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：
10338487
负责人：
Michaela Ulrike Gack
金额：
$ 45.08万
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/10338487
关键词：
Adjuvant Antiviral Agents Antiviral Response B-Cell Activation B-Lymphocytes Binding Binding Proteins Biochemical Biological Cell physiology Cells Clustered Regularly Interspaced Short Palindromic Repeats Cytoplasm DNA DNA Polymerase III DNA-Directed RNA Polymerase Data Detection Disease Encephalitis Epithelial Cells Exhibits Family Fibroblasts Foundations Gene Expression Genes Herpesviridae Herpesviridae Infections Herpesvirus 1 Host Defense Mechanism Human Immune Immune system Immunity Immunologic Deficiency Syndromes Immunology Impairment Infection Innate Immune Response Interferon Type I Interferons Knowledge Laboratories Lead Ligands Mediating Membrane Missense Mutation Molecular Mutation Natural Immunity Nature Patients Pattern recognition receptor Physiological Play Population Protein Biosynthesis Proteins Pseudogenes RNA RNA Viruses RNA, Ribosomal, 5S Ribosomal RNA Role Series Signal Transduction Techniques Toll-like receptors Transcript Untranslated RNA Virus Virus Diseases Work adaptive immunity antiviral immunity base 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innovation insight novel novel therapeutic intervention pathogenic virus receptor response sensor transcription factor unpublished works viral DNA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.

项目摘要来自许多实验室的工作已经确定DNA传感器 - 均膜定位 Toll样受体（例如TLR9）和细胞内DNA传感器（例如CGA） - 有感觉疱疹病毒与罢工相反，我们对细胞质的生理相关性的了解在检测疱疹病毒时，RIG-I样受体（RLR）家族的RNA传感器，例如单纯疱疹病毒1型（HSV-1）是基本的。拟议的研究是基于Gack实验室最近发现Rig-I扮演的一项发现的基础在HSV-1感染的检测和限制中，RIG-I和细胞内DNA的关键作用传感器以暂时的方式起作用。此外，我们确定在HSV-1感染期间宿主衍生的5S核糖体RNA伪元转录本141（RNA5SP141）激活RIG-I和引起细胞因子介导的抗病毒先天免疫诱变。在合作工作中，我们最近确定消融的RNA5SP141基因表达与严重的HSV-1有关人类脑炎。此外，我们发现RNA5SP141是从感染中导出的细胞通过外泌体并被未感染的细胞吸收，在该细胞中触发了RIG-I信号传导。使用协调的一系列分子，生化和细胞生物学方法合并使用CRISPR-GENE编辑技术，我们将定义RNA5SP141基因表达的作用在抗病毒对HSV-1感染和HSV-1相关疾病中的先天免疫反应中（目标1）。此外，我们将阐明RNA5SP141的分子机制外泌体负荷（AIM 2），还确定外泌体递送的生理相关性宿主对HSV-1感染免疫的RNA5SP141（AIM 3）。我们的研究将提供分子了解先天免疫对疱疹病毒感染的检测，这可能提供新治疗方法的基础或指导新型调节器的设计。