Aedes antiviral RNAi pathway

伊蚊抗病毒RNAi途径

• 批准号: 10054161
• 负责人: George Dimopoulos
• 金额: $ 76.27万
• 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 2023-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10054161
• 关键词: Address; Aedes; Animal Model; Antiviral Agents; 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; 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.

概括 arbovirus仍然是巨大的公共卫生威胁，导致年度大型流行病。总体目标 这项研究是为了更好地了解伊德斯伊德斯伊德斯RNA干扰（RNAi）途径的作用 抗病毒防御和先天免疫，并为开发新的知识和工具生成知识和工具 控制Arbovirus传播的方法。用基因修饰的野生型替代野生型 蚊子无法传播病原体作为对其他疾病的有希望的补充 控制方法。因为Ae。 Aegypti传输了经常同胞的多个arbovirus病原体 对于转基因蚊子对多种病原体具有抗性非常重要。 siRNA途径介导 众所周知，抗病毒防御系统会针对广泛的病毒作用。但是，尽管有RNAi 途径的出现是主要的泛动物防御系统，它在蚊子中仍在研究。我们的 研究计划旨在测试据八角蛋白DICER-2（DCR-2），R2D2的总体假设 和Argonaute-2（AGO-2）是介导RNA沉默反应的关键组件，它具有广泛的保护性 抗刺病毒感染。我们将使用缺陷siRNA的功能丧失突变体和转基因 蚊子过表达DCR-2，AGO-2和R2D2，将在AIM 1中产生。使用这些遗传工具 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 AIM 3中垂直传输的组织间信号传导和调节。在AIM 4中，我们将解决互动 在RNAi途径和其他先天免疫防御系统之间。这个项目利用 Dimopoulos博士和迈尔斯博士的补充专业知识与Arbovirus感染系统，蚊子 转带，蚊子先天免疫和RNAi/小RNA生物学。我们提议的项目也将产生 用于研究AE中RNAi途径其他方面的强大工具。埃及生物学。