Necrosis in pulmonary TB granulomas: dynamics, mechanisms, therapies

肺结核肉芽肿坏死：动力学、机制、治疗

• 批准号: 9028706
• 负责人: Igor Kramnik
• 金额: $ 70.94万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9028706
• 关键词: Accounting; Address; Aerosols; Alleles; Animal Model; Antibiotics; Antibodies; Antitubercular Agents; Apoptotic; Bacteria; Blood Circulation; Cells; Cessation of life; Characteristics; Congenic Mice; Development; Disease; Drug resistance; Epidemiology; Evolution; Exhibits; Flow Cytometry; Fluorescent Probes; Functional Imaging; Gene Expression Profiling; Genetic; Genotype; Goals; Granuloma; HIV; Health; Human; Hypoxia; IFNAR1 gene; Image; Immunity; Immunocompetent; In Situ; In Vitro; Inbred Strains Mice; Individual; Infection; Infection Control; Inflammation; Injectable; Integration Host Factors; Interferon Type I; Interferons; Interleukin-10; Intervention; Knock-in; Label; Lesion; Lung; Macrophage Activation; Maintenance; Measures; Mediating; Microscopy; Microspheres; Modeling; Morbidity - disease rate; Mouse Strains; Multidrug-Resistant Tuberculosis; Multimodal Imaging; Mus; Mycobacterium tuberculosis; Necrosis; Pathogenesis; Pathology; Pathway interactions; Patients; Phenotype; Physiologic pulse; Population; Predisposition; Pulmonary Pathology; Pulmonary Tuberculosis; Recruitment Activity; Reporter; Series; Shapes; Site; Staging; TBK1 gene; TNF gene; Testing; Therapeutic; Three-dimensional analysis; Tissues; Tuberculosis; Virulent; amlexanox; base; biological adaptation to stress; genetic analysis; imaging biomarker; immunopathology; in vivo; inhibitor/antagonist; insight; lung imaging; macrophage; monocyte; mortality; mouse model; mutant; mycobacterial; novel; pathogen; prevent; prognostic; pulmonary granuloma; receptor; reconstruction; small molecule; small molecule inhibitor; targeted treatment; transmission process; tuberculosis granuloma; tuberculosis immunity; tuberculosis treatment; type I interferon receptor

 DESCRIPTION (provided by applicant): This proposal addresses a fundamental characteristic of tuberculosis pathogenesis - necrotization of tuberculosis lung lesions and provides a mechanistic basis for host-directed therapies that specifically target tissue damage caused by intracellular bacterial pathogens in susceptible individuals. Lung granulomas is a critical site o host interactions with Mycobacterium tuberculosis (M.tb). M.tb is able to establish a niche in host granulomas, where it may either persist or cause destruction, ultimately leading to cavitation of lung lesions and spread to new hosts via aerosol. However, in-depth mechanistic analysis of host factors that shape the lung granulomas has been limited due to a lack of adequate animal models. Little is known about local tissue-specific host factors that drive granuloma dynamics and pathology in the lungs of susceptible, but immunocompetent, hosts. Using forward genetic analysis in mice, we have developed a genetically standardized and well- characterized mouse model of human-like necrotic granulomas. In this model, a single genetic locus, sst1, is responsible for exuberant immunopathology and necrotization of granulomas specifically in the lung, even though known mechanisms of systemic immunity are intact. Upon activation, macrophages of the sst1 susceptible (sst1S) genotype exhibit hyperactivation of type I interferon (IFN-I) pathway leading to enhanced stress response and accelerated death in vitro. We hypothesize that over-activation of the IFN-I network may, as well, account for the necrotization of granulomas in vivo in the lungs of sst1S mice after M.tb infection. To test this hypothesis, we will 1) compare the dynamics of necrotizing (sst1S) and non-necrotizing (sst1R) pulmonary TB granulomas using multi-modal imaging to define stages of TB granuloma evolution and identify prognostic imaging biomarkers of necrotization; 2) characterize recruitment, maturation and death of IFNβ producing cells in pulmonary TB granulomas; 3) evaluate effects of type I interferon (IFN-I) pathway inhibition on progression and maintenance of necrotic lung granulomas using temporal IFN-I receptor blockade with specific antibodies and small molecule inhibitors. Understanding the dynamics and mechanisms of necrotic granuloma formation and maintenance in genetically susceptible hosts, is essential for the development of rational host-directed therapies for TB. We will determine if pharmacological inhibition of specifi IFN-I mediated pathways can be used to prevent or treat necrotic TB granulomas. This would be an attractive therapeutic strategy in TB patients, as these inhibitors would specifically target harmful pathways leading to immunopathology, but would not compromise essential effector mechanisms of anti-mycobacterial immunity.

 描述（应用程序提供）：该提案介绍了结核病发病机理的基本特征 - 结核病肺部病变的坏死化，并为宿主指导的疗法提供了机械基础，该疗法专门针对易感个体中细胞内细菌病原体造成的组织损伤。肺肉芽肿是与结核分枝杆菌（M.TB）的宿主相互作用的关键部位。 M.TB能够在宿主颗粒瘤中建立一个利基市场，在那里它可能会持续或造成破坏，最终导致肺部病变的气腔，并通过气溶胶传播到新宿主。但是，由于缺乏足够的动物模型，对塑造肺肉芽肿的宿主因子的深入机理分析受到限制。对于易感但免疫能力的宿主肺中驱动肉芽肿的动力学和病理学的局部组织特异性宿主因素知之甚少。使用小鼠的正向遗传分析，我们开发了一种遗传标准化和良好的人类样性坏死性肉芽肿的小鼠模型。在该模型中，一个遗传基因座SST1负责特别是肺部肉芽肿的旺盛免疫病理学和坏死，尽管已知的系统性免疫组织化学机制是完整的。激活后，SST1易感（SST1）基因型的巨噬细胞表现出I型干扰素（IFN-I）途径的过度激活，从而导致胁迫反应增强并在体外加速死亡。我们假设IFN-I网络的过度激活也可以解释M.TB感染后SST1S小鼠肺中肉芽肿的坏死。为了检验这一假设，我们将1）比较坏死（SST1S）和非核酸（SST1R）肺结核TB肉芽肿的动力学，以定义TB颗粒瘤进化的阶段，并识别出预认真成像生物标记的坏死性成像; 2）表征肺结核肉芽肿中IFNβ产生细胞的募集，成熟和死亡； 3）评估I型干扰素（IFN-I）途径对使用特定抗体和小分子抑制剂的临时IFN-I受体阻断对坏死肺肉芽肿的进展和维持的影响。了解一般易感宿主中坏死性肉芽肿的形成和维持的动态和机制对于开发结核病理性宿主指导的疗法至关重要。我们将确定是否可以使用对特定IFN-I介导的途径的药理抑制来预防或治疗坏死TB肉芽肿。在结核病患者中，这将是一种有吸引力的治疗策略，因为这些抑制剂会特别针对 导致免疫病理学的有害途径，但不会损害抗细菌免疫的基本效应机制。