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

• 批准号: 10511464
• 负责人: Jianguo Liu
• 金额: $ 18.94万
• 依托单位: SAINT LOUIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-03 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10511464
• 关键词: 3' 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; Genetic Transcription; 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; Lead; Lung; Mediating; Messenger RNA; Metabolism; Molecular; Mus; Mycobacterium tuberculosis; Myelogenous; Natural Immunity; Oligonucleotides; Pathway interactions; Patients; 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; base; caseating granulomas; chemokine; cyclooxygenase 2; cytokine; global health; in vivo; mTOR inhibition; macrophage; member; mycobacterial; novel; novel strategies; reactivation from latency; systemic inflammatory response; targeted treatment; transmission process; tuberculosis granuloma; tuberculosis immunity; tuberculosis treatment

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.

项目摘要/摘要 结核病（TB）仍然是全球健康问题，有900万个新的Casses和接近1.5 每年与结核病相关的数百万死亡。 巨噬细胞抑制或逃避宿主的免疫反应。 逃避仍然不完整。 治疗（HDT），尤其是对致命的耐药性MTB的疗法。 蛋白质，Tristetraprolin（TTP）有助于逃避，可以成为宿主定向的TB治疗的靶标。 - 结合蛋白在转录后炎症反应的调节结合 到3'未翻译区域内（3'UTR）内的腺嘌呤 - 尿素富含元素（ARE），导致对 编码严重性细胞因子对MTB清除重要的mRNA，我们和其他人已证明 维持稳态的重要调节器。 仍然未知。 在感染分枝杆菌的巨噬细胞中，删除TTP导致分枝杆菌抑制 巨噬细胞的生长。 肺部的肺部静脉m mRNA水平明显更高 结核病患者比正常肺实质中的患者。 颗粒，并释放MTB 雷帕霉素的信号几乎完全消除了基于我们的MTB感染巨噬细胞中的TTP指示 调查结果，我们提出了MTOR/TTP轴在TB免疫evision中的新作用：病毒MTB激活MTOR 诱导TTP的途径，抑制抗TB免疫，MTB重复和主要和 /或潜在的途径 重新激活疾病。 测试这个新的假设：目标1。确定TTP在MTOR介导的MTB生长中的作用 靶向TTP对潜在宿主定向治疗的影响。 MTB在巨噬细胞中的TTP机制。 仅增强我们对MTB逃避机制的理解，但也提供了可以用来用于的目标 开发宿主定向的疗法破坏结核病的ev性。 更好地了解TB免疫逃避机制，并可能导致靶向TTP的治疗， 特别是使用耐药的MTB。