Role of RNA-binding protein in immune evasion of Mtb in macrophages

RNA结合蛋白在巨噬细胞中Mtb免疫逃避中的作用

基本信息

批准号：
10634764
负责人：
Jianguo Liu
金额：
$ 22.73万
依托单位：
SAINT LOUIS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-03 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10634764
关键词：
3&apos Untranslated Regions Adenine Aerosols Affect Antitubercular Agents Arthritis Bacteria Binding Binding Sites Biological Response Modifiers CXCL1 gene Cells Cessation of life Data Development Disease Drug resistant Mycobacteria Tuberculosis Elements FRAP1 gene Genes Genus Mycobacterium Granulocyte-Macrophage Colony-Stimulating Factor Growth Homeostasis Hyperplasia Immune Evasion Immune response Immunity Immunologic Surveillance Infection Inflammation Inflammatory Response Interleukin-10 Interleukin-2 Knockout Mice Lung Macrophage Mediating Messenger RNA Metabolism Molecular Mus Mycobacterium tuberculosis Myelogenous Natural Immunity Oligonucleotides Pathway interactions Patients Production Proteins RNA RNA-Binding Proteins Regulation Role Signal Pathway Signal Transduction Sirolimus Structure of parenchyma of lung TIS11 protein TNF gene Testing Therapeutic Therapeutic Effect Time Tuberculosis Uridine Virulent Wild Type Mouse Zinc Fingers caseating granulomas chemokine cyclooxygenase 2 cytokine global health in vivo mTOR inhibition member mycobacterial novel novel strategies permissiveness posttranscriptional reactivation from latency systemic inflammatory response targeted treatment transmission process tuberculosis granuloma tuberculosis immunity tuberculosis treatment

项目摘要

Project Summary/Abstract Tuberculosis (TB) remains a leading global health problem with about 9 million new cases and nearly 1.5 million TB-related deaths worldwide each year. Mycobacterium tuberculosis (Mtb) infection persists in macrophages when the host immune response is suppressed or evaded. However, mechanisms of TB immune evasion remain incomplete. Better understanding the mechanisms will facilitate development of host-directed therapy (HDT), especially against deadly drug-resistant Mtb. Our preliminary data indicate that an RNA-binding protein, tristetraprolin (TTP) facilitates evasion and can be a target for host-directed TB therapy. TTP is an RNA -binding protein involved in the regulation of inflammatory responses at the post-transcriptional level. TTP binds to adenine-uridine-rich elements (AREs) within the 3’ untranslated region (3'UTR) causing destabilization of mRNAs encoding several cytokines important for Mtb clearance, and has been shown by us and others to be an important regulator maintaining homeostasis. Whether TTP affects Mtb replication or reactivation, however, remains unknown. We found for the first time a significant TTP induction in lungs of Mtb-infected wild type mice and in macrophages infected with mycobacteria, and deleting TTP resulted in suppression of mycobacterial growth in macrophages. Further, mice deficient in TTP challenged with live Mtb had significantly less bacteria in lungs than infected wild type littermates. TTP mRNA levels were significantly higher in caseous granulomas of TB patients than in normal lung parenchyma. Reactivation and transmission of TB involve developing caseous granulomas that cavitate and release Mtb. In addition, our data show for the first time that inhibition of mTOR signaling by rapamycin almost completely abolishes TTP induction in Mtb-infected macrophages. Based on our findings, we propose a novel role for mTOR/TTP axis in TB immune evasion: Virulent Mtb activates mTOR pathway that induces TTP, resulting in suppression of anti-TB immunity, Mtb replicates and primary and/or latent reactivation diseases. TTP may serve as a target to reverse immune evasion of Mtb. We propose two aims to test this novel hypothesis: Aim 1. Determine the role of TTP in macrophages for mTOR-mediated Mtb growth and the effects of targeting TTP on Mtb growth for potential host-directed therapy. Aim 2. Explore the molecular mechanisms of TTP induction by Mtb in macrophages. Identification of the mechanisms of TTP induction will not only enhance our understanding of Mtb evasion mechanisms, but also provide targets that can be used to develop host-directed therapy breaking TB evasion. Results of these exploratory and mechanistic studies will provide a better understanding of TB immune evasion mechanisms and potentially lead to TTP-targeted therapy, especially with drug-resistant Mtb.

项目概要/摘要结核病 (TB) 仍然是全球主要健康问题，新增病例约 900 万，新增病例近 1.5 全球每年有 100 万人死于结核病。然而，当宿主免疫反应被抑制或逃避时，巨噬细胞的免疫机制。更好地理解这些机制将有助于主机导向的发展。疗法 (HDT)，特别是针对致命的耐药 Mtb。我们的初步数据表明 RNA 结合。 Tristetraprolin (TTP) 是一种 RNA 蛋白，有助于逃避，并且可以成为针对宿主的结核病治疗的靶点。 -结合蛋白参与转录后水平的炎症反应调节。 3'非翻译区 (3'UTR) 内富含腺嘌呤-尿苷的元件 (ARE) 导致不稳定编码几种对 Mtb 清除很重要的细胞因子的 mRNA，我们和其他人已证明它是一种然而，TTP 是否影响 Mtb 复制或重新激活，是维持体内平衡的重要调节因子。我们首次发现 Mtb 感染的野生型小鼠肺部存在显着的 TTP 诱导。在感染分枝杆菌的巨噬细胞中，删除 TTP 会导致分枝杆菌受到抑制此外，用活结核分枝杆菌攻击的缺乏 TTP 的小鼠体内的细菌明显减少。肺干酪样肉芽肿中的 TTP mRNA 水平显着高于感染的野生型同窝小鼠。结核病患者的肺实质比正常肺实质的结核病的再激活和传播涉及干酪样的形成。此外，我们的数据首次表明 mTOR 的抑制作用。根据我们的研究，雷帕霉素信号传导几乎完全消除了 Mtb 感染的巨噬细胞中的 TTP 诱导。根据研究结果，我们提出 mTOR/TTP 轴在结核病免疫逃避中的新作用：强毒 Mtb 激活 mTOR 诱导 TTP 的途径，导致抗结核免疫、结核分枝杆菌复制和原发性和/或潜伏性抑制 TTP 可能作为逆转 Mtb 免疫逃逸的目标。测试这个新假设：目标 1. 确定 TTP 在巨噬细胞中对 mTOR 介导的 Mtb 生长的作用以及靶向 TTP 对 Mtb 生长的影响，以实现潜在的宿主定向治疗。目标 2：探索分子生物学。巨噬细胞中 Mtb 诱导 TTP 的机制无法鉴定 TTP 诱导机制。不仅增强了我们对 Mtb 逃逸机制的理解，而且还提供了可用于这些探索性和机制研究的结果将开发针对宿主的治疗方法，以打破结核病逃避。更好地了解结核病免疫逃避机制，并有可能导致 TTP 靶向治疗，尤其是耐药结核分枝杆菌。