Foam cells as drug targets in tuberculosis

泡沫细胞作为结核病的药物靶点

• 批准号: 10436308
• 负责人: Maria Laura Gennaro
• 金额: $ 78.71万
• 依托单位: RBHS-NEW JERSEY MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10436308
• 关键词: 5' -AMP-activated protein kinase; Animal Model; Antibiotics; Antimycobacterial Agents; Antitubercular Agents; Antitubercular Antibiotics; Area; Arterial Fatty Streak; Autophagocytosis; C3HeB/FeJ Mouse; Cell Culture System; Cells; Cholesterol Esters; Chronic; Clinical; Clinical Trials; Complex; Deacetylase; Deposition; Development; Diagnostic; Disease; Dose; Drug Kinetics; Drug Targeting; Equilibrium; FRAP1 gene; Foam Cells; Gene Expression; Genes; Goals; Granuloma; Histology; Homeostasis; Human; Immune system; Immunohistochemistry; Infection; Intervention; Lead; Lesion; Link; Lipid-Laden Macrophage; Lipids; Lung; Measures; Mediating; Metabolic; Metabolic Pathway; Metabolism; Mitochondria; Mouse Strains; Multidrug-Resistant Tuberculosis; Mycobacterium tuberculosis; Nature; Necrosis; Outcome; PET/CT scan; Pathologic; Pathway interactions; Pharmacology; Phosphotransferases; Physiological; Positioning Attribute; Prevention; Proto-Oncogene Proteins c-akt; Pulmonary Tuberculosis; Regimen; Relapse; Resistance; Role; Sampling; Sirtuins; Sputum; Structure of parenchyma of lung; Testing; Therapeutic; Tissues; Triglycerides; Tuberculosis; Work; X-Ray Computed Tomography; antimicrobial; atherogenesis; bactericide; base; detection of nutrient; druggable target; experimental study; immunopathology; improved; lipid metabolism; lung lesion; macrophage; monocyte; mycobacterial; novel; peripheral blood; programs; pulmonary granuloma; response; therapeutic target; transmission process; tuberculosis drugs; tuberculosis treatment

Lipid-laden macrophages (foam cells) are central to maintaining chronic tuberculosis (TB) infection. Foam cells provide a favorable niche for survival of Mycobacterium tuberculosis, because antimicrobial functions are generally down-regulated in these cells. Moreover, foam cells induce tissue damage and caseation, and facilitate TB transmission. Indeed, the extent of TB-induced tissue damage is closely correlated with foam cell abundance in lesions. The overarching hypothesis of this proposal is that blocking foam cell formation will facilitate macrophage-mediated clearance of M. tuberculosis infection. We recently discovered that, unlike the cholesteryl- ester-rich foam cells found in atherosclerotic lesions, foam-cell-rich and necrotic areas of tuberculous granulomas are particularly enriched in triglycerides. Given the different nature of the storage lipid, the underlying lipid accumulation mechanisms in tuberculous foam cells must differ substantially from those known to occur during atherogenesis. Thus, TB-specific interventions are needed to impede foam cell formation in TB. Infection with M. tuberculosis is associated with dysregulation of two cellular pathways involved in triglyceride homeostasis: the first, which is pro-lipogenic, includes two kinases, protein kinase B and mTOR complex 1 (Akt/mTORC1); the second, which is anti-lipogenic, includes AMP-activated protein kinase and the NAD+- dependent deacetylases called sirtuins (AMPK/SIRT). We propose a two-aim plan utilizing clinical samples from human donors and experimental infections of macrophages ex vivo and of a mouse strain producing necrotic tuberculous lung lesions (C3HeB/FeJ). These experiments will characterize: (i) the effect of anti-lipogenic treatments on antimycobacterial functions of human macrophages infected ex vivo; (ii) the relationship between activation of these pathways and control of clinical M. tuberculosis infection; and (iii) the role of anti-lipogenic treatments as adjunctive therapy for TB in C3HeB/FeJ mice. The overall objective of this proposal is to discover druggable targets in the pro-lipogenic and anti-lipogenic pathways, with the long-term goal of shortening the duration of TB treatment and improving TB-related immunopathology. This proposal is expected to lead to clinical trials of novel host-directed therapeutics against TB. More generally, these studies are expected to reveal the potential for pharmacological interventions targeting maladaptive macrophage responses in non-atherogenic diseases and to stimulate their pursuit.

富含脂质的巨噬细胞（泡沫细胞）对于维持慢性结核病 (TB) 感染至关重要。泡沫细胞 为结核分枝杆菌的生存提供有利的生态位，因为抗菌功能 在这些细胞中通常下调。此外，泡沫细胞会引起组织损伤和干酪化，并促进 结核病传播。事实上，结核病引起的组织损伤程度与泡沫细胞丰度密切相关 在病变中。该提案的总体假设是阻止泡沫细胞的形成将促进 巨噬细胞介导的结核分枝杆菌感染清除。我们最近发现，与胆固醇不同的是， 在动脉粥样硬化病变、结核性富含泡沫细胞和坏死区域中发现富含酯的泡沫细胞 肉芽肿尤其富含甘油三酯。鉴于储存脂质的不同性质，潜在的 结核性泡沫细胞中的脂质积累机制必须与已知发生的机制有很大不同 在动脉粥样硬化形成期间。因此，需要针对结核病的干预措施来阻止结核病泡沫细胞的形成。感染 结核分枝杆菌与参与甘油三酯的两条细胞途径的失调有关 稳态：第一个是促脂肪生成，包括两种激酶：蛋白激酶 B 和 mTOR 复合物 1 (Akt/mTORC1)；第二种是抗脂肪生成的，包括 AMP 激活的蛋白激酶和 NAD+- 依赖的脱乙酰酶称为去乙酰化酶 (AMPK/SIRT)。我们提出了一个利用临床样本的两个目标计划 人类供体和巨噬细胞离体实验感染以及产生坏死的小鼠品系的实验感染 结核性肺部病变（C3HeB/FeJ）。这些实验将表征：（i）抗脂肪生成的作用 对离体感染的人巨噬细胞的抗分枝杆菌功能的治疗； (二) 之间的关系 激活这些途径并控制临床结核分枝杆菌感染； (iii) 抗脂肪生成的作用 作为 C3HeB/FeJ 小鼠结核病的辅助治疗。该提案的总体目标是发现 促脂肪生成和抗脂肪生成途径中的药物靶标，长期目标是缩短 结核病治疗的持续时间和改善结核病相关的免疫病理学。该提议预计将导致临床 针对结核病的新型宿主导向疗法的试验。更一般地说，这些研究预计将揭示 针对非动脉粥样硬化患者适应不良巨噬细胞反应的药物干预潜力 疾病并激发他们的追求。

项目成果

Foam Cells: One Size Doesn't Fit All.

泡沫单元：一种尺寸并不适合所有情况。

• DOI: 10.1016/j.it.2019.10.002
• 发表时间: 2019-11-12
• 期刊: Trends in immunology
• 影响因子: 16.8
• 作者: V. Guerrini;M. Gennaro
• 通讯作者: M. Gennaro