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.

项目摘要结核病（TB）仍然是领导全球健康问题，有900万个新的结核病卡斯和每年有130万个与TB相关的死亡。使TB成为当前抗MTB治疗的挑战。巨噬细胞通过抑制宿主免疫反应介导。然而，MTB的支持仍然是Lee仍然理解的。蛋白质，单核细胞趋化蛋白 - 诱导蛋白1（MCPIP1）是MTB的Imune ecision蛋白。 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缺陷小鼠会形成复杂的表型，含有自身免疫性疾病和严重炎症反应。到目前为止负调节器控制炎症和维持稳态。未知MCPIP1是否会影响MTB复制或涉及我们最近的TB激活发现通过Aerouol路线感染了MTB的MCPIP1敲除小鼠的大幅降低与类型小鼠相比，细菌负担，以及肺中MCPIP1表达的增加 WT小鼠。与正常肺实质相比，MCPIP1 mRNA水平也显着增加具有活性和反应性结核的恒河猕猴以及基于我们发现的潜伏的肺部。我们建议通过诱导MCPIP1来逃避宿主的免疫攻击，这是诱发性分枝杆菌抑制抗TB免疫反应。 MTB的MCPIP1指示以及随后对MTB感染的影响；派生的MCPIP1在防止最佳控制分枝杆菌生长以及宿主的翻译潜力 - 最受欢迎的董事疗法对TB免疫逃避和 MCPIP1促进治疗MTB感染的治疗潜力，尤其是那些患者感染了分枝杆菌的MDR阶段。