Role of rRNA-derived short non-coding RNAs in innate immune response

rRNA 衍生的短非编码 RNA 在先天免疫反应中的作用

• 批准号: 10432333
• 负责人: Yohei Kirino
• 金额: $ 23.4万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-07 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10432333
• 关键词: Activation Analysis; Apoptosis; Attention; Biological Markers; Cell Cycle Regulation; Cell Proliferation; Cell surface; Cells; Communicable Diseases; Data; Disease; Elements; Endosomes; Foundations; Future; Generations; Genetic Transcription; Goals; Human; Immune; Immune response; Infection; Innate Immune Response; Innate Immune System; Investigation; Knock-out; Ligands; Lipopolysaccharides; Lysosomes; Mediating; Methods; Microbe; Molecular; Mycobacterium tuberculosis; Non-Insulin-Dependent Diabetes Mellitus; Organism; Pathway interactions; Patients; Pattern; Pattern Recognition; Pattern recognition receptor; Peptidoglycan; Periodicity; Plasma; Play; Population; Positioning Attribute; Prevention; Production; RNA; Receptor Activation; Regulation; Research; Ribosomal RNA; Role; Sampling; Signal Pathway; Signal Transduction Pathway; Surface; Symptoms; System; TLR7 gene; Therapeutic; Toll-Like Receptor Pathway; Toll-like receptors; Transcriptional Activation; Transcriptional Regulation; Transfer RNA; Untranslated RNA; cell type; chemokine; cytokine; experimental study; extracellular; glucose metabolism; immune activation; inorganic phosphate; insight; lipid metabolism; macrophage; monocyte; novel; pathogen; pathogenic microbe; response; sex; therapeutic target; tool; transcription factor; transcriptome; transcriptome sequencing

Project Summary and Abstract Infection of microbes causes a wide range of symptoms and diseases. Sustained efforts to understand the mechanism of cellular defense systems against microbe infections are essential to develop effective prevention methods and therapeutic applications. The innate immune system deploys various pattern-recognition receptors, including Toll-like receptors (TLRs), to recognize the invasion of microbes and initiate protective responses. TLRs are expressed at the cell surface or intracellular compartments (e.g., endosome and lysosome) in various cell types, such as macrophages, and recognize pathogen-associated molecular patterns (PAMPs) such as lipopolysaccharide (LPS) and peptidoglycan (PGN). The PAMP recognition initiates signal transduction pathways that culminate in the activation of transcription factors such as NF-B, resulting in production of cytokines and chemokines to protect the host. Following transcriptional regulation, the downstream of TLR pathways involves regulation at multiple levels including post-transcription steps. In this context, short non- coding RNAs (ncRNAs) have evolved as key post-transcriptional regulators. Among various short ncRNA species, those from ribosomal RNAs (rRNAs), termed rRNA fragments (rRFs), are the most abundant class of short ncRNAs and have recently gained increasing attentions on their expression and functional significance. rRFs are constitutively expressed in multiple organisms including humans, and their expression is involved in regulation of cell cycle and proliferation, apoptosis, and lipid and glucose metabolism. In humans, their expression is modulated in a sex- and population-specific manner, and associated with type 2 diabetes and other diseases. We propose that rRFs play important roles in innate immune response. In preliminary studies, we found that the expression of rRFs is upregulated by the activation of surface TLR in human monocyte-derived macrophages (HMDMs). Importantly, short ncRNA sequencing data demonstrated the abundant accumulation of the rRFs not only in HMDMs but also in their secreted extracellular vehicles (EVs). Further experiments showed that a specific extracellular rRF activates endosomal TLR in the recipient HMDMs to induce cytokine secretion, suggesting that rRFs are not just accumulated as degradation by-products of rRNAs, but are accumulated as functional molecules promoting immune response. In the proposed studies, we will identify the expression profiles of TLR pathway-induced rRFs in HMDMs and their EVs (Aim 1). We will further elucidate the molecular function of extracellular rRFs in endosomal TLR activation (Aim 2). Finally, we will characterize the rRF expression in plasma samples from healthy subjects and patients infected with Mycobacterium tuberculosis (Aim 3). By defining a novel class of TLR pathway-induced rRFs and further establishing their roles, our study will reveal a novel rRNA-engaged ncRNA pathway in the innate immune response and may support the future exploration of biomarkers and efficacious therapeutic applications targeting ncRNAs upon microbe infection.

项目摘要和摘要 微生物的感染会引起广泛的症状和疾病。持续努力了解 细胞防御系统针对微生物感染的机制对于发展有效的预防至关重要 方法和治疗应用。先天免疫系统部署了各种模式识别受体， 包括Toll样受体（TLR），以识别微生物的侵袭并启动保护反应。 TLR在细胞表面或细胞内室（例如内体和溶酶体）中表达。 细胞类型，例如巨噬细胞，并识别病原体相关的分子模式（PAMP），例如 脂多糖（LPS）和Pepperidoglycan（PGN）。 PAMP识别启动信号转导 最终在转录因子（例如NF-B）激活的途径，导致产生 细胞因子和趋化因子保护宿主。在转录调节后，TLR的下游 途径涉及多个级别的调节，包括转录后步骤。在这种情况下，简短的非 - 编码RNA（NCRNA）已演变为转录后调节剂。在各种简短的ncrnas中 核糖体RNA（RRNA）的物种称为rRNA片段（RRF），是最丰富的类 简短的NCRNA，最近对它们的表达和功能意义引起了人们的关注。 RRF始终在包括人在内的多种生物中表达，它们的表达与 细胞周期和增殖，凋亡以及脂质和葡萄糖代谢的调节。在人类中 表达以性别和人群为特定的方式调节，并与2型糖尿病和其他相关 疾病。我们建议RRF在先天免疫反应中起重要作用。在初步研究中，我们 发现RRF的表达是通过人单核细胞中表面TLR的激活来更新的 巨噬细胞（HMDMS）。重要的是，简短的NCRNA测序数据证明了丰富的积累 RRF不仅在HMDM中，而且在其分泌的细胞外车辆（EV）中。进一步的实验 表明特定的细胞外RRF激活受体HMDMS中的内体TLR以诱导细胞因子 分泌物，表明RRF不仅是作为rrNA的降解副产品积累的，而且是 积聚为促进免疫反应的功能分子。在拟议的研究中，我们将确定 TLR途径诱导的HMDMS及其电动汽车中的RRF的表达谱（AIM 1）。我们将进一步阐明 细胞外RRF在内体TLR激活中的分子功能（AIM 2）。最后，我们将表征 来自健康受试者和感染结核分枝杆菌的患者的血浆样品中的RRF表达 （目标3）。通过定义一类新型TLR途径诱导的RRF并进一步确立其角色，我们的研究 将在先天免疫反应中揭示一种新型的RRNA参与的NCRNA途径，并可能支持未来 对微生物感染后针对NCRNA的生物标志物和有效的治疗应用的探索。