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: 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
• 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' 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

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）仍然是全球领先的健康问题，大约900万例新病例，几乎1.5 每年在全球范围内与TB相关的数百万次死亡。结核分枝杆菌（MTB）感染持续存在 当宿主免疫响应被抑制或逃避时，巨噬细胞。但是，结核病的机制 逃避仍然不完整。更好地理解机制将有助于开发主机定向 治疗（HDT），特别是针对致命的耐药MTB。我们的初步数据表明RNA结合 蛋白质，三二烷酸蛋白（TTP）有助于进化，可以成为宿主定向的结核病治疗的靶标。 TTP是RNA - 结合蛋白在转录后水平调节炎症反应。 TTP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 编码几种细胞因子对MTB清除重要的mRNA，并已显示出我们和其他人是一个 维持体内平衡的重要调节器。 TTP是影响MTB复制还是重新激活的MTB 仍然未知。我们首次发现MTB感染的野生型小鼠的肺中有明显的TTP诱导 在感染分枝杆菌的巨噬细胞中，删除TTP导致分生不清 巨噬细胞的生长。此外，缺乏现场MTB挑战的TTP的小鼠的细菌明显降低 肺部比感染的野生窝仔。在有斑的肉芽肿的情况下，TTP mRNA水平明显更高 结核病患者比正常肺实质中的患者。结核病的重新激活和传播涉及发展 肉芽瘤，可捕获并释放MTB。此外，我们的数据首次显示了MTOR的抑制 雷帕霉素的信号几乎完全消除了MTB感染的巨噬细胞中的TTP诱导。基于我们 调查结果，我们提出了MTOR/TTP轴在TB免疫进化中的新作用：有毒MTB激活MTOR 影响TTP的途径，导致抗TB免疫，MTB重复和初级和/或潜在 重新激活疾病。 TTP可以作为逆转MTB免疫进化的靶标。我们提出了两个目标 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 以及靶向TTP对MTB生长对潜在宿主定向治疗的影响。目标2。探索分子 MTB在巨噬细胞中诱导TTP的机制。识别TTP诱导机制不会 仅增强我们对MTB进化机制的理解，但也提供了可以用来用于的目标 开发宿主定向的治疗破坏结核病的演变。这些探索性和机械研究的结果将 更好地了解TB免疫进化机制，并有可能导致靶向TTP的治疗， 特别是使用耐药的MTB。