Elucidating the mechanisms and consequences of MDSC-regulated immunity in TB

阐明结核病中 MDSC 调节的免疫机制和后果

• 批准号: 10670440
• 负责人: Bryan David Bryson
• 金额: $ 60.38万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-22 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10670440
• 关键词: Acute; Address; Affect; Animals; Antimycobacterial Agents; Antitubercular Agents; Bacille Calmette-Guerin vaccination; Bacteria; Biological Assay; Cavia; Cell Communication; Cell Count; Cell physiology; Cells; Cellular biology; Competence; Data; Development; Disease; Disease Progression; Effectiveness; Effector Cell; FDA approved; Flow Cytometry; Functional disorder; Future; Gene Expression Profile; Genetic Transcription; Granuloma; HIV/TB; Human; Image Cytometry; Immune; Immune System Diseases; Immune response; Immunity; Immunosuppression; Impairment; In Situ; Infection; Infiltration; Inflammation; Intervention; Knowledge; Lesion; Link; Literature; Lung; Macaca; Macrophage; Mediating; Microbiology; Modeling; Molecular; Mouse Strains; Mus; Mycobacterium tuberculosis; Myeloid Cells; Myeloid-derived suppressor cells; Nitric Oxide; Organ; Outcome; PET/CT scan; Pathogenesis; Pathogenicity; Pathologic; Patients; Persons; Phagosomes; Pharmaceutical Preparations; Pharmacotherapy; Physiological; Play; Positron-Emission Tomography; Predisposition; Property; Public Health; Publishing; Pulmonary Inflammation; Regimen; Reporter; Resistance; Role; Severities; Severity of illness; Site; Supporting Cell; System; T cell response; T-Cell Activation; T-Lymphocyte; Testing; Tissues; Treatment Efficacy; Tuberculosis; Umbilical Cord Blood; Work; X-Ray Computed Tomography; cell free DNA; cell type; design; experience; fluorescence imaging; high dimensionality; human model; immune function; improved; improved outcome; inhibitor; innovation; interest; molecular imaging; mycobacterial; nonhuman primate; novel; peripheral blood; permissiveness; recruit; response; restraint; safety assessment; small molecule; small molecule inhibitor; success; synergism; targeted agent; targeted treatment; transcriptomics; translational study; tuberculosis drugs; tuberculosis immunity; tuberculosis treatment; vaccination against tuberculosis

PROJECT SUMMARY: Myeloid derived suppressor cells (MDSCs) are immature myeloid cells with potent inhibitory properties for macrophages and T cells. The link between MDSCs and tuberculosis (TB), a disease caused by Mycobacterium tuberculosis (Mtb), is supported by work in mice where MDSC recruitment to the lungs correlates with disease severity, and in humans, where peripheral blood MDSC abundance positively correlates with TB progression. Work in mice also demonstrates that MDSCs are recruited to sites of BCG vaccination where they phagocytose bacteria and suppress local T cell activation, suggesting that MDSCs may reduce the effectiveness of anti-TB vaccination and contribute to TB’s status as a global public health concern. The relationship between MDSCs and TB has generated interest in targeting them with host-directed therapies to improve TB treatment. Recent work using tasquinimod (TSQ), an FDA-approved small molecule MDSC inhibitor, in guinea pigs and mice finds that targeting MDSCs lowers reduces granuloma formation, lowers bacteria loads, and improves the treatment efficacy of anti-TB drugs. These results are encouraging but critical questions need to be answered before MDSCs can be safely targeted in human TB. Knowledge gaps include an incomplete understanding of how MDSCs interact with macrophages in diseased tissue, if MDSCs restrain or promote pathologic inflammation in TB, how MDSC activity relates to bacterial burden in granulomas, and if MDSCs permit or restrict Mtb replication. These gaps are particularly acute in human TB where progress is inhibited by the inability to access granulomas to study MDSCs in situ and fundamental differences between mouse and human TB pathophysiology. Our proposal addresses these gaps with innovative studies using MDSCs from human cord blood and a nonhuman primates (NHPs) model that accurately reflects human TB pathophysiology. We hypothesize that MDSCs suppress macrophage-mediated anti-Mtb activity and are permissive hosts for Mtb and inhibiting their functions will improve immunity, restrict bacterial persistence, and improve outcomes in TB. In Aim 1, we propose mechanistic studies investigating relationships between MDSCs, macrophages, and Mtb that influence immunity. We will determine if cell-free DNA release is a novel MDSC effector that suppresses macrophage function. We also determine if MDSCs support Mtb as a permissive host cell and define molecular features at the phagosomal level that contribute to competency for hosting Mtb. In Aim 2, we infect NHPs with mCherry-expressing Mtb and use TSQ-mediated MDSC inhibition as an intervention to assess how MDSCs regulate lung inflammation, immunity, and if they host Mtb. Here, we use PET/CT and fluorescence imaging, quantitative microbiology, and flow cytometry to identify MDSC-regulated correlates of immunity in granulomas. We also define MDSC transcriptional profiles in scRNAseq and use CosMx spatial molecular imaging to identify how MDSCs regulate granuloma-level immunity in physiologic and spatial context. These studies address significant questions on MDSCs-regulated immunity in TB and provide valuable data for future trials targeting MDSCs in TB.

