我们将讨论相互作用 RNAi途径和其他先天免疫防御系统之间的联系。该项目利用了 Dimopoulos博士和Myles博士在虫媒病毒感染系统、蚊子 转基因、蚊子先天免疫和RNAi/小RNA生物学。我们提出的项目也将产生 这是研究Ae中RNAi途径其他方面的有力工具。埃及生物学