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:
- 金额:$ 18.94万
- 依托单位:
- 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:
- 关键词:AerosolsAffectAnimalsAntisense OligonucleotidesAntitubercular AgentsAutoimmune DiseasesBacteriaBindingBinding SitesCCL2 geneCD4 Positive T LymphocytesCessation of lifeComplexDataDevelopmentDiseaseDrug resistance in tuberculosisGene ExpressionGenus MycobacteriumGranulomaGrowthHigh-Throughput Nucleotide SequencingHomeostasisHumanImmuneImmune EvasionImmune responseImmunoprecipitationImmunosuppressionImmunotherapeutic agentImmunotherapyInflammationInflammatoryInflammatory ResponseInterleukin-1Interleukin-1 betaInterleukin-12Interleukin-6Knockout MiceLeadLungMacacaMacaca mulattaMediatingMessenger RNAMolecularMonocyte Chemoattractant ProteinsMusMycobacterium tuberculosisPathway AnalysisPathway interactionsPatientsPhenotypePropertyProteinsRNA-Binding ProteinsRoleRouteSpleenStainsStimulusStructure of parenchyma of lungT-Cell ActivationT-LymphocyteTNF geneTestingTherapeuticTimeTuberculosisVirulentWild Type Mousebaseconditional knockoutcrosslinkcytokineglobal healthimmunopathologyin vivomRNA Transcript Degradationmacrophagemonocytemycobacterialnovelperipheral bloodpreventreactivation from latencyresponsetargeted treatmenttranscriptome sequencingtransmission processtuberculosis granulomatuberculosis immunitytuberculosis 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)仍然是一个主要的全球健康问题,约有900万新的结核病病例,
全世界每年有近130万人死于结核病。耐药结核分枝杆菌(Mtb)
使得TB成为当前抗Mtb疗法的更加困难的挑战。Mtb感染的持续性
巨噬细胞通过抑制宿主免疫应答来介导。免疫机制
然而,对Mtb抑制作用仍然知之甚少。我们的初步数据表明,
单核细胞趋化蛋白诱导蛋白1(Monocyte chemotactic protein-induced protein 1,MCPIP 1)是一种用于Mtb免疫逃避的蛋白。
MCPIP 1在巨噬细胞中响应于炎性刺激物如TNF、IL-1β和LPS而被快速诱导。
MCPIP 1缺陷小鼠产生复杂的表型,包括自身免疫性疾病和严重的
炎症反应。MCPIP 1抑制几种促炎细胞因子(包括IL-1、IL-6和IL-12),
同时也是T细胞激活的制动器到目前为止,我们和其他人已经证明MCPIP 1是一种
在控制炎症和维持体内平衡中起负调节作用。但在很大程度上,
未知MCPIP 1是否影响结核分枝杆菌复制或参与控制结核激活。我们最近
发现通过气溶胶途径感染Mtb的MCPIP 1基因敲除小鼠,
细菌负荷与野生型小鼠相比,沿着MCPIP 1表达的增加,
WT小鼠。有趣的是,在活动性结核的干酪样肉芽肿中,MCPIP 1 mRNA水平显著较高,
患者肺实质较正常肺实质明显增厚。此外,MCPIP 1 mRNA水平也显著增加,
患有活动性和反应性TB以及潜伏性TB的恒河猴的肺。基于我们的发现,
我们提出,强毒结核分枝杆菌通过诱导MCPIP 1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)理解
Mtb对MCPIP 1的诱导作用及其对Mtb感染的后续影响;(2)确定巨噬细胞-巨噬细胞的体内作用。
衍生的MCPIP 1在阻止分枝杆菌生长的最佳控制和宿主的翻译潜力方面的作用。
定向治疗这项研究的结果将使我们更好地了解结核病的免疫逃避,
MCPIP 1靶向疗法在治疗Mtb感染中的治疗潜力,特别是那些
感染了耐多药分枝杆菌
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Jianguo Liu其他文献
Jianguo Liu的其他文献
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{{ truncateString('Jianguo Liu', 18)}}的其他基金
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 - 财政年份:2022
- 资助金额:
$ 18.94万 - 项目类别:
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 - 财政年份:2022
- 资助金额:
$ 18.94万 - 项目类别:
Pre-clinical testing the effects of MALT1 inhibitor on endocrine resistant breast cancer
MALT1抑制剂对内分泌耐药乳腺癌的临床前测试
- 批准号:
10579334 - 财政年份:2022
- 资助金额:
$ 18.94万 - 项目类别:
Pre-clinical testing the effects of MALT1 inhibitor on endocrine resistant breast cancer
MALT1抑制剂对内分泌耐药乳腺癌的临床前测试
- 批准号:
10435975 - 财政年份:2022
- 资助金额:
$ 18.94万 - 项目类别:
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 - 财政年份:2020
- 资助金额:
$ 18.94万 - 项目类别:
Mechanisms of IL28B genetic variation-mediated clearance of hepatitis C virus
IL28B基因变异介导的丙型肝炎病毒清除机制
- 批准号:
8445769 - 财政年份:2013
- 资助金额:
$ 18.94万 - 项目类别:
Mechanisms of IL28B genetic variation-mediated clearance of hepatitis C virus
IL28B基因变异介导的丙型肝炎病毒清除机制
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8732600 - 财政年份:2013
- 资助金额:
$ 18.94万 - 项目类别:
The role of tristetraprolin in control of breast cancer progression
三四脯氨酸在控制乳腺癌进展中的作用
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9079413 - 财政年份:2012
- 资助金额:
$ 18.94万 - 项目类别:
The role of tristetraprolin in control of breast cancer progression
三四脯氨酸在控制乳腺癌进展中的作用
- 批准号:
8221172 - 财政年份:2012
- 资助金额:
$ 18.94万 - 项目类别:
The role of tristetraprolin in control of breast cancer progression
三四脯氨酸在控制乳腺癌进展中的作用
- 批准号:
8860146 - 财政年份:2012
- 资助金额:
$ 18.94万 - 项目类别:
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