Novel Role for Host Immunostimulatory RNA in Antiviral Immune Defense

宿主免疫刺激 RNA 在抗病毒免疫防御中的新作用

基本信息

批准号：
10676843
负责人：
Michaela Ulrike Gack
金额：
$ 46万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-22 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10676843
关键词：
Ablation Adjuvant Antiviral Response B-Cell Activation B-Lymphocytes Binding Binding Proteins Biochemical Biological Cell physiology Cells Clustered Regularly Interspaced Short Palindromic Repeats Cytoplasm DNA Data Detection Disease Encephalitis Epithelial Cells Exhibits Family Fibroblasts Foundations Gene Expression Genes Herpes Simplex Infections Herpesviridae Herpesviridae Infections Herpesvirus 1 Heterozygote Host Defense Mechanism Human Immune Immune system Immunity Immunologic Deficiency Syndromes Immunology Impairment Infection Innate Immune Response Interferon Type I Knowledge Laboratories Lead Ligands Mediating Membrane Missense Mutation Molecular Mutation Natural Immunity Nature Patients Pattern recognition receptor Physiological Play Polymerase Population Protein Biosynthesis Proteins Pseudogenes RNA RNA Polymerase III RNA Viruses RNA delivery RNA, Ribosomal, 5S Ribosomal RNA Role Series Signal Transduction Techniques Toll-like receptors Transcript Transfer RNA Untranslated RNA Viral Virus Virus Diseases Work adaptive immunity antiviral immunity cofactor cytokine design exosome innate immune sensing innovation insight novel novel therapeutic intervention pathogenic virus receptor response sensor transcription factor unpublished works viral DNA

项目摘要

PROJECT SUMMARY Work from many laboratories has established that DNA sensors – both membrane-localized Toll-like receptors (e.g. TLR9) and intracellular DNA sensors (e.g. cGAS) – sense herpesvirus infection. In striking contrast, our knowledge about the physiologic relevance of cytoplasmic RNA sensors of the RIG-I-like receptor (RLR) family in the detection of herpesviruses, such as herpes simplex virus type 1 (HSV-1), is rudimentary. The proposed study builds on a recent discovery by the Gack laboratory that RIG-I plays a crucial role in the detection and restriction of HSV-1 infection, where RIG-I and intracellular DNA sensors act in a temporal manner. Furthermore, we identified that during HSV-1 infection the host-derived 5S ribosomal RNA pseudogene transcript 141 (RNA5SP141) activates RIG-I and elicits cytokine-mediated antiviral innate immune defense. In collaborative work we recently identified that ablated RNA5SP141 gene expression is associated with severe HSV-1 encephalitis in humans. Furthermore, we discovered that RNA5SP141 is exported from infected cells via exosomes and taken up by uninfected cells, where it triggered RIG-I signaling. Using a coordinated series of molecular, biochemical, and cell biological approaches combined with CRISPR-gene editing techniques, we will define the role of RNA5SP141 gene expression in the antiviral innate immune response to HSV-1 infection and in HSV-1-associated disease (AIM 1). Furthermore, we will elucidate the molecular mechanism(s) underlying RNA5SP141 exosomal loading (AIM 2), and also determine the physiologic relevance of exosomal delivery of RNA5SP141 in host immunity to HSV-1 infection (AIM 3). Our studies will provide a molecular understanding of innate immune detection of herpesvirus infection, which may provide the foundation for new therapeutic approaches or guide the design of novel adjuvants.

项目概要许多实验室的工作已经证实 DNA 传感器 – 都位于膜上 Toll 样受体（例如 TLR9）和细胞内 DNA 传感器（例如 cGAS）——感知疱疹病毒与此形成鲜明对比的是，我们对细胞质生理相关性的了解。 RIG-I 样受体 (RLR) 家族的 RNA 传感器在疱疹病毒检测中的应用，例如 1 型单纯疱疹病毒 (HSV-1) 尚处于初级阶段。这项拟议的研究建立在 Gack 实验室最近的一项发现之上，即 RIG-I 发挥着 RIG-I 和细胞内 DNA 在 HSV-1 感染的检测和限制中发挥着至关重要的作用此外，我们发现在 HSV-1 感染期间，传感器以时间方式起作用。宿主来源的 5S 核糖体 RNA 假基因转录物 141 (RNA5SP141) 激活 RIG-I 并在我们最近的合作工作中，它引发了细胞因子介导的抗病毒先天免疫防御。发现 RNA5SP141 基因表达缺失与严重 HSV-1 相关此外，我们发现RNA5SP141是从感染者中输出的。通过外泌体进入细胞并被未感染的细胞吸收，从而触发 RIG-I 信号传导。使用一系列协调一致的分子、生物化学和细胞生物学方法相结合通过CRISPR基因编辑技术，我们将定义RNA5SP141基因表达的作用 HSV-1 感染的抗病毒先天免疫反应和 HSV-1 相关疾病（目标 1）此外，我们将阐明 RNA5SP141 的分子机制。外泌体负载（AIM 2），并确定外泌体递送的生理相关性 RNA5SP141 在宿主对 HSV-1 感染的免疫中的作用（AIM 3）。了解疱疹病毒感染的先天免疫检测，这可能提供为新的治疗方法奠定基础或指导新型佐剂的设计。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

GTF3A mutations predispose to herpes simplex encephalitis by disrupting biogenesis of the host-derived RIG-I ligand RNA5SP141.

GTF3A 突变通过破坏宿主来源的 RIG-I 配体 RNA5SP141 的生物发生而诱发单纯疱疹脑炎。

DOI：
发表时间：
2022-11-25
期刊：
影响因子：
24.8
作者：
Naesens, Leslie;Muppala, Santoshi;Acharya, Dhiraj;Nemegeer, Josephine;Bogaert, Delfien;Lee, Jung;Staes, Katrien;Debacker, Veronique;De Bleser, Pieter;De Bruyne, Marieke;De Baere, Elfride;van Gent, Michiel;Liu, GuanQun;Lambrecht, Bart N
通讯作者：
Lambrecht, Bart N