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Function and mechanism of the mammalian RNA interference response to virus infection

哺乳动物RNA干扰对病毒感染反应的功能和机制

基本信息

批准号：
10318978
负责人：
Shou-Wei Ding
金额：
$ 57.85万
依托单位：
UNIVERSITY OF CALIFORNIA RIVERSIDE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-09 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10318978
关键词：
Adaptive Immune System Address Adult Animals Antigens Antiviral Response B-Lymphocytes Biogenesis Cells Complex Coxsackie Viruses DICER1 gene Defense Mechanisms Dengue Virus Detection Development Double Stranded RNA Virus Double-Stranded RNA Ebola virus Family Genes Goals Hamsters Health Human Immunity Infection Influenza A virus Innate Immune System Insect Viruses Insecta Interferon Type I Interferons Invertebrates Investigation Lead Mammals Mediating Medical MicroRNAs Modeling Monkeys Mus Natural Immunity Nematoda Nucleic Acids Plant Viruses Plants Process Production Property RNA RNA Interference RNA Interference Pathway RNA Sequences RNA Viruses Rag1 Mouse Role Slice Small Interfering RNA System T-Lymphocyte Therapeutic Intervention Time Viral Virulent Virus Virus Diseases Virus Replication Zika Virus adaptive immunity antiviral immunity combat embryonic stem cell human pathogen in vivo knockout gene mouse model pathogenic virus response stem cell differentiation suckling therapeutic development viral detection

项目摘要

A multitude of human defense systems have evolved to combat viral pathogens. This proposal aims to characterize a new mammalian antiviral immunity mechanism mediated by the RNA interference (RNAi) pathway in an adult mouse model. The innate and adaptive immunity mechanisms have been extensively characterized. The innate immune system is activated upon the detection of viral nucleic acids and is primarily regulated by type I interferons (IFN). The adaptive immune system is under the control of T and B lymphocytes that direct an antigen-specific and long-lasting antiviral immunity. In fungal, plant, insect and nematode hosts, viral dsRNA is processed by Dicer into small interfering RNAs (siRNAs) to direct a potent and specific antiviral defense by the conserved RNAi pathway. Recent studies have revealed production of abundant virus-derived siRNAs in mouse embryonic stem cells, differentiated hamster, monkey and human cells or suckling mice after infection with four positive- or negative-strand RNA viruses from three families. Moreover, three viruses have evolved distinct viral suppressors of RNAi (VSRs) with the same activity to inhibit the biogenesis of viral siRNAs and the RNA slicing activity of Argonaute2 is antiviral in cultured mouse and human cells. These findings lead us to hypothesize that there is a new mammalian antiviral immunity mechanism directed by the RNAi pathway. However, there has been much debate about whether the IFN response is inhibitory to antiviral RNAi. It also remains unknown whether mammalian viral siRNAs from an in vivo response can guide specific, Argonaute2-mediated cleavages of the targeted RNAs. Using Nodamura virus as a model for positive-strand RNA viruses, we will investigate the mechanisms in the induction and suppression of mammalian antiviral RNAi response in adult mice that are either active or defective in the IFN system. The proposed studies will reveal for the first time the properties, abundance and persistence of mammalian viral siRNAs in the infected adult mouse and show whether mammalian VSRs suppress antiviral RNAi and/or the IFN response during in vivo infection. We will characterize the antiviral activity of mammalian viral siRNAs made during active siRNA response of adult mice by two independent approaches. Furthermore, we will develop a conditional gene knockout system in adult mice for defining the in vivo antiviral function of the core RNAi pathway genes Dicer and Argonaute2, which has not been possible thus far in mammals due to their essential roles in animal development. Results from the proposed studies will provide both a mechanistic framework for the new mammalian antiviral response in vivo and an adult mouse model for antiviral RNAi, thereby facilitating investigations on the siRNA response induced by medically important RNA virus pathogens that are a major threat to human health.

许多人类防御系统已经进化到对抗病毒病原体。这项建议旨在描述了一种新的由RNA干扰（RNAi）介导的哺乳动物抗病毒免疫机制在成年小鼠模型中的通路。先天性和适应性免疫机制已被广泛研究，表征了先天免疫系统在检测到病毒核酸时被激活，主要由I型干扰素（IFN）调节。适应性免疫系统受T和B的控制淋巴细胞，指导抗原特异性和持久的抗病毒免疫。在真菌、植物、昆虫和在线虫宿主中，病毒dsRNA被Dicer加工成小干扰RNA（siRNA），以指导有效的干扰。以及通过保守的RNAi途径进行特异性抗病毒防御。最近的研究表明，在小鼠胚胎干细胞、分化的仓鼠、猴和人中存在丰富的病毒衍生siRNA 细胞或乳鼠感染来自三个家族的四种正链或负链RNA病毒后。此外，三种病毒已经进化出具有相同活性的不同的RNAi病毒抑制子（VSRs），抑制病毒siRNA的生物发生，Argonaute 2的RNA切割活性在培养的小鼠和人类细胞。这些发现使我们假设有一种新的哺乳动物抗病毒药物 RNAi途径指导的免疫机制。然而，关于是否 IFN应答对抗病毒RNAi是抑制性。哺乳动物病毒siRNAs 可以引导Argonaute 2介导的靶向RNA的特异性切割。使用 Nodamura病毒作为正链RNA病毒的模型，我们将研究Nodamura病毒的机制。哺乳动物抗病毒RNAi应答在成年小鼠中诱导和抑制，所述成年小鼠是活跃的或干扰素系统的缺陷。拟议中的研究将首次揭示其性质、丰度和哺乳动物病毒siRNA在感染的成年小鼠中的持久性，并显示哺乳动物病毒siRNA是否 VSR在体内感染期间抑制抗病毒RNAi和/或IFN应答。我们将描述在成年小鼠的主动siRNA应答期间产生的哺乳动物病毒siRNA的抗病毒活性，独立的方法。此外，我们将在成年小鼠中开发条件性基因敲除系统用于定义核心RNAi途径基因Dicer和Argonaute 2的体内抗病毒功能，由于它们在动物发育中的重要作用，迄今为止在哺乳动物中还不可能。结果拟议的研究将为新的哺乳动物抗病毒反应提供一个机制框架，体内和成年小鼠抗病毒RNAi模型，从而促进siRNA反应的研究由医学上重要的RNA病毒病原体引起，对人类健康构成重大威胁。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Live-attenuated virus vaccine defective in RNAi suppression induces rapid protection in neonatal and adult mice lacking mature B and T cells.

DOI：
10.1073/pnas.2321170121
发表时间：
2024-04
期刊：
Proceedings of the National Academy of Sciences of the United States of America
影响因子：
11.1
作者：
Gang Chen;Qingxia Han;Wan-Xiang Li;Rong Hai;Shou-Wei Ding
通讯作者：
Gang Chen;Qingxia Han;Wan-Xiang Li;Rong Hai;Shou-Wei Ding

Boosting stem cell immunity to viruses.