项目摘要： 髓样衍生的抑制细胞（MDSC）是未成熟的髓样细胞，具有潜在的抑制特性 巨噬细胞和T细胞。 MDSCS与结核病（TB）之间的联系，这是由分枝杆菌引起的疾病 结核病（MTB）在小鼠中的作品支持MDSC募集到肺部与疾病有关 严重程度，在人类中，外周血MDSC抽象与结核病进展呈正相关。 在小鼠中的工作还表明，将MDSC招募到BCG疫苗接种的部位 细菌并抑制局部T细胞激活，表明MDSC可能会降低抗TB的有效性 疫苗接种并促进结核病作为全球公共卫生关注的地位。 MDSC之间的关系 结核病引起了对宿主定向疗法的靶向，以改善结核病治疗。最近的 使用FDA批准的小分子MDSC抑制剂的Tasquinimod（TSQ）在豚鼠和小鼠中的工作 针对MDSC的降低可降低肉芽肿的形成，降低细菌负荷并改善治疗 抗TB药物的功效。这些结果令人鼓舞，但需要回答关键问题 MDSC可以安全地针对人类结核。知识差距包括对如何 如果MDSC抑制或促进病理炎症，MDSC与巨噬细胞相互作用 TB，MDSC的活性与肉芽肿中的细菌伯嫩有关，以及MDSC是否允许或限制MTB复制。 这些差距在人类结核病中尤其急剧，在这种情况下，无法进入肉芽肿的抑制进展。 研究MDSC的原位和小鼠和人类结核病病理生理学之间的基本差异。我们的 提案通过使用人类脐带血和非人类的MDSC进行创新研究来解决这些差距 精确反映人类结核病病理生理学的灵长类动物（NHP）模型。我们假设MDSCS 抑制巨噬细胞介导的抗MTB活性，是MTB的允许宿主并抑制其功能 将提高免疫力，限制细菌持久性并改善结核病的预后。在AIM 1中，我们建议 机械研究研究了影响免疫学的MDSC，巨噬细胞和MTB之间的关系。 我们将确定无细胞DNA释放是否是抑制巨噬细胞功能的新型MDSC效应子。我们 还要确定MDSC是否支持MTB作为允许的宿主细胞并在吞噬体处定义分子特征 有助于托管MTB的能力的水平。在AIM 2中，我们用表达MCHERRY的MTB感染了NHP， 使用TSQ介导的MDSC抑制作用作为干预措施，以评估MDSC如何调节肺注射， 免疫力，如果他们容纳MTB。在这里，我们使用PET/CT和荧光成像，定量微生物学和 流式细胞仪以识别肉芽肿的MDSC调节的免疫相关性。我们还定义了MDSC scrnaseq中的转录曲线并使用COSMX空间分子成像来识别MDSC如何调节 生理和空间环境中的肉芽肿级免疫。这些研究解决了有关的重大问题 MDSC调节的结核病免疫力，并为针对TB中MDSC的未来试验提供了有价值的数据。