Understanding the functional role of Myeloid Derived Suppressor cells in tuberculosis

了解骨髓源性抑制细胞在结核病中的功能作用

• 批准号: 10757101
• 负责人: Deepak Kaushal
• 金额: $ 89.79万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-06 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10757101
• 关键词: Advanced Development; Animal Model; Automobile Driving; B-Lymphocytes; BCG Live; Bronchus-Associated Lymphoid Tissue; Cessation of life; Characteristics; Chronic; Clinical; Data; Disease; Drug resistant Mycobacteria Tuberculosis; Genes; Granuloma; Human; Hypoxia Inducible Factor; IL17 gene; Immunity; Immunologics; Infection Control; Infiltration; Inflammatory; Knowledge; Lung; Macaca; Mediating; Modeling; Molecular; Mus; Mycobacterium bovis; Mycobacterium tuberculosis; Myeloid Cells; Myeloid-derived suppressor cells; Pathology; Pathway interactions; Pharmaceutical Preparations; Population; Predisposition; Production; Proteins; Publishing; Pulmonary Tuberculosis; Relapse; Role; S100A8 gene; Signal Pathway; Signal Transduction; T cell response; T-Lymphocyte; Therapeutic; Translations; Tretinoin; Tuberculosis; Vaccines; cell type; comparison control; cytokine; extensive drug resistance; improved; in vivo; inhibitor; mouse model; neutrophil; nonhuman primate; novel therapeutics; prevent; transcription factor; translational study; tuberculosis treatment

PROJECT SUMMARY. Mycobacterium tuberculosis (Mtb), the causative agent of the disease tuberculosis (TB), is estimated to infect one-fourth of the world's population, resulting in approximately 1.6 million deaths each year. The emergence of multidrug- and extensively drug-resistant Mtb strains and the variable efficacy of the currently used vaccine, M. bovis Bacille Calmette Guerin (BCG), are barriers to the global control of TB. Thus, there is a critical need to better understand the mechanisms of TB immunopathogenesis, as such mechanisms can be targeted to improve host control of Mtb infection. The tubercle granuloma is long been considered a hallmark of TB. Our published data suggest that the presence of inducible bronchus-associated lymphoid tissue (iBALT)-containing granulomas is indicative of protective granulomas that mediate Mtb control during TB latency. In contrast, infiltrating myeloid derived suppressor cells (MDSCs) as well as neutrophils producing proinflammatory molecules are characteristic of non-protective granulomas during pulmonary TB. MDSCs are induced during pulmonary TB in humans, nonhuman primates (NHPs) and mice and suppress protective T cell responses. Our new data show a protective role for the proinflammatory cytokine, Interleukin (IL)-17 in dampening lung MDSC accumulation and limiting T cell suppression in the lung during TB. Additionally, we show that the MDSC-derived proinflammatory proteins, S100A8/A9 heterodimers are induced upon Mtb infection in humans, NHPs and mice. Furthermore, S100A8/A9-expressing myeloid cells accumulate within the tubercle granuloma and amplify lung MDSC accumulation to mediate Mtb susceptibility. In the current proposal, using mouse and NHP models of TB, we will elucidate the mechanism(s) which regulate and promote MDSC accumulation during TB, and characterize whether MDSCs and their pathways can be targeted as host-directed therapeutics (HDTs) for TB. In Specific Aim 1, using gene deficient and conditional gene deficient mouse models we will determine the IL-17-dependent pathways that limit MDSC accumulation during TB. In Specific Aim 2, we will evaluate the role of S100A8/A9 proteins in driving MDSC accumulation and susceptibility to TB, and also determine whether blocking S100A8/A9 signaling will limit TB relapse. Finally, in Specific Aim 3 we will evaluate if MDSC depletion can prevent TB progression in nonhuman primates (NHPs). At the completion of the aims proposed here, we will have considerably expanded our understanding of the Mtb-specific signaling pathways and factors that positively (S100A8/A9 pathways) and negatively (IL-17 dependent pathways) regulate MDSC accumulation during TB. Additionally, our translational studies in NHPs will enable the use of HDTs to limit MDSCs during TB.

项目摘要。结核分枝杆菌（MTB），该疾病的致病药物 结核病（TB）估计会感染世界四分之一的人口，大约导致 每年160万人死亡。多药和广泛耐药的MTB菌株的出现 以及当前使用的疫苗的可变功效，牛乳杆菌Calmette Guerin（BCG）是 全球控制结核病的障碍。因此，迫切需要更好地理解机制 TB免疫致病发生，因为可以针对改善MTB的宿主控制的机制 感染。结节肉芽肿长期以来一直被认为是结核病的标志。我们已发布的数据 表明存在诱导支气管相关淋巴组织（IBALT）的存在 颗粒瘤表示在结核病潜伏期中介导MTB控制的保护性肉芽肿。在 对比，渗透髓样衍生的抑制细胞（MDSC）以及产生的中性粒细胞 促炎分子是肺结核期间非保护肉芽肿的特征。 MDSC在人类，非人类灵长类动物（NHP）和小鼠的肺结核期间诱导 抑制保护性T细胞反应。我们的新数据显示了促炎的保护作用 细胞因子，白介素（IL）-17在抑制肺MDSC积累和限制T细胞抑制中 在结核病期间的肺中。此外，我们表明了MDSC衍生的促炎蛋白， S100A8/A9异二聚体是在人类，NHP和小鼠的MTB感染后诱导的。此外， S100A8/表达表达髓样细胞在结核肉芽肿内积聚并扩增肺 MDSC积累以介导MTB敏感性。在当前建议中，使用鼠标和NHP TB的模型，我们将阐明调节和促进MDSC积累的机制 在结核病期间，并表征MDSC及其途径是否可以作为主机定向 TB的治疗剂（HDTS）。在特定的目标1中，使用缺乏和条件基因缺乏的基因 鼠标模型我们将确定IL-17依赖性途径，该途径限制MDSC在 TB。在特定目标2中，我们将评估S100A8/A9蛋白在驱动MDSC积累中的作用 以及对结核病的敏感性，还确定阻断S100A8/A9信号是否会限制TB 复发。最后，在特定目标3中，我们将评估MDSC耗竭是否可以防止TB进展 非人类灵长类动物（NHP）。在此处提出的目标完成时，我们将有相当多的 扩展了我们对MTB特异性信号通路和积极的因素的理解 （S100A8/A9途径）和负（IL-17依赖途径）调节MDSC的积累 在结核病期间。此外，我们在NHP中的翻译研究将使使用HDT限制MDSC 在结核病期间。