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死亡的主要单一原因;新的治疗方法正在 需要改变疫情的形态一个拟议的办法是扩大现有的武器库， 抗结核药物针对宿主因子，以增强细菌杀菌或调节炎症， 导致组织损伤感染背景下的组织损伤通常被概念化为线性损伤。 “太多”导致宿主介导的组织破坏，“太少”导致 细菌感染然而，这种线性模型未能捕捉到结核病炎症的复杂性;事实上， 炎症的一些单独组分，包括组织重塑酶，如基质 金属蛋白酶（MMPs）可能有助于破坏而不促进灭菌。抑制这种 酶可以在不损害细菌杀灭的情况下改善结果。我们建议采取系统的 鉴定和靶向结核感染中导致组织破坏的基质酶的方法 有两个首要目标：详细说明单个酶在结核病发病机制中的作用， 测试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导向疗法。在 初步的工作是使用空洞型结核病的小鼠模型，我们对感染的 肺，以确定感染期间上调的破坏性基质酶。MT 1-MMP脱颖而出， 在早期和持续的模式中上调;这种酶以前与人类TB相关。 使用由Sagi实验室开发的高度特异性MT 1-MMP抑制剂，我们进行了初步实验 为了确定在感染后前8周内低水平给药的耐受性， TB.小鼠对抑制剂耐受良好，尽管抑制剂的剂量不是为了达到最大功效， 组织病理学分析显示病变大小减小和致密炎性细胞减少趋势 渗透在这项拟议的工作中，我们将建立在这些结果的基础上，以测试MT 1-MMP在 在该模型中的发病机制和抑制对分子，细胞和组织学结果的影响， 疾病在目标1中，我们将优化剂量以最大限度地抑制而不诱导副作用;然后我们将测试 MT 1-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 转录谱分析，以鉴定MT 1-MMP产生的细胞驱动因子和测试MT 1-MMP的影响。 MMP抑制炎症细胞向感染肺的募集。然后，我们将测试MT 1-MMP的影响 使用多重细胞因子分析和高分辨率显微镜观察对炎性环境的抑制。后 为了实现这些目标，我们预期已经确定了MT 1-MMP在肿瘤病理进展中的作用， 小鼠疾病模型中的结核病。我们预计这些结果将告知有针对性的研究矩阵的作用， 酶在人类结核病发病机制中的作用;此外，我们预计这些结果将最终告知 开发MMP抑制剂作为TB的预防性治疗。