A new target for host-directed therapy against TB infection

针对结核感染的宿主定向治疗的新靶点

基本信息

批准号：
10256733
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
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-08 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10256733
关键词：
Aerosols Affect Animals Antisense Oligonucleotides Antitubercular Agents Autoimmune Diseases Bacteria Binding Binding Sites CCL2 gene CD4 Positive T Lymphocytes Cessation of life Complex Data Development Disease Drug resistance in tuberculosis Gene Expression Genus Mycobacterium Granuloma Growth High-Throughput Nucleotide Sequencing Homeostasis Human Immune Immune Evasion Immune response Immunoprecipitation Immunosuppression Immunotherapeutic agent Immunotherapy Inflammation Inflammatory Inflammatory Response Interleukin-1 Interleukin-1 beta Interleukin-12 Interleukin-6 Knockout Mice Lead Lung Macaca Macaca mulatta Mediating Messenger RNA Molecular Monocyte Chemoattractant Proteins Mus Mycobacterium tuberculosis Pathway Analysis Pathway interactions Patients Phenotype Property Proteins RNA-Binding Proteins Role Route Spleen Stains Stimulus Structure of parenchyma of lung T-Cell Activation T-Lymphocyte TNF gene Testing Therapeutic Time Tuberculosis Virulent Wild Type Mouse base conditional knockout crosslink cytokine global health immunopathology in vivo mRNA Transcript Degradation macrophage monocyte mycobacterial novel peripheral blood prevent reactivation from latency response targeted treatment transcriptome sequencing transmission process tuberculosis granuloma tuberculosis immunity tuberculosis treatment

项目摘要

PROJECT SUMMARY Tuberculosis (TB) remains a leading global health problem with about 9 million new tuberculosis cases and nearly 1.3 million TB-related deaths worldwide each year. Drug-resistant Mycobacterium tuberculosis (Mtb) makes TB an even more difficult challenge for current anti-Mtb therapy. Persistence of Mtb infection in macrophages is mediated by suppression of host immune responses. The mechanisms of immune suppression by Mtb, however, are still poorly understood. Our preliminary data indicate a new RNA-binding protein, monocyte chemotactic protein-induce protein 1 (MCPIP1) is such a protein for immune evasion of Mtb. MCPIP1 is rapidly induced in macrophages in response to inflammatory stimuli such as TNF, IL-1β and LPS. MCPIP1-deficient mice develop complex phenotypes, including autoimmune disorders and severe inflammatory responses. MCPIP1 inhibits several proinflammatory cytokines (including IL-1, IL-6 and IL-12), and also acts like a brake for T cell activation. So far, MCPIP1 has been shown by us and others to be a negative regulator in controlling inflammation and maintaining homeostasis. However, it remains largely unknown whether MCPIP1 affects Mtb replication or involves in control of TB activation. We have recently found that MCPIP1 knockout mice infected with Mtb via the aerosol route have a significant reduction of bacterial burden compared with wild type mice, along with an increase in MCPIP1 expression in lungs of the WT mice. Interestingly, MCPIP1 mRNA levels are significantly higher in caseous granulomas of active TB patients than normal lung parenchyma. Moreover, MCPIP1 mRNA levels are also significantly increased in lungs of rhesus macaques with active and reactive TB as well as those with latent TB. Based on our discovery, we propose that virulent Mycobacterium tuberculosis evades host immune attack by inducing MCPIP1 which suppresses anti-TB immune responses. In this application, we propose to (1) understand the mechanisms of MCPIP1 induction by Mtb and subsequent effects on Mtb infection; (2) define in vivo role of macrophage- derived MCPIP1 in preventing optimal control of mycobacterial growth and the translational potential for host- directed therapy. Results of this study will provide us a better understanding of TB immune evasion and therapeutic potential of MCPIP1-targeted therapy in treatment of Mtb infection, especially those patients infected with MDR stains of mycobacteria.

项目概要结核病 (TB) 仍然是全球主要健康问题，新增结核病例约 900 万例，全球每年有近 130 万人因耐药结核杆菌 (Mtb) 死亡。结核分枝杆菌感染的持续存在使得结核病成为当前抗结核分枝杆菌治疗面临的更加困难的挑战。巨噬细胞通过抑制宿主免疫反应介导免疫机制。然而，我们对 Mtb 的抑制作用仍知之甚少。我们的初步数据表明存在一种新的 RNA 结合。单核细胞趋化蛋白诱导蛋白1（MCPIP1）就是这样一种用于结核分枝杆菌免疫逃避的蛋白。 MCPIP1 在巨噬细胞中快速诱导，以响应 TNF、IL-1β 和 LPS 等炎症刺激。 MCPIP1 缺陷小鼠会出现复杂的表型，包括自身免疫性疾病和严重的 MCPIP1 抑制多种促炎细胞因子（包括 IL-1、IL-6 和 IL-12），到目前为止，MCPIP1 已被我们和其他人证明是一种 T 细胞激活的制动器。然而，它在很大程度上仍然是控制炎症和维持体内平衡的负调节因子。未知 MCPIP1 是否影响 Mtb 复制或参与 TB 激活的控制。发现通过气溶胶途径感染 Mtb 的 MCPIP1 敲除小鼠显着减少与野生型小鼠相比，细菌负荷增加，并且肺部 MCPIP1 表达增加 WT 小鼠提示，MCPIP1 mRNA 水平在活动性结核病的干酪肉芽肿中显着较高。患者肺实质中的MCPIP1 mRNA水平也显着升高。根据我们的发现，患有活动性和反应性结核病以及潜伏性结核病的恒河猴的肺部。我们提出，有毒力的结核分枝杆菌通过诱导 MCPIP1 来逃避宿主免疫攻击，抑制抗结核免疫反应在本申请中，我们建议（1）了解其机制。 Mtb 诱导 MCPIP1 及其对 Mtb 感染的后续影响；(2) 定义巨噬细胞的体内作用；衍生的 MCPIP1 在分枝杆菌生长的最佳控制和宿主的转化潜力中这项研究的结果将使我们更好地了解结核病的免疫逃避和治疗。 MCPIP1 靶向治疗治疗 Mtb 感染的治疗潜力，特别是那些患者感染了分枝杆菌的 MDR 染色。