Targeting MT1-MMP to inhibit pathologic inflammation in TB

靶向 MT1-MMP 抑制结核病病理炎症

• 批准号: 9808747
• 负责人: Amy K Barczak
• 金额: $ 23.55万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-07 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9808747
• 关键词: Alveolar Macrophages; Antibiotics; Antibodies; Antitubercular Agents; Area; Automobile Driving; Bacillus (bacterium); Bacteria; Bacterial Infections; Bacteriology; C3HeB/FeJ Mouse; Cause of Death; Cells; Cessation of life; Chronic; Clinical; Coupled; Data; Development; Disease; Disease Outcome; Disease model; Dose; Drug resistance; Enzyme Inhibitor Drugs; Enzymes; Epidemic; Evolution; Fibrosis; Future; Gene Expression Profiling; Goals; Granuloma; Growth; Histologic; Histopathology; Homeostasis; Human; Immune; Immunohistochemistry; Individual; Infection; Inflammation; Inflammatory; Inflammatory Response; Integration Host Factors; Knowledge; Laboratories; Lesion; Linear Models; Lung; Lung diseases; Lung infections; Mediating; Metalloproteases; Microscopy; Modeling; Molecular; Mus; Mycobacterium tuberculosis; Necrosis; Outcome; Pathogenesis; Pathologic; Pathology; Pattern; Penetration; Pharmaceutical Preparations; Production; Pulmonary Tuberculosis; Reporting; Resolution; Role; Shapes; Sterilization; Structure of parenchyma of lung; Testing; Time; Tissues; Treatment outcome; Tuberculosis; Work; cytokine; efficacy testing; experimental study; functional outcomes; high resolution imaging; improved; improved outcome; inflammatory milieu; inhibitor/antagonist; lead candidate; mouse model; novel strategies; organizational structure; recruit; side effect; trend; tuberculosis drugs; tuberculosis treatment

Tuberculosis remains the leading single cause of death from infection around the world; new treatments are needed to change the shape of the epidemic. One proposed approach to expanding the available arsenal of anti-TB drugs is targeting host factors to either enhance bacterial sterilization or modulate inflammation that drives tissue damage. Tissue damage in the context of infection is typically conceptualized on a linear spectrum, with “too much” driving host-mediated tissue destruction and “too little” resulting in progression of bacterial infection. However, this linear model fails to capture the complexity of inflammation in TB; in fact, some individual components of inflammation, including tissue remodeling enzymes such as matrix metalloproteases (MMPs), likely contribute to destruction without promoting sterilization. Inhibiting such enzymes could improve outcomes without compromising bacterial killing. We propose to take a systematic approach to identifying and targeting the matrix enzymes that contribute to tissue destruction in TB infection with two overarching goals: detailing the role of individual enzymes in TB pathogenesis and developing and testing highly specific inhibitors of those enzymes as adjunct host-directed therapies in TB treatment. In preliminary work using a murine model of cavitary TB, we performed serial transcriptional profiling of infected lungs to identify the destructive matrix enzymes upregulated during infection. MT1-MMP stood out as upregulated in an early and sustained pattern; this enzyme has previously been associated with human TB. Using a highly specific MT1-MMP inhibitor developed by the Sagi laboratory, we performed a pilot experiment to determine tolerability of low-level dosing over the first 8 weeks post-infection in the murine cavitary model of TB. Mice tolerated the inhibitor well, and although the inhibitor was not dosed for maximum efficacy, histopathologic analysis demonstrated a trend toward decreased lesion size and fewer dense inflammatory cell infiltrates. In this proposed work, we will build upon those results to test both a role for MT1-MMP in pathogenesis in this model and the effect of inhibition on molecular, cellular, and histologic outcomes of disease. In aim 1, we will optimize dosing to maximize inhibition without inducing side-effects; we will then test the effect of MT1-MMP inhibition on bacterial growth and lung histopathology. In aim 2, we will use single-cell transcriptional profiling to both identify cellular drivers of MT1-MMP production and test the impact of MT1- MMP inhibition on inflammatory cell recruitment to the infected lung. We will then test the impact of MT1-MMP inhibition on the inflammatory milieu using multiplexed cytokine profiling and high resolution microscopy. Upon achieving these aims, we anticipate having characterized the role of MT1-MMP in the pathologic progression of TB in a murine model of disease. We anticipate these results will inform targeted studies of the role of matrix enzymes in the pathogenesis of human TB; further, we anticipate these results will ultimately inform the development of MMP inhibitors as adjunctive therapies for TB.

结核病仍然是世界各地感染导致死亡的主要原因。新疗法是 需要改变流行病的形状。一种扩大可用武器库的建议方法 抗TB药物靶向宿主因素，以增强细菌灭菌或调节注射 驱动组织损伤。在感染的背景下，组织损伤通常在线性上概念化 频谱，“太多”驱动宿主介导的组织破坏和“太少”，导致进展 细菌感染。但是，该线性模型无法捕获结核病中感染的复杂性。实际上， 一些炎症的单个成分，包括组织重塑酶，例如基质 金属蛋白酶（MMP）可能在不促进灭菌的情况下导致破坏。抑制这种 酶可以改善预后，而不会损害细菌。我们建议采取系统 识别和靶向有助于组织破坏结核病感染的基质酶的方法 具有两个总体目标：详细说明单个酶在结核病发病机理和发育和发展中的作用 将这些酶的高度特异性抑制剂作为结核病治疗中的辅助宿主指导疗法。在 使用腔TB的鼠模型的初步工作，我们进行了感染的串行转录分析 肺部识别感染过程中更新的破坏性基质酶。 MT1-MMP失速为 以早期和持续的模式更新；该酶以前与人类结核病有关。 使用萨吉实验室开发的高度特异性MT1-MMP抑制剂，我们进行了一个试验实验 在感染后的前8周内，在鼠洞模型的前8周内确定低级剂量的耐受性 TB。小鼠可以很好地耐受抑制剂，尽管抑制剂并未达到最大效率，但 组织病理学分析表明，病变大小和密度较少的炎症细胞的趋势 浸润。在这项拟议的工作中，我们将基于这些结果来测试MT1-MMP的角色 该模型的发病机理以及抑制对分子，细胞和组织学结局的影响 疾病。在AIM 1中，我们将优化给药以最大程度地抑制，而无需引起副作用。然后我们将测试 MT1-MMP抑制对细菌生长和肺组织病理学的影响。在AIM 2中，我们将使用单细胞 转录分析既鉴定MT1-MMP产生的细胞驱动因素，又测试MT1-的影响 MMP抑制对感染肺的炎症细胞募集。然后，我们将测试MT1-MMP的影响 使用多路复用细胞因子分析和高分辨率显微镜对炎症环境的抑制作用。之上 实现这些目标，我们预计已经表征了MT1-MMP在病理发展中的作用 TB中的疾病模型。我们预计这些结果将为矩阵的作用提供针对性的研究 人结核病的发病机理中的酶；此外，我们预计这些结果最终将告知 MMP抑制剂作为结核病的辅助疗法的发展。