Necrosis in Pulmonary TB granulomas: dynamics, mechanisms, and therapies

肺结核肉芽肿坏死：动力学、机制和治疗

• 批准号: 10584526
• 负责人: Igor Kramnik
• 金额: $ 69.51万
• 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 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10584526
• 关键词: Aerosols; Antibiotics; Antioxidants; Automobile Driving; Cause of Death; Cells; Cessation of life; Data; Dissection; Drug resistance; Drug resistance in tuberculosis; Evolution; Ferritin; Genetic; Genetic Transcription; Goals; Granuloma; Human; Hydrolysis; Hyperactivity; Immune; Immune response; Immunity; Immunocompetent; Immunologics; Impairment; In Vitro; Inbred Mouse; Individual; Inflammatory; Interferon Type I; Intervention; Iron; Knowledge; Laboratories; Lead; Lesion; Link; Lipid Peroxidation; Lung; Macrophage; Mediating; Minor; Mus; Mycobacterium tuberculosis; NADP; Necrosis; Necrosis Induction; Outcome; Pathogenesis; Pathway interactions; Pattern; Population; Predisposition; Production; Pulmonary Tuberculosis; Reporter; Resistance; Role; Sterilization; Susceptibility Gene; TNF gene; Testing; Therapeutic; Tissues; Toxin; Tuberculosis; Virulence; Virulent; Visualization; genomic locus; human model; improved; improved outcome; in vivo; mouse genetics; mouse model; mutant; non-necrotizing granulomas; oxidative damage; pathogen; prevent; proteostasis; resilience; response; stress resilience; success; synergism; transmission process; tuberculosis chemotherapy; tuberculosis granuloma

PROJECT SUMMARY/ABSTRACT Most humans are resistant to Mycobacterium tuberculosis (Mtb) and form granulomas that limit inflammatory tissue damage. Nevertheless, tuberculosis (TB) remains a leading infectious cause of death globally because a fraction of infected individuals develops massive necrotic granulomas and transmit Mtb via aerosols. This outcome of Mtb infection is relatively uncommon among immunocompetent humans, and its mechanisms are poorly characterized. We will study both host vulnerability (predisposition to necrotization of TB granulomas) and Mtb virulence determinants (the necrosis-inducing factor) to determine how their interactions lead to necrosis in susceptible but otherwise immunocompetent hosts. We will address this major knowledge gap using a well-characterized mouse model developed in our laboratory that recapitulates the formation of organized human-like necrotic pulmonary TB granulomas (mice with the susceptibility allele of the sst1(super-susceptibility to tuberculosis, sst1) locus) Our recent studies reveal that inadequate antioxidant defense (AOD) drives an aberrant response of the sst1 mutant macrophages to TNF and induce hyperactivity of type I interferon pathway (IFN-I). This mouse model also provides a unique opportunity to study the role of a recently discovered Tuberculosis Necrotizing Toxin (TNT). The major premise of this application is that impaired stress resilience of macrophages due to inadequate antioxidant defense (AOD) is exploited by Mtb to subvert local immunity within pulmonary TB granulomas of immunocompetent hosts and induce necrosis. We will investigate: (i) Crosstalk of Myc and IFN-I pathways in the deregulation of antioxidant response in activated macrophages. (ii) Host regulators of the anti-oxidant response and necrosis in vivo. This aim will address our hypothesis about the hierarchy of the antioxidant defense and IFN-I pathways in vivo and test whether boosting the antioxidant defense prevents the granuloma necrotization and reduce the IFN-I hyperactivity. (iii) Role of the Mtb Tuberculosis Necrotizing Toxin (TNT) in driving necrosis in TB granulomas of the susceptible but immunocompetent hosts. The ultimate goal of our studies is to develop mechanistic interventions to target necrosis in TB granulomas in order to overcome a major obstacle to the sterilization of TB lesions with antibiotics. This will improve the outcomes of TB chemotherapy and prevent the evolution and spread of drug resistant TB.

项目摘要/摘要 大多数人对结核分枝杆菌（MTB）具有抗药性，并形成肉芽肿，以限制炎症 组织损伤。然而，结核病（TB）仍然是全球主要的感染性死亡原因，因为 受感染个体的部分会形成大量坏死肉芽肿，并通过气溶胶传输MTB。这 在免疫能力的人类中，MTB感染的结果相对罕见，其机制是 特征不佳。我们将研究既有宿主的脆弱性（易于结核病的坏死）和 MTB毒力决定因素（坏死因子），以确定其相互作用如何导致坏死 易感性但其他免疫能力的宿主。 我们将使用在实验室中开发的良好特征的鼠标模型来解决这一主要知识差距 这概括了有组织的人类坏死性肺结核肉芽肿的形成（小鼠 我们最近的研究表明，SST1的敏感性等位基因（对结核病的超易感性，SST1）座位表明 抗氧化防御不足（AOD）驱动SST1突变巨噬细胞对TNF的异常反应 诱导I型干扰素途径（IFN-I）的多动症。该鼠标模型还提供了独特的机会 研究最近发现的结核病坏死毒素（TNT）的作用。 该应用的主要前提是，由于不足而导致的巨噬细胞的压力弹性受损 MTB利用抗氧化剂防御（AOD）来颠覆肺结核内局部免疫力 免疫能力宿主并诱导坏死。我们将调查：（i）MYC和IFN-I途径的串扰 激活巨噬细胞中抗氧化反应的管制。 （ii）抗氧化剂反应的宿主调节剂 和坏死在体内。这个目的将解决我们关于抗氧化防御等层次结构的假设 体内IFN-I途径并测试是否促进抗氧化剂防御可防止颗粒状颗粒坏死 并减少IFN-I多动症。 （iii）MTB结核病坏死性毒素（TNT）在驱动坏死中的作用 在易感但免疫能力的宿主的结核病肉芽肿中。 我们研究的最终目的是制定机械干预措施，以靶向结核病肉芽肿的坏死 为了克服用抗生素灭菌的主要障碍。这将改善 结核病化疗的结果并防止耐药性结核病的进化和扩散。