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: 10211126
• 负责人: Deepak Kaushal
• 金额: $ 72.03万
• 依托单位: WASHINGTON UNIVERSITY
• 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/10211126
• 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 resistance in tuberculosis; Genes; Granuloma; Human; Hypoxia Inducible Factor; Immunity; Immunologics; Infection Control; Interleukin-17; Knowledge; Lung; Macaca; Mediating; Modeling; Molecular; Mus; Mycobacterium bovis; Mycobacterium tuberculosis; Myeloid Cells; Myeloid-derived suppressor cells; Pathway interactions; 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; cytokine; extensive drug resistance; improved; in vivo; inhibitor/antagonist; 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)，该疾病的病原体 据估计，结核病 (TB) 感染了世界四分之一的人口，导致大约 每年有 160 万人死亡。多重耐药和广泛耐药 Mtb 菌株的出现 目前使用的疫苗卡介苗 (BCG) 的不同功效是 全球结核病控制的障碍。因此，迫切需要更好地理解其机制 结核病免疫发病机制，因为此类机制可用于改善宿主对结核分枝杆菌的控制 感染。结节肉芽肿长期以来被认为是结核病的标志。我们公布的数据 表明存在含有诱导支气管相关淋巴组织（iBALT）的 肉芽肿是结核潜伏期介导结核分枝杆菌控制的保护性肉芽肿的表现。在 相比之下，浸润性骨髓源性抑制细胞（MDSC）以及中性粒细胞产生 促炎分子是肺结核期间非保护性肉芽肿的特征。 MDSC 在人类、非人灵长类动物 (NHP) 和小鼠的肺结核过程中被诱导产生 抑制保护性 T 细胞反应。我们的新数据显示促炎细胞的保护作用 细胞因子、白细胞介素 (IL)-17 抑制肺 MDSC 积聚并限制 T 细胞抑制 结核病期间在肺部。此外，我们还发现 MDSC 衍生的促炎蛋白， S100A8/A9 异二聚体在人类、NHP 和小鼠中 Mtb 感染后诱导产生。此外， 表达 S100A8/A9 的骨髓细胞在结节肉芽肿内积聚并扩增肺 MDSC 积累调节 Mtb 易感性。在当前的提案中，使用鼠标和 NHP 结核病模型，我们将阐明调节和促进 MDSC 积累的机制 结核病期间，并表征 MDSC 及其途径是否可以作为宿主导向的目标 结核病治疗 (HDT)。在具体目标 1 中，使用基因缺陷和条件基因缺陷 小鼠模型中，我们将确定限制 MDSC 积累的 IL-17 依赖性途径 结核病。在具体目标 2 中，我们将评估 S100A8/A9 蛋白在驱动 MDSC 积累中的作用 和对结核病的易感性，并确定阻断 S100A8/A9 信号传导是否会限制结核病 复发。最后，在具体目标 3 中，我们将评估 MDSC 消耗是否可以预防结核病进展 非人类灵长类动物（NHP）。完成此处提出的目标后，我们将取得相当大的成果 扩大了我们对 Mtb 特异性信号通路和因素的理解，这些信号通路和因素积极地 （S100A8/A9 途径）和负向（IL-17 依赖性途径）调节 MDSC 积累 结核病期间。此外，我们在 NHP 方面的转化研究将能够使用 HDT 来限制 MDSC 结核病期间。