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: 10548970
• 负责人: Bryan David Bryson
• 金额: $ 54.78万
• 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/10548970
• 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; 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; Pharmaceutical Preparations; Pharmacotherapy; Physiological; Play; Predisposition; Property; Public Health; Publishing; Pulmonary Inflammation; Regimen; Reporter; Resistance; Role; Safety; 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; base; cell free DNA; cell type; experience; fluorescence imaging; high dimensionality; human model; immune function; improved; improved outcome; inhibitor; innovation; interest; macrophage; man; molecular imaging; mycobacterial; nonhuman primate; novel; peripheral blood; recruit; response; small molecule; small molecule inhibitor; success; 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.

项目概要： 髓源性抑制细胞（MDSC）是未成熟的髓样细胞，其对以下细胞具有有效的抑制特性： 巨噬细胞和T细胞。MDSC与结核病（TB）（一种由分枝杆菌引起的疾病）之间的联系 在小鼠中，MDSC向肺的募集与疾病相关， 严重程度，以及在人类中，其中外周血MDSC丰度与TB进展正相关。 在小鼠中的工作也表明，MDSC被募集到BCG疫苗接种的部位，在那里它们吞噬 细菌和抑制局部T细胞活化，这表明MDSC可能会降低抗结核病的有效性， 结核病是一个全球性的公共卫生问题。MDSC之间的关系 结核病已经引起了人们对用宿主导向疗法靶向它们以改善结核病治疗的兴趣。最近 在豚鼠和小鼠中使用FDA批准的小分子MDSC抑制剂tasquinimod（TSQ）的研究发现， 靶向MDSC可以减少肉芽肿形成，降低细菌负荷，并改善治疗效果。 抗结核药物的疗效。这些结果是令人鼓舞的，但关键的问题需要回答之前， MDSC可以安全地靶向人类TB。知识差距包括不完全理解如何 MDSC与患病组织中的巨噬细胞相互作用，如果MDSC抑制或促进 TB，MDSC活性如何与肉芽肿中的细菌负荷相关，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为严重，因为无法进入肉芽肿， 原位研究MDSC以及小鼠和人TB病理生理学之间的根本差异。我们 一项提案通过使用来自人脐带血和非人骨髓基质干细胞的创新研究解决了这些差距。 灵长类动物（NHP）模型，准确反映人类结核病的病理生理学。我们假设MDSC 抑制巨噬细胞介导抗Mtb活性，是Mtb的容许宿主并抑制其功能 将提高免疫力，限制细菌持久性，并改善结核病的结果。在目标1中，我们建议 研究MDSC、巨噬细胞和影响免疫的Mtb之间关系的机制研究。 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 还确定MDSC是否支持Mtb作为允许宿主细胞，并确定吞噬体的分子特征 有助于提高托管结核病的能力的水平。在目标2中，我们用表达mCherry的Mtb感染NHP， 使用TSQ介导的MDSC抑制作为干预来评估MDSC如何调节肺部炎症， 免疫力，如果他们持有结核病。在这里，我们使用PET/CT和荧光成像，定量微生物学， 流式细胞术鉴定肉芽肿中MDSC调节的免疫相关性。我们还定义了MDSC scRNAseq中的转录谱，并使用CosMx空间分子成像来鉴定MDSC如何调节 在生理和空间背景下的肉芽肿水平免疫。这些研究涉及以下重要问题： MDSC调节结核病的免疫力，并为未来针对结核病MDSC的试验提供有价值的数据。