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

项目总结/摘要 大多数人对结核分枝杆菌（Mtb）具有耐药性，并形成肉芽肿， 组织损伤尽管如此，结核病仍然是全球主要的传染性死因， 一部分感染个体发展成巨大的坏死性肉芽肿并通过气溶胶传播Mtb。这 结核分枝杆菌感染的结果在免疫功能正常的人中相对少见，其机制是 特征不佳。我们将研究宿主的脆弱性（结核肉芽肿坏死的倾向）， 结核分枝杆菌毒力决定因子（坏死诱导因子），以确定它们之间的相互作用如何导致 易感染但具有免疫活性的宿主。 我们将使用我们实验室开发的具有良好特征的小鼠模型来解决这一主要的知识差距 它重现了有组织的类人坏死性肺结核肉芽肿的形成（小鼠， sst 1（对结核病的超易感性，sst 1）基因座的易感性等位基因）我们最近的研究表明， 不充分的抗氧化防御（AOD）驱动sst 1突变巨噬细胞对TNF的异常反应， 诱导I型干扰素途径（IFN-I）过度活性。这种小鼠模型也提供了一个独特的机会， 研究最近发现的结核坏死毒素（TNT）的作用。 本申请的主要前提是，由于不充分的细胞毒性，巨噬细胞的应激恢复能力受损。 抗氧化防御（AOD）被Mtb利用来破坏肺结核肉芽肿内的局部免疫， 免疫活性宿主并诱导坏死。我们将研究：（i）Myc和IFN-I通路在细胞内的串扰。 激活的巨噬细胞抗氧化反应失调。(ii)抗氧化反应的宿主调节因子 和坏死。这一目标将解决我们关于抗氧化防御层次的假设， 体内IFN-1通路，并测试增强抗氧化防御是否能防止肉芽肿坏死 并减少IFN-1的过度活跃。(iii)结核分枝杆菌坏死毒素（TNT）在驱动坏死中的作用 在易感但免疫活性宿主的结核肉芽肿中。 我们研究的最终目标是开发针对结核肉芽肿坏死的机械干预措施， 以克服用抗生素对结核病病灶进行消毒的主要障碍。这将改善 结核病化疗的结果，并防止耐药结核病的演变和传播。

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.