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

• 批准号: 10057563
• 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: 2020
• 资助国家: 美国
• 起止时间: 2020-09-08 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10057563
• 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

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.

项目摘要 结核病（TB）仍然是全球领先的健康问题，大约有900万例新结核病病例和 全世界在全球近130万次与结核病有关的死亡。耐药性分枝杆菌结核病（MTB） 对于当前的抗MTB疗法，TB成为更加困难的挑战。 MTB感染的持久性 巨噬细胞是通过抑制宿主免疫回报介导的。免疫调查的机制 然而，MTB的抑制仍然知之甚少。我们的初步数据表示新的RNA结合 蛋白质，单核细胞趋化蛋白诱导的蛋白1（MCPIP1）是MTB免疫进化的蛋白质。 MCPIP1在巨噬细胞中迅速诱导，响应于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 炎症反应。 MCPIP1抑制几种促炎细胞因子（包括IL-1，IL-6和IL-12）， 并且还像是用于T细胞激活的制动器。到目前为止，MCPIP1已被我们和其他人证明 负调节器控制炎症和维持稳态。但是，它仍然很大 未知MCPIP1是影响MTB复制还是涉及控制结核病激活。我们最近有 发现通过气溶胶路线感染了MTB的MCPIP1敲除小鼠的大幅降低 与野生型小鼠相比，细菌灼伤，以及MCPIP1在肺中的表达增加 WT小鼠。有趣的是，在活性结核的有斑性肉芽肿中，MCPIP1 mRNA水平明显更高 患者比正常肺实质。此外，MCPIP1 mRNA水平也显着增加 具有活性和反应性结核的恒河猕猴的肺以及潜在的结核病。基于我们的发现 我们提出，有毒的分枝杆菌结核病逃避了诱导的MCPIP1的宿主免疫攻击， 抑制抗TB免疫反应。在此应用中，我们建议（1）了解 MTB诱导MCPIP1以及随后对MTB感染的影响； （2）定义巨噬细胞的体内作用 衍生的MCPIP1在防止最佳控制分枝杆菌生长以及宿主的翻译潜力 - 定向治疗。这项研究的结果将使我们更好地了解结核病免疫进化和 MCPIP1靶向治疗在MTB感染中的治疗潜力，尤其是这些患者 感染分枝杆菌的MDR污渍。